Lrrn1 Regulates Medial Boundary Formation in the Developing Mouse Organ of Corti.

One of the most striking aspects of the sensory epithelium of the mammalian cochlea, the organ of Corti (OC), is the presence of precise boundaries between sensory and nonsensory cells at its medial and lateral edges. A particular example of this precision is the single row of inner hair cells (IHCs) and associated supporting cells along the medial (neural) boundary. Despite the regularity of this boundary, the developmental processes and genetic factors that contribute to its specification are poorly understood. In this study we demonstrate that Leucine Rich Repeat Neuronal 1 (Lrrn1), which codes for a single-pass, transmembrane protein, is expressed before the development of the mouse organ of Corti in the row of cells that will form its medial border. Deletion of Lrrn1 in mice of mixed sex leads to disruptions in boundary formation that manifest as ectopic inner hair cells and supporting cells. Genetic and pharmacological manipulations demonstrate that Lrrn1 interacts with the Notch signaling pathway and strongly suggest that Lrrn1 normally acts to enhance Notch signaling across the medial boundary. This interaction is required to promote formation of the row of inner hair cells and suppress the conversion of adjacent nonsensory cells into hair cells and supporting cells. These results identify Lrrn1 as an important regulator of boundary formation and cellular patterning during development of the organ of Corti.SIGNIFICANCE STATEMENT Patterning of the developing mammalian cochlea into distinct sensory and nonsensory regions and the specification of multiple different cell fates within those regions are critical for proper auditory function. Here, we report that the transmembrane protein Leucine Rich Repeat Neuronal 1 (LRRN1) is expressed along the sharp medial boundary between the single row of mechanosensory inner hair cells (IHCs) and adjacent nonsensory cells. Formation of this boundary is mediated in part by Notch signaling, and loss of Lrrn1 leads to disruptions in boundary formation similar to those caused by a reduction in Notch activity, suggesting that LRRN1 likely acts to enhance Notch signaling. Greater understanding of sensory/nonsensory cell fate decisions in the cochlea will help inform the development of regenerative strategies aimed at restoring auditory function.

Associations between physical activity, sedentary behaviour and cognitive domain performance of people living with mild cognitive impairment in the community.

INTRODUCTION: Physical activity is known to positively influence cognitive performance. For adults with mild cognitive impairment (MCI), the relationship between physical activity levels and cognitive performance is unknown. This cross-sectional study aimed to determine if cognitive performance [as measured by the Montreal Cognitive Assessment (MoCA)] of people living in the community with MCI is associated with their physical activity levels or sedentary behaviour. METHODS: ActivPAL™ accelerometers were used to objectively measure physical activity and sedentary behaviour for seven full days. Cognitive performance was measured using the MoCA. CONSUMER AND COMMUNITY INVOLVEMENT: No involvement other than as research participants RESULTS: Eighty-two participants from the Balance on the Brain randomised controlled trial were included. Most participants were retired (88%), with 33 (40%) reporting a fall in the last year. The median MoCA score was 24 (IQR 22-26). Participants achieved a mean of 6296 (±2420) steps per day and were sedentary for 10.6 (±2) hours per day. The only physical activity outcomes that had a fair, positive correlation were moderate- to vigorous-intensity physical activity measures of total stepping time and total number of steps (with a cadence of ≥100 steps/min) with the orientation MoCA domain score (r(82) = 0.36, p ≤ 0.001 and r(82) = 0.37, p ≤ 0.001, respectively). Higher total sedentary time had a weak, positive correlation with better visuospatial/executive performance (r(82) = 0.23, p = 0.041). The orientation outcomes remained significant when analysed in an adjusted logistic regression model. CONCLUSION: This study found that performance in the MoCA orientation domain had a fair-positive correlation with moderate-intensity physical activity (i.e., stepping time and step count with a cadence of ≥100 steps/min) as measured by a thigh-worn accelerometer for community-dwelling older adults with MCI. When considering the relationship between cognitive domains and sedentary behaviour, consideration may be needed regarding whether cognitive enhancing activities (such as crosswords and other brain games) are being performed, which may confound this relationship. Further investigation is required to confirm these results.

Antimicrobial usage and resistance in scottish dairy herds: a survey of farmers' knowledge, behaviours and attitudes.

Antimicrobial resistance (AMR) poses a major threat to global health. Understanding how antimicrobials are used on dairy farms and stakeholder beliefs relating to their use is essential to ensure responsible antimicrobial usage (AMU) to tackle the emergence of AMR. This study explored Scottish dairy farmers' knowledge about the meaning of AMR and antimicrobial activity, behaviour and practices related to farm AMU and attitudes towards AMR mitigation. An online survey was designed based on the findings of two focus groups and was completed by 61 respondents (7.3% of the total population of Scottish dairy farmers). Knowledge of antimicrobials and AMR was variable, and almost half of the participants believed that antimicrobials could have anti-inflammatory or analgesic activity. Veterinarians' opinions and advice about AMU were ranked significantly more important than other social referents or advisors. The majority of farmers (90%) reported having implemented practices to reduce reliance on antimicrobials (e.g., selective dry cow therapy, AMU treatment protocols) and having reduced farm AMU over recent years. Feeding waste milk to calves is still widespread, being reported by up to 30% of respondents. The main factors described to hinder responsible farm AMU were limited facilities (e.g., lack of isolation pens for sick animals) and knowledge of appropriate AMU recommendations, followed by time and financial constraints. Most farmers (89%) agreed that it is important to reduce AMU on dairy farms, but fewer (52%) acknowledged that AMU on UK dairy farms is currently too high, suggesting a mismatch between their intention to reduce antimicrobials and AMU behaviour. These results indicate that dairy farmers are aware of AMR, and their self-reported farm AMU has been reduced. However, some do not clearly comprehend the activity of antimicrobials and their correct usage. More work is needed to improve dairy farmers' knowledge of appropriate AMU and intentions to combat AMR. Farmers would benefit from more regular AMU discussions and advice from herd veterinarians, as they were described as highly trusted information resources. Training on how to reduce AMU should involve all farm staff administering antimicrobials and should be tailored to farm-specific barriers, such as limited facilities and workforce shortages.

Examination of the Feasibility, Acceptability, and Efficacy of the Online Personalised Training in Memory Strategies for Everyday Program for Older Adults: Single-Arm Pre-Post Trial.

BACKGROUND: Memory strategy training for older adults helps maintain and improve cognitive health but is traditionally offered face-to-face, which is resource intensive, limits accessibility, and is challenging during a pandemic. Web-based interventions, such as the Online Personalised Training in Memory Strategies for Everyday (OPTIMiSE) program, may overcome such barriers. OBJECTIVE: We report on OPTIMiSE's feasibility, acceptability, and efficacy. METHODS: Australians aged ≥60 years reporting subjective cognitive decline participated in this single-arm pre-post web-based intervention. OPTIMiSE is a 6-module web-based program offered over 8-weeks with a 3-month booster. It has a problem-solving approach to memory issues, focusing on psychoeducation about memory and aging, knowledge and practice of compensatory memory strategies, and personalized content related to individual priorities. We examined the feasibility (recruitment, attrition, and data collection), acceptability (recommendation to others, suggestions for improvement, and withdrawal reasons), and efficacy (change in goal satisfaction, strategy knowledge and use, self-reported memory, memory satisfaction and knowledge, and mood; thematic content analysis of the most significant change; and the application of knowledge and strategies in daily life) of OPTIMiSE. RESULTS: OPTIMiSE was feasible, demonstrated by strong interest (633 individuals screened), a satisfactory level of attrition (158/312, 50.6%), and minimal missing data from those completing the intervention. It was acceptable, with 97.4% (150/154) of participants agreeing they would recommend OPTIMiSE, the main suggestion for improvement being more time to complete modules, and withdrawal reasons similar to those in in-person interventions. OPTIMiSE was also efficacious, with linear mixed-effects analyses revealing improvements, of moderate to large effect sizes, across all primary outcomes (all P<.001): memory goal satisfaction (Cohen d after course=1.24; Cohen d at 3-month booster=1.64), strategy knowledge (Cohen d after course=0.67; Cohen d at 3-month booster=0.72) and use (Cohen d after course=0.79; Cohen d at 3-month booster=0.90), self-reported memory (Cohen d after course=0.80; Cohen d at 3-month booster=0.83), memory satisfaction (Cohen d after course=1.25; Cohen d at 3-month booster=1.29) and knowledge (Cohen d after course=0.96; Cohen d at 3-month booster=0.26), and mood (Cohen d after course=-0.35; nonsignificant Cohen d at booster). Furthermore, the most significant changes reported by participants (strategy use, improvements in daily life, reduced concern about memory, confidence and self-efficacy, and sharing and shame busting with others) reflected the course objectives and were consistent with themes arising from previous in-person interventions. At the 3-month booster, many participants reported continued implementation of knowledge and strategies in their daily lives. CONCLUSIONS: This feasible, acceptable, and efficacious web-based program has the potential to enable access to evidence-based memory interventions for older adults worldwide. Notably, the changes in knowledge, beliefs, and strategy use continued beyond the initial program. This is particularly important for supporting the growing number of older adults living with cognitive concerns. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12620000979954; https://tinyurl.com/34cdantv. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.3233/ADR-200251.

Behavioral Activation in Nursing Homes to Treat Depression (BAN-Dep): Results From a Clustered, Randomized, Single-Blinded, Controlled Clinical Trial.

OBJECTIVES: To determine if behavioral activation (BA) delivered by trained staff decreases prevalence of clinically significant symptoms of depression among older adults living in residential aged care facilities (RACFs). METHODS: Clustered, randomized, single-blinded, controlled trial of BA for adults aged over 60 years living permanently in a RACF with symptoms of depression (Patient Health Questionnaire, PHQ-9 ≥ 5). BA was delivered over 8-12 weeks using a structured workbook. The proportion of residents with PHQ-9 ≥ 10 at weeks 12, 26, and 52, as well as anxiety symptoms (GAD-7), physical (PCS), and mental (MCS) quality of life, loneliness, and loss to follow-up were main outcomes of interest RESULTS: We recruited 54 RACFs (26 intervention) and 188 of their residents (89 intervention). Participants were aged 61-100 years and 132 (70.2%) were women. PHQ-9 ≥ 10 interacted with BA at week 12 (OR = 0.34, 95%CI = 0.11-1.07), but differences between the groups were not statistically significant at any time-point. GAD-7 ≥ 10 interacted with BA at week 26 (OR = 0.12, 95%CI = 0.02-0.58), but not at any other time-point. Overall, the intervention had no effect on the scores of the PHQ-9, GAD-7, PCS, MCS, and loneliness scale. Loss to follow-up was similar between groups. Adherence to all stages of the intervention was poor (36.2%). CONCLUSIONS: Disruption by the COVID-19 pandemic and staffing issues in RACFs undermined recruitment and adherence. In such a context, a BA program delivered by RACF staff was not associated with better mental health outcomes for residents over 52 weeks.

Aggregation of Abnormal Memory Scores and Risk of Incident Alzheimer's Disease Dementia: A Measure of Objective Memory Impairment in Amnestic Mild Cognitive Impairment.

OBJECTIVES: The criteria for objective memory impairment in mild cognitive impairment (MCI) are vaguely defined. Aggregating the number of abnormal memory scores (NAMS) is one way to operationalise memory impairment, which we hypothesised would predict progression to Alzheimer's disease (AD) dementia. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 896 older adults who did not have dementia were administered a psychometric battery including three neuropsychological tests of memory, yielding 10 indices of memory. We calculated the number of memory scores corresponding to z ≤ -1.5 (i.e., NAMS) for each participant. Incident diagnosis of AD dementia was established by consensus of an expert panel after 3 years. RESULTS: Of the 722 (80.6%) participants who were followed up, 54 (7.5%) developed AD dementia. There was a strong correlation between NAMS and probability of developing AD dementia (r = .91, p = .0003). Each abnormal memory score conferred an additional 9.8% risk of progressing to AD dementia. The area under the receiver operating characteristic curve for NAMS was 0.87 [95% confidence interval (CI) .81-.93, p < .01]. The odds ratio for NAMS was 1.67 (95% CI 1.40-2.01, p < .01) after correcting for age, sex, education, estimated intelligence quotient, subjective memory complaint, Mini-Mental State Exam (MMSE) score and apolipoprotein E ϵ4 status. CONCLUSIONS: Aggregation of abnormal memory scores may be a useful way of operationalising objective memory impairment, predicting incident AD dementia and providing prognostic stratification for individuals with MCI.

Dementia knowledge and associated factors among older Chinese adults: a cross-national comparison between Melbourne and Beijing.

OBJECTIVES: This study compared dementia knowledge between older Chinese adults in Melbourne, Australia, and Beijing, China, and explored factors associated with dementia knowledge between these two groups. Ultimately, this study aimed to inform the development of tailored dementia education programs for older Chinese adults. DESIGN: A cross-sectional design was employed in this study. SETTING: Participants were recruited from 5 Chinese community senior groups in Melbourne and 10 community health centers in Beijing from March to May 2019. PARTICIPANTS: A total of 379 older Chinese adults aged 50 and over completed the questionnaire, including 153 from Melbourne and 226 from Beijing. MEASUREMENTS: Dementia knowledge was assessed using the Alzheimer's Disease Knowledge Scale (ADKS). Demographic characteristics, dementia-related experience, and the mental health status of participants were collected. Stepwise linear regression was used to analyze the factors associated with dementia knowledge. RESULTS: In general, older Chinese adults in Melbourne and Beijing reported similar levels of dementia knowledge for both the overall ADKS scale (mean ± SD: 17.2 ± 2.9 in Melbourne vs. 17.5 ± 2.9 in Beijing, p > 0.05) and the seven subdomains. Of the subdomains, the highest correct response rates were observed in the life impact of the dementia subdomain, and the lowest rates were observed in the caregiving subdomain. Stepwise linear regression analysis revealed that younger age and self-reported dementia worry were significantly associated with higher levels of dementia knowledge in the Melbourne group, whereas a positive family history of dementia was significantly associated with higher levels of dementia knowledge in the Beijing group. CONCLUSIONS: Older Chinese adults living in Melbourne and Beijing share similar levels of dementia knowledge, but factors associated with their knowledge are different. These findings will inform the development of culturally and socially appropriate dementia education programs for older Chinese populations in different countries.

Risk factors for poor colostrum quality and failure of passive transfer in Scottish dairy calves.

Failure of passive transfer (FPT) has health, welfare and economic implications for calves. Immunoglobulin G (IgG) concentration of 370 dairy calf serum samples from 38 Scottish dairy farms was measured via radial immunodiffusion (RID) to determine FPT prevalence. IgG concentration, total bacteria count (TBC) and total coliform count (TCC) of 252 colostrum samples were also measured. A questionnaire was completed at farm enrollment to investigate risk factors for FPT and poor colostrum quality at farm-level. Multivariable mixed effect logistic and linear regressions were carried out to determine significant risk factors for FPT and colostrum quality. Prevalence of FPT at calf level was determined to be 14.05%. Of 252 colostrum samples, 111 (44.05%) failed to meet Brix thresholds for colostrum quality. Of these 28 and 38 samples also exceeded TBC and TCC thresholds, respectively. Increased time between parturition and colostrum harvesting was numerically (non-significantly) associated with a colostrum Brix result <22%, and increased time spent in a bucket prior to feeding or storing was significantly associated with high TBC (≥100 000 cfu/ml and also ≥10 000 cfu/ml). High TBC values in colostrum were significantly associated with lower serum IgG concentrations. This study highlights associations between colostrum quality and FPT in dairy calves as well as potential risk factors for reduced colostrum quality; recommending some simple steps producers can take to maximise colostrum quality on farm.

GSK3 regulates hair cell fate in the developing mammalian cochlea.

The development of asymmetric patterns along biologically relevant axes is a hallmark of many vertebrate organs or structures. One example is the sensory epithelium of the mammalian auditory system. Two distinct types of mechanosensory hair cells (inner and outer) and at least six types of associated supporting cells are precisely and asymmetrically arrayed along the radial (medial-lateral) axis of the cochlear spiral. Immunolabeling of developing cochleae indicates differential expression of Glycogen synthase kinase 3ß (GSK3ß) along the same axis. To determine whether GSK3ß plays a role in specification of cell fates along the medial-lateral axis, GSK3 activity was blocked pharmacologically in cochlear explants. Results indicate significant changes in both the number of hair cells and in the specification of hair cell phenotypes. The overall number of inner hair cells increased as a result of both a shift in the medial boundary between sensory and non-sensory regions of the cochlea and a change in the specification of inner and outer hair cell phenotypes. Previous studies have inhibited GSK3 as a method to examine effects of canonical Wnt signaling. However, quantification of changes in Wnt pathway target genes in GSK3-inhibited cochleae, and treatment with more specific Wnt agonists, indicated that the Wnt pathway is not activated. Instead, expression of Bmp4 in a population of GSK3ß-expressing cells was shown to be down-regulated. Finally, addition of BMP4 to GSK3-inhibited cochleae achieved a partial rescue of the hair cell phenotype. These results demonstrate a role for GSK3ß in the specification of cellular identities along the medial-lateral axis of the cochlea and provide evidence for a positive role for GSK3ß in the expression of Bmp4.

Combined effects of continuous exercise and intermittent active interruptions to prolonged sitting on postprandial glucose, insulin, and triglycerides in adults with obesity: a randomized crossover trial.

BACKGROUND: Postprandial glucose, insulin, and triglyceride metabolism is impaired by prolonged sitting, but enhanced by exercise. The aim of this study was to assess the effects of a continuous exercise bout with and without intermittent active interruptions to prolonged sitting on postprandial glucose, insulin, and triglycerides. METHODS: Sedentary adults who were overweight to obese (n = 67; mean age 67 yr SD ± 7; BMI 31.2 kg∙m- 2 SD ± 4.1), completed three conditions: SIT: uninterrupted sitting (8-h, control); EX+SIT: sitting (1-h), moderate-intensity walking (30-min), uninterrupted sitting (6.5-h); EX+BR: sitting (1-h), moderate-intensity walking (30- min), sitting interrupted every 30-min with 3-min of light-intensity walking (6.5 h). Participants consumed standardized breakfast and lunch meals and blood was sampled at 13 time-points. RESULTS: When compared to SIT, EX+SIT increased total area under the curve (tAUC) for glucose by 2% [0.1-4.1%] and EX+BR by 3% [0.6-4.7%] (all p < 0.05). Compared to SIT, EX+SIT reduced insulin and insulin:glucose ratio tAUC by 18% [11-22%] and 21% [8-33%], respectively; and EX+BR reduced values by 25% [19-31%] and 28% [15-38%], respectively (all p < 0.001 vs SIT, all p < 0.05 EX+SIT-vs-EX+BR). Compared to SIT, EX+BR reduced triglyceride tAUC by 6% [1-10%] (p = 0.01 vs SIT), and compared to EX+SIT, EX+BR reduced this value by 5% [0.1-8.8%] (p = 0.047 vs EX+SIT). The magnitude of reduction in insulin tAUC from SIT-to-EX+BR was greater in those with increased basal insulin resistance. No reduction in triglyceride tAUC from SIT-to-EX+BR was apparent in those with high fasting triglycerides. CONCLUSIONS: Additional reductions in postprandial insulin-glucose dynamics and triglycerides may be achieved by combining exercise with breaks in sitting. Relative to uninterrupted sitting, this strategy may reduce postprandial insulin more in those with high basal insulin resistance, but those with high fasting triglycerides may be resistant to such intervention-induced reductions in triglycerides. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ( ACTRN12614000737639 ).

Alcohol Use, Mental Health, and Functional Capacity as Predictors of Workplace Disability in a Cohort With Manifest Huntington's Disease.

OBJECTIVE: Huntington's disease (HD) is an inherited neurodegenerative disease involving motor, cognitive, psychiatric, and behavioral impairments that eventually affect work-role functioning. There is limited research regarding predictors of workplace disability in HD. The authors examined predictors of work impairment and disability in a cross-sectional cohort of employed persons with symptomatic HD participating in the worldwide Enroll-HD study. METHODS: The study sample (N=316) comprised individuals with manifest HD and a CAG repeat length range between 39 and 60 and were currently engaged in paid full- or part-time employment. Univariate and multivariate logistic regression analyses identified predictors and the effect of all predictors in a fully adjusted model. RESULTS: Of the sample, 20.3% reported missing work due to HD, 60.1% reported experiencing impairment while working due to HD, 79.1% reported having work-related activity impairment due to HD, and 60.8% reported impairment in overall work productivity due to HD. Individuals had 25% higher odds of missing work time if they had a higher level of functional impairment (odds ratio=0.76, 95% CI=0.64, 0.91) and had three times greater odds of missing work if they were current alcohol drinkers, compared with nondrinkers (odds ratio=2.86, 95% CI=1.62, 5.03). Individuals with lower self-perceived mental health were also 5% more likely to experience impairment at work due to HD. Motor impairment was not a strong predictor of workplace disability. CONCLUSIONS: These findings provide important new knowledge that can inform the development of strategies or targeted intervention trials to support persons with symptomatic HD to maintain their work roles.

Distinct effects of acute exercise and breaks in sitting on working memory and executive function in older adults: a three-arm, randomised cross-over trial to evaluate the effects of exercise with and without breaks in sitting on cognition.

BACKGROUND: Sedentary behaviour is associated with impaired cognition, whereas exercise can acutely improve cognition. OBJECTIVE: We compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, on cognition in older adults. METHODS: Sedentary overweight/obese older adults with normal cognitive function (n=67, 67±7 years, 31.2±4.1 kg/m2) completed three conditions (6-day washout): SIT (sitting): uninterrupted sitting (8 hours, control); EX+SIT (exercise + sitting): sitting (1 hour), moderate-intensity walking (30 min), uninterrupted sitting (6.5 hours); and EX+BR (exercise + breaks): sitting (1 hour), moderate-intensity walking (30 min), sitting interrupted every 30 min with 3 min of light-intensity walking (6.5 hours). Cognitive testing (Cogstate) was completed at four time points assessing psychomotor function, attention, executive function, visual learning and working memory. Serum brain-derived neurotrophic growth factor (BDNF) was assessed at six time points. The 8-hour net area under the curve (AUC) was calculated for each outcome. RESULTS: Working memory net AUC z-score·hour (95% CI) was improved in EX+BR with a z-score of +28 (-26 to +81), relative to SIT, -25 (-79 to +29, p=0.04 vs EX+BR). Executive function net AUC was improved in EX+SIT, -8 (- 71 to +55), relative to SIT, -80 (-142 to -17, p=0.03 vs EX+SIT). Serum BDNF net AUC ng/mL·hour (95% CI) was increased in both EX+SIT, +171 (-449 to +791, p=0.03 vs SIT), and EX+BR, +139 (-481 to +759, p=0.045 vs SIT), relative to SIT, -227 (-851 to +396). CONCLUSION: A morning bout of moderate-intensity exercise improves serum BDNF and working memory or executive function in older adults, depending on whether or not subsequent sitting is also interrupted with intermittent light-intensity walking. TRIAL REGISTRATION NUMBER: ACTRN12614000737639.

Baseline Amnestic Severity Predicts Progression From Amnestic Mild Cognitive Impairment to Alzheimer Disease Dementia at 3 Years.

BACKGROUND: Given the long preclinical disease course of Alzheimer disease (AD) pathology, novel treatments may be more efficacious if administered before the emergence of dementia. Thus, accurate prediction of who will develop AD dementia is of key importance in selecting individuals for trials of treatment and may become crucial for future selection of patients for therapy. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 901 individuals who did not have dementia were recruited. We assigned individuals according to Petersen criteria and Winblad criteria for Mild Cognitive Impairment (MCI) at baseline. We then stratified individuals with amnestic MCI into 2 groups according to the severity of their memory impairment on baseline neuropsychological assessment. Incident diagnosis of AD dementia was established by consensus of an expert panel at 36 months. RESULTS: At 36 months, 725 (80.5%) participants were followed up, 54 (7.4%) of whom developed AD dementia. Subjects with amnestic MCI according to Petersen criteria were more likely to develop AD dementia [positive predictive value; PPV, 24.1%; 95% confidence interval (CI), 18.4-30.6] than healthy controls (PPV, 1.0%; 95% CI, 0.3-2.3). Winblad criteria were also effective, with multiple domain amnestic MCI being most accurate at predicting AD dementia (PPV, 47.3%; 95% CI, 33.7-61.2). Finally, more severe amnestic impairment below the median was useful for predicting the development of AD dementia in single domain amnestic MCI (PPV, 28.1%; 95% CI, 17.0-41.5) and in multiple domain amnestic MCI (PPV, 65.7%; 95% CI, 47.8-80.9). CONCLUSIONS: Memory impairment per se, impairment in multiple cognitive domains and severity of memory impairment were all associated with greater risk of developing AD dementia in this sample. Characterizing the severity of memory impairment may provide prognostic stratification within Petersen or Winblad taxonomies of amnestic MCI.

Predictors of Workplace Disability in a Premanifest Huntington's Disease Cohort.

Huntington's disease (HD) is an inherited neurodegenerative disease involving motor, cognitive, and psychiatric/behavioral impairments that will eventually affect work role functioning. Few objective data exist regarding predictors of workplace disability in HD. The authors explored the predictors of work impairment and disability in a cross-sectional cohort of 656 employed, premanifest HD (preHD) individuals. In this cohort-the majority of whom were female, urban-dwelling, married/partnered, and working full-time, with minimal cognitive impairment, good function, minimal motor abnormality, and no indication of significant mental health issues-the number of participants who reported that they had missed work due to HD was low (2.4%). However, 12% of the study sample reported experiencing impairment while working due to preHD, 12.2% reported work-related activity impairment due to preHD, and 12.7% reported impairment in their overall work ability. Higher numbers of CAG repeats on the mutant allele and having more motor symptoms were associated with significantly higher odds of experiencing workplace impairment. Importantly, several modifiable factors were also found to predict workplace disability. Specifically, higher levels of anxiety symptoms were associated with significantly higher odds of experiencing workplace impairment. Good mental and physical health served as protective factors, where good physical health was associated with 6% lower odds of experiencing impairment or missing work time and good mental health was associated with of 10%-12% lower. The results provide important new knowledge for the development of future targeted intervention trials to support preHD individuals in maintaining their work roles as long as possible.

Trajectories of depressive and anxiety symptoms in older adults: a 6-year prospective cohort study.

OBJECTIVE: Depressive and anxiety symptoms are common in older adults, significantly affect quality of life, and are risk factors for Alzheimer's disease. We sought to identify the determinants of predominant trajectories of depressive and anxiety symptoms in cognitively normal older adults. METHOD: Four hundred twenty-three older adults recruited from the general community underwent Aß positron emission tomography imaging, apolipoprotein and brain-derived neurotrophic factor genotyping, and cognitive testing at baseline and had follow-up assessments. All participants were cognitively normal and free of clinical depression at baseline. Latent growth mixture modeling was used to identify predominant trajectories of subthreshold depressive and anxiety symptoms over 6 years. Binary logistic regression analysis was used to identify baseline predictors of symptomatic depressive and anxiety trajectories. RESULTS: Latent growth mixture modeling revealed two predominant trajectories of depressive and anxiety symptoms: a chronically elevated trajectory and a low, stable symptom trajectory, with almost one in five participants falling into the elevated trajectory groups. Male sex (relative risk ratio (RRR) = 3.23), lower attentional function (RRR = 1.90), and carriage of the brain-derived neurotrophic factor Val66Met allele in women (RRR = 2.70) were associated with increased risk for chronically elevated depressive symptom trajectory. Carriage of the apolipoprotein epsilon 4 allele (RRR = 1.92) and lower executive function in women (RRR = 1.74) were associated with chronically elevated anxiety symptom trajectory. CONCLUSION: Our results indicate distinct and sex-specific risk factors linked to depressive and anxiety trajectories, which may help inform risk stratification and management of these symptoms in older adults at risk for Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd.

A randomized controlled trial of physical activity with individual goal-setting and volunteer mentors to overcome sedentary lifestyle in older adults at risk of cognitive decline: the INDIGO trial protocol.

BACKGROUND: Increasing physical activity (PA) effectively in those who are inactive is challenging. For those who have subjective memory complaints (SMC) or mild cognitive impairment (MCI) this is a greater challenge necessitating the need for more engaging and innovative approaches. The primary aim of this trial is to determine whether a home-based 6-month PA intervention with individual goal-setting and peer mentors (GM-PA) can significantly increase PA levels in insufficiently active older adults at increased risk of developing Alzheimer's disease (AD). METHODS: Community living 60-80 year olds with SMC or MCI who do not engage in more than 60 min per week of moderate intensity PA will be recruited from memory clinics and the community via media advertisements to participate in this randomized, single-blind controlled trial. All participants will receive an individually tailored home-based PA program of 150 min of moderate intensity walking/week for 6 months. The intervention group will undertake individual goal-setting and behavioral education workshops with mentor support via telephone (GM-PA). Those randomized to the control group will have standard education workshops and Physical Activity Liaison (PAL) contact via telephone (CO-PA). Increase in PA is the primary outcome, fitness, cognitive, personality, demographic and clinical parameters will be measured and a health economic analysis performed. A saliva sample will be collected for APOE e4 genotyping. All participants will have a goal-setting interview to determine their PA goals. Active volunteers aged 50-85 years will be recruited from the community randomized and trained to provide peer support as mentors (intervention group) or PALS (control group) for the 6-month intervention. Mentors and PALS will have PA, exercise self-efficacy and mentoring self-efficacy measured. Participants in both groups are asked to attend 3 workshops in 6 months. At the first workshop, they will meet their allocated Mentor or PAL who will deliver their respective programs and support via 6 telephone calls during the intervention. DISCUSSION: If the GM-PA program is successful in increasing the PA levels of the target group it will potentially provide another strategy and community resource that can be translated into practice. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12613001181796 . (29/10/2013) retrospectively registered.

Associations of neighborhood environment with brain imaging outcomes in the Australian Imaging, Biomarkers and Lifestyle cohort.

INTRODUCTION: "Walkable" neighborhoods offer older adults opportunities for activities that may benefit cognition-related biological mechanisms. These have not previously been examined in this context. METHODS: We objectively assessed neighborhood walkability for participants (n = 146) from the Australian Imaging, Biomarkers and Lifestyle study with apolipoprotein E (APOE) genotype and two 18-month-apart brain volumetric and/or amyloid ß burden assessments. Linear mixed models estimated associations of neighborhood walkability with levels and changes in brain imaging outcomes, the moderating effect of APOE ε4 status, and the extent to which associations were explained by physical activity. RESULTS: Cross-sectionally, neighborhood walkability was predictive of better neuroimaging outcomes except for left hippocampal volume. These associations were to a small extent explained by physical activity. APOE ε4 carriers showed slower worsening of outcomes if living in walkable neighborhoods. DISCUSSION: These findings indicate associations between neighborhood walkability and brain imaging measures (especially in APOE ε4 carriers) minimally attributable to physical activity.

Implementation of subjective cognitive decline criteria in research studies.

INTRODUCTION: Subjective cognitive decline (SCD) manifesting before clinical impairment could serve as a target population for early intervention trials in Alzheimer's disease (AD). A working group, the Subjective Cognitive Decline Initiative (SCD-I), published SCD research criteria in the context of preclinical AD. To successfully apply them, a number of issues regarding assessment and implementation of SCD needed to be addressed. METHODS: Members of the SCD-I met to identify and agree on topics relevant to SCD criteria operationalization in research settings. Initial ideas and recommendations were discussed with other SCD-I working group members and modified accordingly. RESULTS: Topics included SCD inclusion and exclusion criteria, together with the informant's role in defining SCD presence and the impact of demographic factors. DISCUSSION: Recommendations for the operationalization of SCD in differing research settings, with the aim of harmonization of SCD measurement across studies are proposed, to enhance comparability and generalizability across studies.

Subjective memory decline predicts greater rates of clinical progression in preclinical Alzheimer's disease.

INTRODUCTION: The objective of this study was to determine the utility of subjective memory decline (SMD) to predict episodic memory change and rates of clinical progression in cognitively normal older adults with evidence of high ß-amyloid burden (CN Aß+). METHODS: Fifty-eight CN Aß+ participants from the Australian Imaging, Biomarkers, and Lifestyle study responded to an SMD questionnaire and underwent comprehensive neuropsychological assessments. Participant data for three follow-up assessments were analyzed. RESULTS: In CN Aß+, subjects with high SMD did not exhibit significantly greater episodic memory decline than those with low SMD. High SMD was related to greater rates of progression to mild cognitive impairment or Alzheimer's disease (AD) dementia (hazard ratio = 5.1; 95% confidence interval, 1.4-20.0, P = .02) compared with low SMD. High SMD was associated with greater depressive symptomatology and smaller left hippocampal volume. DISCUSSION: High SMD is a harbinger of greater rates of clinical progression in preclinical AD. Although SMD reflects broader diagnostic implications for CN Aß+, more sensitive measures may be required to detect early subtle cognitive change.

Semi-automated hippocampal segmentation in people with cognitive impairment using an age appropriate template for registration.

BACKGROUND: To evaluate a new semi-automated segmentation method for calculating hippocampal volumes and to compare results with standard software tools in a cohort of people with subjective memory complaints (SMC) and mild cognitive impairment (MCI). METHODS: Data from 58 participants, 39 with SMC (17 male, 22 female, mean age 72.6) and 19 with MCI (6 male, 13 female, mean age 74.3), were analyzed. For each participant, T1-weighted images were acquired using an MPRAGE sequence on a 3 Tesla MRI system. Hippocampal volumes (left, right, and total) were calculated with a new, age appropriate registration template, based on older people and using the advanced software tool ANTs (Advanced Normalization Tools). The results were compared with manual tracing (seen as the reference standard) and two widely accepted automated software tools (FSL, FreeSurfer). RESULTS: The hippocampal volumes, calculated by using the age appropriate registration template were significantly (P < 0.05) more accurate (mean volume accuracy more than 90%) than those obtained with FreeSurfer and FSL (both less than 70%). Dice coefficients for the hippocampal segmentations with the new template method (75.3%) were slightly, but significantly (P < 0.05) higher than those from FreeSurfer (72.4%). CONCLUSION: These results suggest that an age appropriate registration template might be a more accurate alternative to calculate hippocampal volumes when manual segmentation is not feasible.