Publications by authors named "Elsdon Storey"

114 Publications

Trajectories of cognitive function in community-dwelling older adults: A longitudinal study of population heterogeneity.

Alzheimers Dement (Amst) 2021 2;13(1):e12180. Epub 2021 May 2.

School of Public Health and Preventive Medicine Monash University Melbourne Australia.

Introduction: This study aimed to investigate cognitive aging trajectories, the associated sociodemographic characteristics, and the association of these trajectories with dementia.

Methods: Generally healthy older adults (n = 19,114) were followed for up to 7 years, with regular cognitive assessments. Group-based trajectory modeling identified distinct cognitive trajectories.

Results: Four to seven trajectories were identified per cognitive domain. Stable trajectories were observed across domains. Improvement in verbal fluency and minor psychomotor slowing were common. Substantial decline in global cognition and episodic memory were observed in a small proportion of individuals. Older, less educated participants and men were more common in lower-functioning trajectories ( < .001). The highest proportions of dementia cases were in trajectories with major decline in global cognition (56.9%) and memory (33.2%).

Discussion: Inter-individual variability in cognitive trajectories was observed across all domains. Some individuals appear resilient to cognitive decline even with advancing age. Further research into factors promoting cognitive resilience is needed.
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http://dx.doi.org/10.1002/dad2.12180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088593PMC
May 2021

Genetic testing in dementia-A medical genetics perspective.

Int J Geriatr Psychiatry 2021 Mar 12. Epub 2021 Mar 12.

Department of Genomic Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia.

Objective: When a genetic cause is suspected in a person with dementia, it creates unique diagnostic and management challenges to the treating clinician. Many clinicians may be unaware of the practicalities surrounding genetic testing for their patients, such as when to test and what tests to use and how to counsel patients and their families. This review was conducted to provide guidance to clinicians caring for patients with dementia regarding clinically relevant genetics.

Methods: We searched PubMed for studies that involved genetics of dementia up to March 2020. Patient file reviews were also conducted to create composite cases.

Results: In addition to families where a strong Mendelian pattern of family history is seen, people with younger age of onset, especially before the age of 65 years were found to be at an increased risk of harbouring a genetic cause for their dementia. This review discusses some of the most common genetic syndromes, including Alzheimer disease, frontotemporal dementia, vascular dementia, Parkinson disease dementia/dementia with Lewy bodies and some rarer types of genetic dementias, along with illustrative clinical case studies. This is followed by a brief review of the current genetic technologies and a discussion on the unique genetic counselling issues in dementia.

Conclusions: Inclusion of genetic testing in the diagnostic pathway in some patients with dementia could potentially reduce the time taken to diagnose the cause of their dementia. Although a definite advantage as an addition to the diagnostic repository, genetic testing has many pros and cons which need to be carefully considered first.
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http://dx.doi.org/10.1002/gps.5535DOI Listing
March 2021

'Essential Tremor' Phenotype in FMR1 Premutation/Gray Zone Sibling Series: Exploring Possible Genetic Modifiers.

Twin Res Hum Genet 2021 Mar 24:1-8. Epub 2021 Mar 24.

Department of Medicine (Neuroscience), Monash University, Melbourne, Victoria, Australia.

Fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in carriers of fragile X mental retardation 1 (FMR1) X-linked small CGG expansion (gray zone [GZ] and premutation [PM]) alleles, containing 41-200 repeats. Major features comprise kinetic tremor, gait ataxia, cognitive decline and cerebellar peduncular white matter lesions, but atypical/incomplete FXTAS may occur. We explored the possibility of polygenic effects modifying the FXTAS spectrum phenotypes. We used three motor scales and selected cognitive tests in a series of three males and three females from a single sibship carrying PM or GZ alleles (44 to 75 repeats). The molecular profiles from these siblings were determined by genomewide association study with single-nucleotide polymorphism (SNP) genotyping by Illumina Global Screening Array. Nonparametric linkage analysis was applied and Parkinson's disease (PD) polygenic risk scores (PRSs) were calculated for all the siblings, based on 107 known risk variants. All male and female siblings manifested similar kinetic tremor phenotypes. In contrast to FXTAS, they showed negligible gait ataxia, and few white matter lesions on MRI. Cognitive functioning was unaffected. Suggestive evidence of linkage to a broad region of the short arm of chromosome 10 was obtained, and median PD PRS for the sibship fell within the top 30% of a sample of over 500,000 UK and Australian controls. The genomewide study results are suggestive of modifying effects of genetic risk loci linked to PD, on the neurological phenotype of FMR1-CGG small expansion carriers, resulting in an oligosymptomatic kinetic tremor seen in FXTAS spectrum, but also consistent with essential tremor.
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http://dx.doi.org/10.1017/thg.2021.10DOI Listing
March 2021

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults.

J Gen Intern Med 2021 Mar 22. Epub 2021 Mar 22.

Department of Pharmacy Practice and Science, College of Pharmacy and Department of Family Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.

Background: Anticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking.

Objective: Compare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people.

Design: Prospective cohort study.

Setting: Primary care (Australia and USA).

Participants: 19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100.

Measurements: Baseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition.

Results: At baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1-2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications.

Limitations: Residual confounding and reverse causality are possible. Assessment of dose or duration was not possible.

Conclusions: High anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.
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http://dx.doi.org/10.1007/s11606-020-06550-2DOI Listing
March 2021

The Utility of Assessing Health-Related Quality of Life to Predict Cognitive Decline and Dementia.

J Alzheimers Dis 2021 ;80(2):895-904

School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Background: Health-related quality of life (HRQoL) has been shown to predict adverse health outcome in the general population.

Objective: We examined the cross-sectional association between HRQoL and cognitive performance at baseline. Next, we explored whether baseline HRQoL predicted 5-year incident cognitive decline and dementia and whether there were gender differences.

Methods: 19,106 community-dwelling participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, aged 65-98 years, free of major cognitive impairments, and completed the HRQoL 12-item short-form (SF-12) at baseline (2010-2014), were followed until June 2017. The physical (PCS) and mental component scores (MCS) of SF-12 were calculated. The cognitive tests were assessed at baseline, year 1, 3, 5, and 7 or close-out visit. Cognitive decline was defined as > 1.5 SD drop from baseline on any of the cognitive tests. Dementia was adjudicated according to DSM-IV criteria. Linear and Cox proportional-hazards regressions were used to examine the cross-sectional and longitudinal associations respectively.

Results: At baseline, higher PCS and MCS were associated with better cognition. Over a median 4.7-year follow-up, higher MCS was associated with a reduced risk of cognitive decline and dementia (12% and 15% respectively, per 10-unit increase) and a 10-unit higher PCS was associated with a 6% decreased risk of cognitive decline. PCS did not predict dementia incidence. Findings were not different by gender.

Conclusion: Our study found that higher HRQoL, in particular MCS, predicted a reduced risk of cognitive decline and dementia over time in community-dwelling older people.
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http://dx.doi.org/10.3233/JAD-201349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093030PMC
January 2021

Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement.

Front Mol Biosci 2020 12;7:577246. Epub 2021 Jan 12.

Department of Medicine (Neuroscience), Monash University, Alfred Hospital Campus, Melbourne, VIC, Australia.

Expansions of the CGG repeat in the non-coding segment of the FMR1 X-linked gene are associated with a variety of phenotypic changes. Large expansions (>200 repeats), which cause a severe neurodevelopmental disorder, the fragile x syndrome (FXS), are transmitted from the mothers carrying smaller, unstable expansions ranging from 55 to 200 repeats, termed the fragile X premutation. Female carriers of this premutation may themselves experience a wide range of clinical problems throughout their lifespan, the most severe being the late onset neurodegenerative condition called "Fragile X-Associated Tremor Ataxia Syndrome" (FXTAS), occurring between 8 and 16% of these carriers. Male premutation carriers, although they do not transmit expanded alleles to their daughters, have a much higher risk (40-50%) of developing FXTAS. Although this disorder is more prevalent and severe in male than female carriers, specific sex differences in clinical manifestations and progress of the FXTAS spectrum have been poorly documented. Here we compare the pattern and rate of progression (per year) in three motor scales including tremor/ataxia (ICARS), tremor (Clinical Tremor Rating scale, CRST), and parkinsonism (UPDRS), and in several cognitive and psychiatric tests scores, between 13 female and 9 male carriers initially having at least one of the motor scores ≥10. Moreover, we document the differences in each of the clinical and cognitive measures between the cross-sectional samples of 21 female and 24 male premutation carriers of comparable ages with FXTAS spectrum disorder (FSD), that is, who manifest one or more features of FXTAS. The results of progression assessment showed that it was more than twice the rate in male than in female carriers for the ICARS-both gait ataxia and kinetic tremor domains and twice as high in males on the CRST scale. In contrast, sex difference was negligible for the rate of progress in UPDRS, and all the cognitive measures. The overall psychiatric pathology score (SCL-90), as well as Anxiety and Obsessive/Compulsive domain scores, showed a significant increase only in the female sample. The pattern of sex differences for progression in motor scores was consistent with the results of comparison between larger, cross-sectional samples of male and female carriers affected with the FSD. These results were in concert with sex-specific distribution of MRI T2 white matter hyperintensities: all males, but no females, showed the middle cerebellar peduncle white matter hyperintensities (MCP sign), although the distribution and severity of these hyperintensities in the other brain regions were not dissimilar between the two sexes. In conclusion, the magnitude and specific pattern of sex differences in manifestations and progression of clinically recorded changes in motor performance and MRI lesion distribution support, on clinical grounds, the possibility of certain sex-limited factor(s) which, beyond the predictable effect of the second, normal FMR1 alleles in female premutation carriers, may have neuroprotective effects, specifically concerning the cerebellar circuitry.
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http://dx.doi.org/10.3389/fmolb.2020.577246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835843PMC
January 2021

Effects of aspirin on the long-term management of depression in older people: a double-blind randomised placebo-controlled trial.

Mol Psychiatry 2021 Jan 27. Epub 2021 Jan 27.

School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia.

Late-life depression is common and often inadequately managed using existing therapies. Depression is also associated with increased markers of inflammation, suggesting a potential role for anti-inflammatory agents. ASPREE-D is a sub-study of ASPREE, a large multi-centre, population-based, double-blind, placebo-controlled trial of aspirin vs placebo in older Australian and American adults (median follow-up: 4.7 years) of whom 1879 were depressed at baseline. Participants were given 100 mg daily dose of aspirin or placebo. Depressive symptoms were assessed annually using the validated, self-rated short version of the Center for Epidemiological Studies Depression scale. There was a significant increase in depressive scores (0.6; 95% CI 0.2 to 0.9; χ (1) = 10.37; p = 0.001) and a decreased score in the mental health component of a quality of life scale (-0.7; 95% CI -1.4 to -0.1; χ (1) = 4.74; p = 0.029) in the aspirin group compared to the placebo group. These effects were greater in the first year of follow-up and persisted throughout the study, albeit with small to very small effect sizes. This study failed to demonstrate any benefit of aspirin in the long-term course of depression in this community-dwelling sample of older adults over a 5-year period, and identified an adverse effect of aspirin in the course of depression in those with pre-existing depressive symptoms.
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http://dx.doi.org/10.1038/s41380-021-01020-5DOI Listing
January 2021

Effect of Aspirin on Activities of Daily Living Disability in Community-Dwelling Older Adults.

J Gerontol A Biol Sci Med Sci 2020 Dec 26. Epub 2020 Dec 26.

Center for Aging and Population Health, University of Pittsburgh, Pittsburgh, PA, U.S.

Background: Cerebrovascular events, dementia and cancer can contribute to physical disability with activities of daily living (ADL). It is unclear whether low-dose aspirin reduces this burden in aging populations. In a secondary analysis, we now examine aspirin's effects on incident and persistent ADL disability within a primary prevention aspirin trial in community-dwelling older adults.

Methods: The ASPREE (ASPirin in Reducing Events in the Elderly) trial of daily 100mg aspirin versus placebo recruited 19,114 healthy adults aged 70+ years (65+ years if U.S. minority) in Australia and the U.S. Six basic ADLs were assessed every six months. Incident ADL disability was defined as inability or severe difficulty with ≥1 ADL; persistence was confirmed if the same ADL disability remained after six months. Proportional hazards modelling compared time to incident or persistent ADL disability for aspirin versus placebo; death without prior disability was a competing risk.

Results: Over a median 4.7 years, incident ADL disability was similar in those receiving aspirin (776/9525) and placebo (787/9589) with walking, bathing, dressing and transferring the most commonly reported. Only 24% of incident ADL disability progressed to persistent. Persistent ADL disability was lower in the aspirin group (4.3 versus 5.3 events/1000py; HR=0.81, 95% CI:0.66-1.00), with bathing and dressing the most common ADL disabilities in both groups. Following persistent ADL disability there were more deaths in the aspirin group (24 versus 12).

Discussion: Low-dose aspirin in initially healthy older people did not reduce risk of incident ADL disability, although there was evidence of reduced persistent ADL disability.
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http://dx.doi.org/10.1093/gerona/glaa316DOI Listing
December 2020

Effect of Aspirin on Activities of Daily Living Disability in Community-Dwelling Older Adults.

J Gerontol A Biol Sci Med Sci 2020 Dec 26. Epub 2020 Dec 26.

Center for Aging and Population Health, University of Pittsburgh, Pittsburgh, PA, U.S.

Background: Cerebrovascular events, dementia and cancer can contribute to physical disability with activities of daily living (ADL). It is unclear whether low-dose aspirin reduces this burden in aging populations. In a secondary analysis, we now examine aspirin's effects on incident and persistent ADL disability within a primary prevention aspirin trial in community-dwelling older adults.

Methods: The ASPREE (ASPirin in Reducing Events in the Elderly) trial of daily 100mg aspirin versus placebo recruited 19,114 healthy adults aged 70+ years (65+ years if U.S. minority) in Australia and the U.S. Six basic ADLs were assessed every six months. Incident ADL disability was defined as inability or severe difficulty with ≥1 ADL; persistence was confirmed if the same ADL disability remained after six months. Proportional hazards modelling compared time to incident or persistent ADL disability for aspirin versus placebo; death without prior disability was a competing risk.

Results: Over a median 4.7 years, incident ADL disability was similar in those receiving aspirin (776/9525) and placebo (787/9589) with walking, bathing, dressing and transferring the most commonly reported. Only 24% of incident ADL disability progressed to persistent. Persistent ADL disability was lower in the aspirin group (4.3 versus 5.3 events/1000py; HR=0.81, 95% CI:0.66-1.00), with bathing and dressing the most common ADL disabilities in both groups. Following persistent ADL disability there were more deaths in the aspirin group (24 versus 12).

Discussion: Low-dose aspirin in initially healthy older people did not reduce risk of incident ADL disability, although there was evidence of reduced persistent ADL disability.
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http://dx.doi.org/10.1093/gerona/glaa316DOI Listing
December 2020

Baseline characteristics and age-related macular degeneration in participants of the "ASPirin in Reducing Events in the Elderly" (ASPREE)-AMD trial.

Contemp Clin Trials Commun 2020 Dec 11;20:100667. Epub 2020 Oct 11.

Department of Epidemiology and Preventive Medicine, Monash University, The Alfred Centre 99 Commercial Road, Melbourne, VIC, 3004, Australia.

Purpose: To describe the baseline participant characteristics in the ASPREE-AMD study, investigating the effect of aspirin on AMD incidence and progression.

Methods: Australian participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, randomized to 100 mg aspirin daily or placebo, had non-mydriatic, digital color fundus images graded according to the Beckman AMD classification. Associations with AMD were determined for baseline characteristics and genetic risk variants.

Results: ASPREE-AMD sub-study enrolled 4993 participants with gradable macular images. Median age was 73.4 years (IQR, 71.5, 76.6), 52% were female, 10% had diabetes mellitus, 73% had hypertension, and 44% were former/current smokers. Early, intermediate and late AMD (detected in 20.6%, 16.1%, 1.1%, respectively), significantly associated with age, were also associated with increasing HDL levels: OR = 1.52 (95%CI, 1.26, 1.84), OR = 1.43 (1.17, 1.77) and OR = 1.96 (1.02, 3.76), respectively. Female sex was associated with early [OR = 1.37 (1.16, 1.62)], and intermediate [OR = 1.35 (1.12, 1.63)] AMD, as was previous regular use of aspirin, with OR = 1.46 (1.11, 1.92) and OR = 1.37 (1.01, 1.85), respectively. Current smoking had increased odds for late AMD, OR = 4.02 (1.42, 11.36). Genetic risk variant rs3750846 () was associated with each AMD stage ( < 0.001), risk variants rs570618 and rs10922109 ( with intermediate and late AMD ( < 0.001), and rare variant rs147859257 () with late AMD ( < 0.001). The randomized groups were well balanced for all analyzed AMD risk factors.

Conclusions: Observed associations are typical of AMD. The ASPREE-AMD clinical trial provides a unique opportunity to determine the risks and benefits of low-dose aspirin for AMD incidence and progression in elderly population.

Trial Registration: Australian New Zealand Clinical Trial Registry: ACTRN 12613000755730.
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http://dx.doi.org/10.1016/j.conctc.2020.100667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658662PMC
December 2020

Neuroprotective Effects of Motherhood on Brain Function in Late Life: A Resting-State fMRI Study.

Cereb Cortex 2021 Jan;31(2):1270-1283

Turner Institute for Brain and Mental Health, Monash University, Melbourne, VIC 3800, Australia.

The maternal brain undergoes structural and functional plasticity during pregnancy and the postpartum period. Little is known about functional plasticity outside caregiving-specific contexts and whether changes persist across the lifespan. Structural neuroimaging studies suggest that parenthood may confer a protective effect against the aging process; however, it is unknown whether parenthood is associated with functional brain differences in late life. We examined the relationship between resting-state functional connectivity and number of children parented in 220 healthy older females (73.82 ± 3.53 years) and 252 healthy older males (73.95 ± 3.50 years). We compared the patterns of resting-state functional connectivity with 3 different models of age-related functional change to assess whether these effects may be functionally neuroprotective for the aging human parental brain. No relationship between functional connectivity and number of children was obtained for males. For females, we found widespread decreasing functional connectivity with increasing number of children parented, with increased segregation between networks, decreased connectivity between hemispheres, and decreased connectivity between anterior and posterior regions. The patterns of functional connectivity related to the number of children an older woman has parented were in the opposite direction to those usually associated with age-related cognitive decline, suggesting that motherhood may be beneficial for brain function in late life.
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http://dx.doi.org/10.1093/cercor/bhaa293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906778PMC
January 2021

Normative Data for the Symbol Digit Modalities Test in Older White Australians and Americans, African-Americans, and Hispanic/Latinos.

J Alzheimers Dis Rep 2020 Aug 4;4(1):313-323. Epub 2020 Aug 4.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Background: Processing speed, which can be assessed using the Symbol Digit Modalities Test (SDMT), is central to many brain functions. Processing speed declines with advanced age but substantial impairments are indicative of brain injury or disease.

Objective: The purpose of this study was to provide SDMT normative data for older community-dwelling individuals in the U.S. and Australia.

Methods: The ASPREE trial recruited 19,114 relatively healthy older men and women in Australia and the U.S. from the general community. All participants were without a diagnosis of dementia and with a Modified Mini-Mental State examination score of 78 or more at enrolment. The SDMT was administered at baseline as part of a neuropsychological test battery.

Results: The median age of participants was 74 years (range 65-99), and 56% were women. The median years of education was 12. Ethno-racial differences in SDMT performance were observed and normative data were thus presented separately for 16,289 white Australians, 1,082 white Americans, 891 African-Americans, and 316 Hispanic/Latinos. There were consistent positive associations found between SDMT and education level, and negative associations between SDMT and age. Mean scores for women were consistently higher than men with the exception of Hispanic/Latinos aged ≥70 years.

Conclusion: This study provides comprehensive SDMT normative data for whites (Australian and U.S.), Hispanic/Latinos, and African-Americans, according to gender, age, and education level. These norms can be used clinically as reference standards to screen for cognitive impairments in older individuals.
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http://dx.doi.org/10.3233/ADR-200194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504980PMC
August 2020

Impact of the 2017 American Heart Association and American College of Cardiology hypertension guideline in aged individuals.

J Hypertens 2020 12;38(12):2527-2536

Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Victoria.

Objectives: The AHA/ACC-2017 hypertension guideline recommends an age-independent target blood pressure (BP) of less than 130/80 mmHg. In an elderly cohort without established cardiovascular disease (CVD) at baseline, we determined the impact of this guideline on the prevalence of hypertension and associated CVD risk.

Methods: Nineteen thousand, one hundred and fourteen participants aged at least 65 years from the ASPirin in Reducing Events in the Elderly (ASPREE) study were grouped by baseline BP: 'pre-2017 hypertensive' (BP ≥140/90 mmHg and/or on antihypertensive drugs); 'reclassified hypertensive' (normotensive by pre-2017 guidelines; hypertensive by AHA/ACC-2017 guideline), and 'normotensive' (BP <130 and <80 mmHg). For each group, we evaluated CVD risk factors, predicted 10-year CVD risk using the Atherosclerotic Cardiovascular Disease (ASCVD) risk equation, and reported observed CVD event rates during a median 4.7-year follow-up.

Results: Overall, 74.4% (14 213/19 114) were 'pre-2017 hypertensive'; an additional 12.3% (2354/19 114) were 'reclassified hypertensive' by the AHA/ACC-2017 guideline. Of those 'reclassified hypertensive', the majority (94.5%) met criteria for antihypertensive treatment although 29% had no other traditional CVD risk factors other than age. Further, a relatively lower mean 10-year predicted CVD risk (18% versus 26%, P < 0.001) and lower CVD rates (8.9 versus 12.1/1000 person-years, P = 0.01) were observed in 'reclassified hypertensive' compared with 'pre-2017 hypertensive'. Compared with 'normotensive', a hazard ratio (95% confidence interval) for CVD events of 1.60 (1.26-2.02) for 'pre-2017 hypertensive' and 1.26 (0.93-1.71) for 'reclassified hypertensive' was observed.

Conclusion: Applying current CVD risk calculators in the elderly 'reclassified hypertensive', as a result of shifting the BP threshold lower, increases eligibility for antihypertensive treatment but documented CVD rates remain lower than hypertensive patients defined by pre2017 BP thresholds.
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http://dx.doi.org/10.1097/HJH.0000000000002582DOI Listing
December 2020

Relationship between parenthood and cortical thickness in late adulthood.

PLoS One 2020 28;15(7):e0236031. Epub 2020 Jul 28.

Turner Institute for Brain and Mental Health, Monash University, Melbourne, Australia.

Pregnancy and the early postpartum period alter the structure of the brain; particularly in regions related to parental care. However, the enduring effects of this period on human brain structure and cognition in late life is unknown. Here we use magnetic resonance imaging to examine differences in cortical thickness related to parenthood in late life, for both sexes. In 235 healthy older women, we find a positive relationship between parity (number of children parented) and memory performance in mothers. Parity was also associated with differences in cortical thickness in women in the parahippocampus, precuneus, cuneus and pericalcarine sulcus. We also compared non-parents to parents of one child, in a sub-sample of older women (N = 45) and men (N = 35). For females, six regions differed in cortical thickness between parents and non-parents; these regions were consistent with those seen earlier in life in previous studies. For males, five regions differed in cortical thickness between parents and non-parents. We are first to reveal parenthood-related brain differences in late-life; our results are consistent with previously identified areas that are altered during pregnancy and the postpartum period. This study provides preliminary evidence to suggest that neural changes associated with early stages of parenthood persist into older age, and for women, may be related to marginally better cognitive outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236031PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386609PMC
September 2020

Individual differences in haemoglobin concentration influence bold fMRI functional connectivity and its correlation with cognition.

Neuroimage 2020 11 25;221:117196. Epub 2020 Jul 25.

Monash Biomedical Imaging, Monash University, 770 Blackburn Rd, Melbourne, Victoria 3800, Australia; Turner Institute for Brain and Mental Health, Monash University, Melbourne, Victoria, Australia; Australian Research Council Centre of Excellence for Integrative Brain Function, Melbourne, Victoria, Australia. Electronic address:

Resting-state connectivity measures the temporal coherence of the spontaneous neural activity of spatially distinct regions, and is commonly measured using BOLD-fMRI. The BOLD response follows neuronal activity, when changes in the relative concentration of oxygenated and deoxygenated haemoglobin cause fluctuations in the MRI T2* signal. Since the BOLD signal detects changes in relative concentrations of oxy/deoxy-haemoglobin, individual differences in haemoglobin levels may influence the BOLD signal-to-noise ratio in a manner independent of the degree of neural activity. In this study, we examined whether group differences in haemoglobin may confound measures of functional connectivity. We investigated whether relationships between measures of functional connectivity and cognitive performance could be influenced by individual variability in haemoglobin. Finally, we mapped the neuroanatomical distribution of the influence of haemoglobin on functional connectivity to determine where group differences in functional connectivity are manifest. In a cohort of 518 healthy elderly subjects (259 men), each sex group was median-split into two groups with high and low haemoglobin concentration. Significant differences were obtained in functional connectivity between the high and low haemoglobin groups for both men and women (Cohen's d 0.17 and 0.03 for men and women respectively). The haemoglobin connectome in males showed a widespread systematic increase in functional connectivity correlation values, whilst the female connectome showed predominantly parietal and subcortical increases and temporo-parietal decreases. Despite the haemoglobin groups having no differences in cognitive measures, significant differences in the linear relationships between cognitive performance and functional connectivity were obtained for all 5 cognitive tests in males, and 4 out of 5 tests in females. Our findings confirm that individual variability in haemoglobin levels that give rise to group differences are an important confounding variable in BOLD-fMRI-based studies of functional connectivity. Controlling for haemoglobin variability as a potentially confounding variable is crucial to ensure the reproducibility of human brain connectome studies, especially in studies that compare groups of individuals, compare sexes, or examine connectivity-cognition relationships.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994014PMC
November 2020

Effect of Aspirin vs Placebo on the Prevention of Depression in Older People: A Randomized Clinical Trial.

JAMA Psychiatry 2020 10;77(10):1012-1020

School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

Importance: Depression is associated with increased inflammation, which may precede its onset, especially in older people. Some preclinical data suggest potential antidepressant effects of aspirin, supported by limited observational data suggesting lower rates of depression in individuals treated with aspirin. There currently appears to be no evidence-based pharmacotherapies for the primary prevention of depression.

Objective: To determine whether low-dose aspirin (100 mg) reduces the risk of depression in healthy older adults.

Design, Setting, And Participants: This double-blinded, placebo-controlled randomized clinical trial was a substudy of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, which examined if aspirin increased healthy life span, defined as survival free of dementia and disability. The prespecified secondary outcome was depression. Individuals of all races/ethnicities older than 70 years in Australia, as well as white individuals older than 70 years and black and Hispanic individuals older than 65 years in the United States, were included.

Interventions: Participants were randomized to aspirin (100 mg daily) or placebo, with a median (interquartile range) follow-up of 4.7 (3.5-5.6) years.

Main Outcomes And Measures: The primary outcome was a proxy measure of major depressive disorder defined as a score of 8 or more on the Center for Epidemiologic Studies Depression 10-item (CES-D-10) scale.

Results: Of the 19 114 participants enrolled in the trial, 9525 received aspirin and 9589 received a placebo. The mean (SD) age was 75.2 (4.0) years in the aspirin group and 75.1 (4.5) years in the placebo group; 9531 (56.4%) were women. Participants' demographics and clinical characteristics at baseline were similar between groups. A total of 79 886 annual CES-D-10 measurements were taken, with a mean of 4.2 measurements per participant. There were no significant differences at annual visits in the proportions of CES-D-10 scores of 8 or more between the aspirin and placebo groups. The incidence rate of new CES-D-10 scores of 8 or more was 70.4 events per 1000 person-years in the aspirin group and 69.1 in the placebo group (hazard ratio, 1.02 [95% CI, 0.96-1.08]; P = .54).

Conclusions And Relevance: Low-dose aspirin did not prevent depression in this large-scale study of otherwise healthy older adults.

Trial Registration: ClinicalTrials.gov Identifier: NCT01038583.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.1214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271558PMC
October 2020

Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline.

Neurology 2020 07 25;95(3):e320-e331. Epub 2020 Mar 25.

From the School of Public Health and Preventive Medicine (J.R., E.S., R.L.W., R.W., C.M.R., S.A.W., J.E.L., S.G.O., R.T., J.J.M.) and the Turner Institute for Brain and Mental Health (T.T.J.C.), Monash University, Melbourne, Australia; Berman Center for Outcomes and Clinical Research (A.M.M., B.K.), Hennepin Health Research Institute; Division of Geriatrics, Department of Medicine (A.M.M., B.K.), Hennepin Healthcare, Minneapolis, MN; School of Public Health (C.M.R.), Curtin University, Perth; Menzies Institute for Medical Research (M.R.N.), University of Tasmania, Hobart, Australia; Sticht Center on Aging and Alzheimer's Prevention, Section on Gerontology and Geriatric Medicine, Department of Internal Medicine (J.D.W.), Wake Forest School of Medicine, Winston-Salem, NC; Center for Aging and Population Health (A.B.N.), University of Pittsburgh, PA; Department of Pharmacy Practice and Science, College of Pharmacy, and the Department of Family Medicine, Carver College of Medicine (M.E.E.), University of Iowa, Iowa City; and Department of Family Medicine and Rush Alzheimer's Disease Center (R.C.S.), Rush University Medical Center, Chicago, IL.

Objective: To determine the effect of low-dose aspirin vs placebo on incident all-cause dementia, incident Alzheimer disease (AD), mild cognitive impairment (MCI), and cognitive decline in older individuals.

Methods: Aspirin in Reducing Events in the Elderly (ASPREE) was a double-blind, placebo-controlled trial of low-dose aspirin. In the United States and Australia, community-dwelling individuals aged ≥70 years (US minorities ≥65 years) and free of cardiovascular disease, physical disability, and diagnosed dementia were enrolled. Participants were randomized 1:1-100 mg daily aspirin or placebo. The Modified Mini-Mental State Examination, Hopkins Verbal Learning Test-Revised, Symbol Digit Modalities Test, and Controlled Oral Word Association Test assessed cognition at baseline and over follow-up. Additional cognitive testing was performed in participants with suspected dementia ("trigger") based on within-study assessments or clinical history. Dementia was adjudicated according to DSM-IV criteria. National Institute on Aging-Alzheimer's Association criteria were used for AD and MCI subclassification.

Results: A total of 19,114 participants were followed over a median 4.7 years and 964 triggered further dementia assessments. There were 575 adjudicated dementia cases, and 41% were classified as clinically probable AD. There was no substantial difference in the risk of all dementia triggers (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.91-1.17), probable AD (HR, 0.96; 95% CI, 0.74-1.24), or MCI (HR, 1.12; 95% CI, 0.92-1.37) between aspirin and placebo. Cognitive change over time was similar in the aspirin and placebo groups.

Conclusions: There was no evidence that aspirin was effective in reducing risk of dementia, MCI, or cognitive decline. Follow-up of these outcomes after initial exposure is ongoing.

Classification Of Evidence: This study provides Class II evidence that for healthy older individuals, low-dose aspirin does not significantly reduce the incidence of dementia, probable AD, MCI, or cognitive decline.

Clinicaltrialsgov Identifier: NCT01038583.
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http://dx.doi.org/10.1212/WNL.0000000000009277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455352PMC
July 2020

Normative performance of older individuals on the Hopkins Verbal Learning Test-Revised (HVLT-R) according to ethno-racial group, gender, age and education level.

Clin Neuropsychol 2020 Feb 26:1-17. Epub 2020 Feb 26.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

The Hopkins Verbal Learning Test-Revised (HVLT-R) provides a measure of verbal learning and memory. The aim of this study was to provide normative performance data on the HVLT-R for community-dwelling older individuals according to ethno-racial group, age, gender, and years of completed education, in Australia and the U.S. The ASPirin in Reducing Events in the Elderly (ASPREE) study recruited 19,114 generally healthy community dwelling individuals aged 70 years and over (65 years and over for U.S minorities), who were without a diagnosis of dementia and scored above 77 on the modified Mini-Mental State (3MS) examination. Included in the analysis presented here were 16,251 white Australians, and in the U.S. 1,082 white, 894 African American and 314 Hispanic/Latino individuals at baseline. Performance on each of the components of the HVLT-R (trials 1-3, total, learning, delayed recall, delayed recognition, percentage retention and recognition discrimination index [RDI]) differed by demographic variables. In country and ethno-racial stratified analyses, female gender, younger age and higher education were significantly associated with better total recall, delayed recall and RDI. Among white Australians these characteristics were also associated with better retention. Age, education and gender-specific reference values across ethno-racial categories were determined. Ethno-racial, age, gender and education-stratified normative data from this large cohort of community-dwelling older individuals will serve as important reference standards in Australia and the U.S. to assess cognition in older individuals.
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http://dx.doi.org/10.1080/13854046.2020.1730444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483610PMC
February 2020

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE-FRDA study.

Hum Brain Mapp 2020 05 6;41(7):1920-1933. Epub 2020 Jan 6.

School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Melbourne, Victoria, Australia.

Friedreich ataxia is a progressive neurodegenerative disorder with reported abnormalities in cerebellar, brainstem, and cerebral white matter. White matter structure can be measured using in vivo neuroimaging indices sensitive to different white matter features. For the first time, we examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities. Diffusion-tensor, magnetization transfer, and T1-weighted structural images were acquired from 31 individuals with Friedreich ataxia and 36 controls. Six white matter indices were extracted: fractional anisotropy, diffusivity (mean, axial, radial), magnetization transfer ratio (microstructure), and volume (macrostructure). For each index, whole-brain voxel-wise between-group comparisons and correlations with disease severity, onset age, and gene triplet-repeat length were undertaken. Correlations between pairs of indices were assessed in the Friedreich ataxia cohort. Spatial similarities in the voxel-level pattern of between-group differences across the indices were also assessed. Microstructural abnormalities were maximal in cerebellar and brainstem regions, but evident throughout the brain, while macroscopic abnormalities were restricted to the brainstem. Poorer microstructure and reduced macrostructural volume correlated with greater disease severity and earlier onset, particularly in peri-dentate nuclei and brainstem regions. Microstructural and macrostructural abnormalities were largely independent. Reduced fractional anisotropy was most strongly associated with axial diffusivity in cerebral tracts, and magnetization transfer in cerebellar tracts. Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways.
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http://dx.doi.org/10.1002/hbm.24921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267947PMC
May 2020

Longitudinal Increases in Cerebral Brain Activation During Working Memory Performance in Friedreich Ataxia: 24-Month Data from IMAGE-FRDA.

Cerebellum 2020 Apr;19(2):182-191

School of Psychological Sciences and the Turner Institute for Brain and Mental Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.

Friedreich ataxia (FRDA) has been associated with functional abnormalities in cerebral and cerebellar networks, particularly in the ventral attention network. However, how functional alterations change with disease progression remains largely unknown. Longitudinal changes in brain activation, associated with working memory performance (N-back task), and grey matter volume were assessed over 24 months in 21 individuals with FRDA and 28 healthy controls using functional and structural magnetic resonance imaging, respectively. Participants also completed a neurocognitive battery assessing working memory (digit span), executive function (Stroop, Haylings), and set-shifting (Trail Making Test). Individuals with FRDA displayed significantly increased brain activation over 24 months in ventral attention brain regions, including bilateral insula and inferior frontal gyrus (pars triangularis and pars opercularis), compared with controls, but there was no difference in working memory (N-back) performance between groups. Moreover, there were no significant differences in grey matter volume changes between groups. Significant correlations between brain activations and both clinical severity and age at disease onset were observed in FRDA individuals only at 24 months. There was significant longitudinal decline in Trail Making Test (TMT) difference score (B-A) in individuals with FRDA, compared with controls. These findings provide the first evidence of increased longitudinal activation over time in the cerebral cortex in FRDA, compared with controls, despite comparable working memory performance. This finding represents a possible compensatory response in the ventral attention network to help sustain working memory performance in individuals with FRDA.
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http://dx.doi.org/10.1007/s12311-019-01094-6DOI Listing
April 2020

Factors Associated With Treatment and Control of Hypertension in a Healthy Elderly Population Free of Cardiovascular Disease: A Cross-sectional Study.

Am J Hypertens 2020 04;33(4):350-361

Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Background: Despite readily available treatments, control of blood pressure (BP) with population aging remains suboptimal. Further, there are gaps in the understanding of the management of high BP in the aged. We explored antihypertensive treatment and control among elderly hypertensive participants free from overt cardiovascular disease (CVD), and identified factors related to both "untreated" and "treated but uncontrolled" high BP.

Methods: We analyzed baseline data from 19,114 individuals aged ≥65 years enrolled from Australia and United States (US) in the ASPirin in Reducing Events in the Elderly study. Hypertension was defined as an average systolic/diastolic BP ≥140/90 mm Hg and/or the use of any BP lowering medication. "Controlled hypertension" was defined if participants were receiving antihypertensive medication and BP <140 and 90 mm Hg. Descriptive analyses were used to summarize hypertension control rates; logistic regression was used to investigate relationships with treatment and BP control.

Results: Overall, 74% (14,213/19,114) of participants were hypertensive; and of these 29% (4,151/14,213) were untreated. Among those treated participants, 53% (5,330/10,062) had BP ≥140/90 mm Hg. Participants who were untreated were more likely to be men, have higher educational status, and be in good physical health, and less likely to have significant comorbidities. The factors related to "treated but uncontrolled" BP included older age, male, Black race (vs. White), using antihypertensive monotherapy (vs. multiple) and residing in Australia (vs. US).

Conclusions: High levels of "untreated" and "treated but uncontrolled" BP occur in healthy elderly people without CVD, suggesting there are opportunities for better BP control in the primary prevention of CVD in this population.

Clinical Trials Registration: NCT01038583.
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http://dx.doi.org/10.1093/ajh/hpz192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109352PMC
April 2020

Total and Regional White Matter Lesions Are Correlated With Motor and Cognitive Impairments in Carriers of the Premutation.

Front Neurol 2019 13;10:832. Epub 2019 Aug 13.

Department of Medicine (Neuroscience), Central Clinical School, Monash University, Melbourne, VIC, Australia.

This study explores the relationships between hemispheric and cerebellar white matter lesions and motor and cognitive impairments in male carriers of Fragile-X Mental Retardation 1 () premutation alleles, and in a subgroup of these carriers affected with Fragile X-Associated Tremor/Ataxia syndrome (FXTAS). Regional and total white matter hyperintensities () on MRI, assessed using semiquantitative scores, were correlated with three motor rating scales (ICARS, UPDRS, Tremor), and neuropsychological measures of non-verbal reasoning, working memory and processing speed, in a sample of 30 male premutation carriers aged 39-81 years, and separately in a subsample of 17 of these carriers affected with FXTAS. There were significant relationships between in the infratentorial region and all three motor scales, as well as several cognitive measures-Prorated IQ, Matrix Reasoning, Similarities, and the Symbol Digit Modalities Test (SDMT), in the total sample of carriers, as well as in the FXTAS group separately. This shows that within the infratentorial region correlates across the categories of clinical status with a range of motor and cognitive impairments. In the FXTAS group, there was a highly significant relationship between supratentorial (periventricular) lesions and parkinsonism, and between both periventricular and supratentorial deep white matter and ICARS ataxia score. These findings further support the relevance of white matter changes in different brain regions to the motor and cognitive deficits across the spectrum of premutation involvement. Future longitudinal studies using larger sample sizes will be necessary to examine the factors that lead to conversion to a greater extent of neurological involvement as seen in the progression across the FXTAS spectrum.
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http://dx.doi.org/10.3389/fneur.2019.00832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700239PMC
August 2019

Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.

Am J Hum Genet 2019 07 20;105(1):151-165. Epub 2019 Jun 20.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612533PMC
July 2019

Prevalence of depressive symptoms and its associated factors among healthy community-dwelling older adults living in Australia and the United States.

Int J Geriatr Psychiatry 2019 08 8;34(8):1208-1216. Epub 2019 May 8.

School of Medicine, IMPACT Strategic Research Centre, Deakin University, Geelong, Victoria, Australia.

Objective: This study was conducted to estimate prevalence rates and factors associated with depressive symptoms indexed by the Centre for Epidemiological Studies-Depression (CES-D-10) score in a large sample of community-dwelling healthy older adults from Australia and the United States. Convergent and divergent validity of the CES-D-10 were also examined.

Methods: A total of 19 114 individuals aged greater than or equal to 65 years old were enrolled from a primary prevention clinical trial. Depressive symptoms were classified using the CES-D-10 score greater than or equal to 8 and greater than or equal to 10. Gender-specific prevalence for subgroups according to sociodemographic characteristics were reported, and factors associated with depressive symptoms were estimated.

Results: The overall prevalence rates of depressive symptoms were 9.8%, 95% CI, 8.5-11.2 and 5.0%, 95% CI, 4.0-6.0, according to the CES-D-10 score greater than or equal to 8 and greater than or equal to 10, respectively. Depressive symptoms were more common in women, individuals with less than 12 years of education, those living alone or in a residential care, ethnic minorities, current smokers, and former alcohol users. Convergent and divergent validities of the CES-D-10 were confirmed by observing strong negative association with the SF-12 mental health component and a modest negative association with SF-12 physical component, respectively.

Conclusions: This study reports the prevalence of depressive symptoms in Australian and US community-dwelling healthy older populations. These findings emphasize the high burden of the condition and factors associated with depressive symptoms, to better inform clinicians and help with early detection and treatment of depression in this age group.
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http://dx.doi.org/10.1002/gps.5119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924573PMC
August 2019

Speech treatment improves dysarthria in multisystemic ataxia: a rater-blinded, controlled pilot-study in ARSACS.

J Neurol 2019 May 6;266(5):1260-1266. Epub 2019 Mar 6.

Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Germany and Center for Neurology, University of Tübingen, University Hospital Tübingen, Tübingen, Germany.

We aimed to provide proof-of-principle evidence that intensive home-based speech treatment can improve dysarthria in complex multisystemic degenerative ataxias, exemplified by autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS). Feasibility and piloting efficacy of speech training specifically tailored to cerebellar dysarthria was examined through a 4-week program in seven patients with rater-blinded assessment of intelligibility (primary outcome) and naturalness and acoustic measures of speech (secondary outcomes) performed 4 weeks before, immediately prior to, and directly after training (intraindividual control design). Speech intelligibility and naturalness improved post treatment. This provides piloting evidence that ataxia-tailored speech treatment might be effective in degenerative cerebellar disease.
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http://dx.doi.org/10.1007/s00415-019-09258-4DOI Listing
May 2019

Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in friedreich ataxia.

Mov Disord 2019 03 9;34(3):335-343. Epub 2019 Jan 9.

Monash Biomedical Imaging, Monash University, Melbourne, Australia.

Background: Friedreich ataxia is a recessively inherited, progressive neurological disease characterized by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of abnormalities in these structures.

Methods: Using in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n = 20) and healthy controls (n = 18) over a 2-year period.

Results: The longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Specifically, atrophy was maximal in individuals early in the disease course, whereas the rate of iron concentration increased with disease progression.

Conclusions: Progressive dentate nucleus abnormalities are evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a 2-year period highlight the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27606DOI Listing
March 2019

The Spectrum of Neurological and White Matter Changes and Premutation Status Categories of Older Male Carriers of the Alleles Are Linked to Genetic (CGG and FMR1 mRNA) and Cellular Stress (AMPK) Markers.

Front Genet 2018 12;9:531. Epub 2018 Nov 12.

Department of Medicine (Neuroscience), Monash University, Melbourne, VIC, Australia.

The fragile X premutation (PM) allele contains a CGG expansion of 55-200 repeats in the gene's promoter. Male PM carriers have an elevated risk of developing neurological and psychiatric changes, including an approximately 50% risk of the fragile X-associated tremor/ataxia syndrome (FXTAS). The aim of this study was to assess the relationships of regional white matter hyperintensities () semi-quantitative scores, clinical status, motor (UPDRS, ICARS, Tremor) scales, and cognitive impairments, with -specific genetic changes, in a sample of 32 unselected male PM carriers aged 39-81 years. Half of these individuals were affected with FXTAS, while the non-FXTAS group comprised subcategories of non-affected individuals and individuals affected with non-syndromic changes. The dynamics of pathological processes at the cellular level relevant to the clinical status of PM carriers was investigated using the enzyme AMP-activated protein kinase (AMPK), which is a highly sensitive cellular stress-sensing alarm protein. This enzyme, as well as genetic markers - CGG repeat number and the levels of the mRNA - were assessed in blood lymphoblasts. The results showed that the repeat distribution for FXTAS individuals peaked at 85-90 CGGs; non-FXTAS carriers were distributed within the lowest end of the PM repeat range, and non-syndromic carriers assumed an intermediate position. The size of the CGG expansion was significantly correlated, across all three categories, with infratentorial and total and with all motor scores, and the mRNA levels with all the scores, whilst AMPK activity showed considerable elevation in the non-FXTAS combined group, decreasing in the FXTAS group, proportionally to increasing severity of the and tremor/ataxia. We conclude that the size of the CGG expansion relates to the risk for FXTAS, to severity of infratentorial lesions, and to all three motor scale scores. mRNA shows a strong association with the extent of , which is the most sensitive marker of the pathological process. However, the AMPK activity findings - suggestive of a role of this enzyme in the risk of FXTAS - need to be verified and expanded in future studies using larger samples and longitudinal assessment.
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http://dx.doi.org/10.3389/fgene.2018.00531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241173PMC
November 2018

Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly.

N Engl J Med 2018 10 16;379(16):1509-1518. Epub 2018 Sep 16.

From the Department of Epidemiology and Preventive Medicine, Monash University (J.J.M., R.W., R.L.W., A.M.T., M.R.N., C.M.R., J.E.L., E.S., S.M.F., S.G.O., R.E.T., C.I.J., J.R., E.M.W., S.E.M.), Baker Heart and Diabetes Institute (C.I.J.), the Department of Cardiology, St. Vincent's Hospital (M.J.), and the Department of Clinical Neurosciences, Central Clinical School, Monash University and Alfred Hospital (G.C.), Melbourne, and Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville (G.A.D.), VIC, Menzies Institute for Medical Research, University of Tasmania, Hobart (M.R.N.), the School of Public Health, Curtin University (C.M.R.), and the School of Medicine, Royal Perth Hospital, University of Western Australia (L.J.B.), Perth, the College of Medicine, Biology and Environment, Australian National University, Canberra, ACT (W.P.A.), and the Discipline of General Practice, University of Adelaide, Adelaide, SA (N.S.) - all in Australia; the Berman Center for Outcomes and Clinical Research, Hennepin Healthcare Research Institute, Hennepin Healthcare (B.K., R.G., A.M.M.), HealthPartners Institute (K.L.M.), and the Division of Geriatrics, Department of Medicine, Hennepin Healthcare and the University of Minnesota (A.M.M.), Minneapolis, and the School of Nursing, Minnesota State University, Mankato (D.B.) - all in Minnesota; the Department of Family Medicine and Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago (R.C.S.); Sticht Center on Aging and Alzheimer's Prevention, Section on Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (J.D.W.); the Department of Pharmacy Practice and Science, College of Pharmacy and Department of Family Medicine, Carver College of Medicine, University of Iowa, Iowa City (M.E.E.); the Division of Geriatrics and Clinical Gerontology, National Institute on Aging, Bethesda, MD (B.R.); the Department of Cardiovascular Medicine, Vascular Medicine Section, Cleveland Clinic, Cleveland (M.M.); the Center for Primary Care and Prevention, Brown University, Providence, RI (C.B.E.); and the University of Tennessee Health Science Center, Memphis (S.S.).

Background: Aspirin is a well-established therapy for the secondary prevention of cardiovascular events. However, its role in the primary prevention of cardiovascular disease is unclear, especially in older persons, who have an increased risk.

Methods: From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure).

Results: Of the 19,114 persons who were enrolled in the trial, 9525 were assigned to receive aspirin and 9589 to receive placebo. After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001).

Conclusions: The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).
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http://dx.doi.org/10.1056/NEJMoa1805819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289056PMC
October 2018