Publications by authors named "Perminder S Sachdev"

393 Publications

Novel genetic variants associated with brain functional networks in 18,445 adults from the UK Biobank.

Sci Rep 2021 Jul 16;11(1):14633. Epub 2021 Jul 16.

Centre for Healthy Brain Aging, CHeBA, School of Psychiatry, University of New South Wales Medicine, Kensington, Sydney, NSW, 2052, Australia.

Here, we investigated the genetics of weighted functional brain network graph theory measures from 18,445 participants of the UK Biobank (44-80 years). The eighteen measures studied showed low heritability (mean h = 0.12) and were highly genetically correlated. One genome-wide significant locus was associated with strength of somatomotor and limbic networks. These intergenic variants were located near the PAX8 gene on chromosome 2. Gene-based analyses identified five significantly associated genes for five of the network measures, which have been implicated in sleep duration, neuronal differentiation/development, cancer, and susceptibility to neurodegenerative diseases. Further analysis found that somatomotor network strength was phenotypically associated with sleep duration and insomnia. Single nucleotide polymorphism (SNP) and gene level associations with functional network measures were identified, which may help uncover novel biological pathways relevant to human brain functional network integrity and related disorders that affect it.
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http://dx.doi.org/10.1038/s41598-021-94182-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285376PMC
July 2021

Deep brain stimulation for treatment-refractory obsessive-compulsive disorder should be an accepted therapy in Australia.

Aust N Z J Psychiatry 2021 Jul 15:48674211031482. Epub 2021 Jul 15.

Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.

Deep brain stimulation has shown promise for the treatment of severe, treatment-refractory obsessive-compulsive disorder. With the recent publication of the first Australian, randomised, sham-controlled trial of deep brain stimulation for obsessive-compulsive disorder, there are now four placebo-controlled trials demonstrating the efficacy of this therapy. Together with recent data identifying a biological substrate of effective stimulation that can predict response and that has been successfully reproduced, studies comparing and finding equivalent efficacy among different targets, as well as recent, large, open trials supporting the long-term effectiveness of deep brain stimulation, we argue that this should now be considered an accepted therapy for a select group of patients in the Australasian setting. We call on the Royal Australian and New Zealand College of Psychiatrists to revise their memorandum describing deep brain stimulation for obsessive-compulsive disorder as an '' treatment and recognise that it has proven efficacy. We stress that this should remain a therapy offered only to those with high treatment-refractory illnesses and only at specialised centres where there is an experienced multidisciplinary team involved in work-up, implantation and follow-up and also where frameworks are in place to provide careful clinical governance and ensure appropriate fully informed consent.
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http://dx.doi.org/10.1177/00048674211031482DOI Listing
July 2021

Difference in distribution functions: A new diffusion weighted imaging metric for estimating white matter integrity.

Neuroimage 2021 Jul 9;240:118381. Epub 2021 Jul 9.

Centre for Healthy Brain Aging (CHeBA), School of Psychiatry, UNSW Sydney, New South Wales 2052, Australia; Neuropsychiatric Institute (NPI), Euroa Centre, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.

Diffusion weighted imaging (DWI) is a widely recognized neuroimaging technique to evaluate the microstructure of brain white matter. The objective of this study is to establish an improved automated DWI marker for estimating white matter integrity and investigating ageing related cognitive decline. The concept of Wasserstein distance was introduced to help establish a new measure: difference in distribution functions (DDF), which captures the difference of reshaping one's mean diffusivity (MD) distribution to a reference MD distribution. This new DWI measure was developed using a population-based cohort (n=19,369) from the UK Biobank. Validation was conducted using the data drawn from two independent cohorts: the Sydney Memory and Ageing Study, a community-dwelling sample (n=402), and the Renji Cerebral Small Vessel Disease Cohort Study (RCCS), which consisted of cerebral small vessel disease (CSVD) patients (n=171) and cognitively normal controls (NC) (n=43). DDF was associated with age across all three samples and better explained the variance of changes than other established DWI measures, such as fractional anisotropy, mean diffusivity and peak width of skeletonized mean diffusivity (PSMD). Significant correlations between DDF and cognition were found in the UK Biobank cohort and the MAS cohort. Binary logistic analysis and receiver operator characteristic curve analysis of RCCS demonstrated that DDF had higher sensitivity in distinguishing CSVD patients from NC than the other DWI measures. To demonstrate the flexibility of DDF, we calculated regional DDF which also showed significant correlation with age and cognition. DDF can be used as a marker for monitoring the white matter microstructural changes and ageing related cognitive decline in the elderly.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118381DOI Listing
July 2021

Increased reporting of subjective cognitive complaints over time predicts cognitive decline and incident dementia.

Int J Geriatr Psychiatry 2021 Jul 3. Epub 2021 Jul 3.

CHeBA (Centre for Healthy Brain Ageing), School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.

Background: Subjective cognitive complaints (SCCs) are a risk factor for dementia; however, little is known about their trajectories.

Method: Participants were 873 older adults (mage = 78.65 years; 55% females) from the Sydney Memory and Ageing Study that were followed-up biennially. SCCs were measured using the six-item Memory Complaint Questionnaire. Associations between initial level of SCC reporting, linear change in SCC reporting, and change in global cognition over 6 years was examined using latent growth curve analysis. Risk of dementia was examined over 10 years using Cox regression.

Results: After controlling for demographics, mood and personality, results revealed a negative longitudinal association between the slope of SCCs and the slope of global cognition scores (b = -0.01, p = 0.005, β = -0.44), such that participants who reported increasing SCCs showed a steeper rate of decline in global cognition over 6 years. Cox regression also revealed participants who reported increasing SCCs had a nearly fourfold increased risk of developing dementia over 10 years (hazard ratio 3.70, 1.24-11.01).

Conclusion: This study explored whether initial levels of, and change in, SCCs over time are associated with both cognitive decline and risk of dementia. These findings are clinically relevant as GPs should note patients reporting increasing SCCs as they may be at greater risk of cognitive decline and incident dementia.
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http://dx.doi.org/10.1002/gps.5594DOI Listing
July 2021

Quantum dots as a theranostic approach in Alzheimer's disease: a systematic review.

Nanomedicine (Lond) 2021 Jun 28. Epub 2021 Jun 28.

Centre for Healthy Brain Aging, School of Psychiatry, University of New South Wales (UNSW), Sydney, Australia.

Quantum dots (QDs) are nanoparticles that have an emerging application as theranostic agents in several neurodegenerative diseases. The advantage of QDs as nanomedicine is due to their unique optical properties that provide high sensitivity, stability and selectivity at a nanoscale range. To offer renewed insight into current QD research and elucidate its promising application in Alzheimer's disease (AD) diagnosis and therapy. A comprehensive literature search was conducted in PubMed and Google Scholar databases that included the following search terms: 'quantum dots', 'blood-brain barrier', 'cytotoxicity', 'toxicity' and 'Alzheimer's disease'; PRISMA guidelines were adhered to. Thirty-four publications were selected to evaluate the ability of QDs to cross the blood-brain barrier, potential toxicity and current AD diagnostic and therapeutic applications. QD's unique optical properties and versatility to conjugate to various biomolecules, while maintaining a nanoscale size, render them a promising theranostic tool in AD.
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http://dx.doi.org/10.2217/nnm-2021-0104DOI Listing
June 2021

Plasma lipidome is dysregulated in Alzheimer's disease and is associated with disease risk genes.

Transl Psychiatry 2021 06 7;11(1):344. Epub 2021 Jun 7.

Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, Australia.

Lipidomics research could provide insights of pathobiological mechanisms in Alzheimer's disease. This study explores a battery of plasma lipids that can differentiate Alzheimer's disease (AD) patients from healthy controls and determines whether lipid profiles correlate with genetic risk for AD. AD plasma samples were collected from the Sydney Memory and Ageing Study (MAS) Sydney, Australia (aged range 75-97 years; 51.2% male). Untargeted lipidomics analysis was performed by liquid chromatography coupled-mass spectrometry (LC-MS/MS). We found that several lipid species from nine lipid classes, particularly sphingomyelins (SMs), cholesterol esters (ChEs), phosphatidylcholines (PCs), phosphatidylethanolamines (PIs), phosphatidylinositols (PIs), and triglycerides (TGs) are dysregulated in AD patients and may help discriminate them from healthy controls. However, when the lipid species were grouped together into lipid subgroups, only the DG group was significantly higher in AD. ChEs, SMs, and TGs resulted in good classification accuracy using the Glmnet algorithm (elastic net penalization for the generalized linear model [glm]) with more than 80% AUC. In general, group lipids and the lipid subclasses LPC and PE had less classification accuracy compared to the other subclasses. We also found significant increases in SMs, PIs, and the LPE/PE ratio in human U251 astroglioma cell lines exposed to pathophysiological concentrations of oligomeric Aβ. This suggests that oligomeric Aβ plays a contributory, if not causal role, in mediating changes in lipid profiles in AD that can be detected in the periphery. In addition, we evaluated the association of plasma lipid profiles with AD-related single nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of AD. We found that FERMT2 and MS4A6A showed a significantly differential association with lipids in all lipid classes across disease and control groups. ABCA7 had a differential association with more than half of the DG lipids (52.63%) and PI lipids (57.14%), respectively. Additionally, 43.4% of lipids in the SM class were differentially associated with CLU. More than 30% of lipids in ChE, PE, and TG classes had differential associations with separate genes (ChE-PICALM, SLC24A4, and SORL1; PE-CLU and CR1; TG-BINI) between AD and control group. These data may provide renewed insights into the pathobiology of AD and the feasibility of identifying individuals with greater AD risk.
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http://dx.doi.org/10.1038/s41398-021-01362-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180517PMC
June 2021

Nutrition Module design in Maintain Your Brain: an internet-based randomised controlled trial to prevent cognitive decline and dementia.

Br J Nutr 2021 Jun 3:1-10. Epub 2021 Jun 3.

Sydney School of Health Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.

The Maintain Your Brain (MYB) trial is one of the largest internet-delivered multidomain randomised controlled trial designed to target modifiable risk factors for dementia. It comprises four intervention modules: physical activity, nutrition, mental health and cognitive training. This paper explains the MYB Nutrition Module, which is a fully online intervention promoting the adoption of the 'traditional' Mediterranean Diet (MedDiet) pattern for those participants reporting dietary intake that does not indicate adherence to a Mediterranean-type cuisine or those who have chronic diseases/risk factors for dementia known to benefit from this type of diet. Participants who were eligible for the Nutrition Module were assigned to one of the three diet streams: Main, Malnutrition and Alcohol group, according to their medical history and adherence to the MedDiet at baseline. A short dietary questionnaire was administered weekly during the first 10 weeks and then monthly during the 3-year follow-up to monitor whether participants adopted or maintained the MedDiet pattern during the intervention. As the Nutrition Module is a fully online intervention, resources that promoted self-efficacy, self-management and process of change were important elements to be included in the module development. The Nutrition Module is unique in that it is able to individualise the dietary advice according to both the medical and dietary history of each participant; the results from this unique intervention will contribute substantively to the evidence that links the Mediterranean-type diet with cognitive function and the prevention of dementia and will increase our understanding of the benefits of a MedDiet in a Western country.
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http://dx.doi.org/10.1017/S0007114521001859DOI Listing
June 2021

Alzheimer's disease research progress in Australia: The Alzheimer's Association International Conference Satellite Symposium in Sydney.

Alzheimers Dement 2021 May 31. Epub 2021 May 31.

Departments of Neuroscience and Neurology, Center for Translational Research in Neurodegenerative Disease, Normal Fixel Center for Neurological Diseases, University of Florida College of Medicine, Gainesville, Florida, USA.

The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.
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http://dx.doi.org/10.1002/alz.12380DOI Listing
May 2021

Harmonizing neuropsychological assessment for mild neurocognitive disorders in Europe.

Alzheimers Dement 2021 May 13. Epub 2021 May 13.

Department of Medicine and Surgery, Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.

Introduction: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts.

Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives.

Results: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes.

Discussion: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.
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http://dx.doi.org/10.1002/alz.12365DOI Listing
May 2021

Investigating Olfactory Gene Variation and Odour Identification in Older Adults.

Genes (Basel) 2021 Apr 29;12(5). Epub 2021 Apr 29.

Centre for Healthy Brain Ageing, Faculty of Medicine, School of Psychiatry, University of New South Wales (UNSW), Sydney, NSW 2031, Australia.

Ageing is associated with a decrease in odour identification. Additionally, deficits in olfaction have been linked to age-related disease and mortality. Heritability studies suggest genetic variation contributes to olfactory identification. The olfactory receptor (OR) gene family is the largest in the human genome and responsible for overall odour identification. In this study, we sought to find olfactory gene family variants associated with individual and overall odour identification and to examine the relationships between polygenic risk scores (PRS) for olfactory-related phenotypes and olfaction. Participants were Caucasian older adults from the Sydney Memory and Ageing Study and the Older Australian Twins Study with genome-wide genotyping data ( = 1395, mean age = 75.52 ± 6.45). The Brief-Smell Identification Test (BSIT) was administered in both cohorts. PRS were calculated from independent GWAS summary statistics for Alzheimer's disease (AD), white matter hyperintensities (WMH), Parkinson's disease (PD), hippocampal volume and smoking. Associations with olfactory receptor genes ( = 967), previously identified candidate olfaction-related SNPs ( = 36) and different PRS with BSIT scores (total and individual smells) were examined. All of the relationships were analysed using generalised linear mixed models (GLMM), adjusted for age and sex. Genes with suggestive evidence for odour identification were found for 8 of the 12 BSIT items. Thirteen out of 36 candidate SNPs previously identified from the literature were suggestively associated with several individual BSIT items but not total score. PRS for smoking, WMH and PD were negatively associated with chocolate identification. This is the first study to conduct genetic analyses with individual odorant identification, which found suggestive olfactory-related genes and genetic variants for multiple individual BSIT odours. Replication in independent and larger cohorts is needed.
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http://dx.doi.org/10.3390/genes12050669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145954PMC
April 2021

Polygenic risk score analysis for amyotrophic lateral sclerosis leveraging cognitive performance, educational attainment and schizophrenia.

Eur J Hum Genet 2021 Apr 27. Epub 2021 Apr 27.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.

Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R) of the case-control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R) of 0.027 (P value = 4.6 × 10), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96-5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS.
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http://dx.doi.org/10.1038/s41431-021-00885-yDOI Listing
April 2021

The influence of rs53576 polymorphism in the oxytocin receptor () gene on empathy in healthy adults by subtype and ethnicity: a systematic review and meta-analysis.

Rev Neurosci 2021 Apr 23. Epub 2021 Apr 23.

Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia.

Empathy is essential for navigating complex social environments. Prior work has shown associations between rs53576, a single nucleotide polymorphism (SNP) located in the oxytocin receptor gene (), and generalized empathy. We undertook a systematic review and meta-analysis to assess the effects of rs53576 on subdomains of empathy, specifically cognitive empathy (CE) and affective empathy (AE), in healthy adults. Twenty cohorts of 8933 participants aged 18-98 were identified, including data from the Sydney Memory and Ageing Study, a cohort of older community adults. Meta-analyses found G homozygotes had greater generalized empathic abilities only in young to middle-aged adults. While meta-analyses of empathy subdomains yielded no significant overall effects, there were differential effects based on ethnicity. G homozygotes were associated with greater CE abilities in Asian cohorts (standardized mean difference; SMD: 0.09 [2.8·10-0.18]), and greater AE performance in European cohorts [SMD: 0.12 (0.04-0.21)]. The current literature highlights a need for further work that distinguishes between genetic and ethnocultural effects and explores effects of advanced age on this relationship.
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http://dx.doi.org/10.1515/revneuro-2021-0038DOI Listing
April 2021

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.

Genome Biol 2021 Mar 26;22(1):90. Epub 2021 Mar 26.

Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4019, Australia.

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.

Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.

Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
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http://dx.doi.org/10.1186/s13059-021-02275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004462PMC
March 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs.

Hum Brain Mapp 2021 Feb 21. Epub 2021 Feb 21.

Center for Neuroimaging, Genetics and Genomics, School of Psychology, NUI Galway, Galway, Ireland.

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.
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http://dx.doi.org/10.1002/hbm.25354DOI Listing
February 2021

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 17. Epub 2021 Feb 17.

Laboratory of Psychiatric Neuroimaging, Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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http://dx.doi.org/10.1002/hbm.25364DOI Listing
February 2021

The Contribution of Cerebral Vascular Neuropathology to Mild Stage of Alzheimer's Dementia Using the NACC Database.

Curr Alzheimer Res 2020 ;17(13):1167-1176

Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, Australia.

Background: The interaction between cerebral vessel disease (CVD) pathology and Alzheimer's disease (AD) pathology in the development of dementia is controversial. We examined the association of cerebral vascular neuropathology and cerebrovascular risk factors with the mild stage of Alzheimer's dementia and cognitive function.

Methods: This cross-sectional study included men and women aged 60 years or over who had yearly clinical assessments and had agreed to brain autopsy at the time of death, and who contributed to data stored at the National Alzheimer's Coordinating Center (NACC) in the USA. Cognitively normal and impaired subjects with presumptive aetiology of AD, including mild cognitive impairment (ADMCI) and dementia (Alzheimer's dementia), and with complete neuropathological data, were included in our analyses. We used neuropsychological data proximate to death to create summary measures of global cognition and cognitive domains. Systematic neuropathological assessments documenting the severity of cerebral vascular pathology were included. Logistic and linear regression analyses corrected for age at death, sex and Lewy body pathology were used to examine associations of vessel disease with the severity of Alzheimer's disease dementia, and cognitive function, respectively.

Results: No significant relationship was observed between late-life risk factors and Alzheimer's dementia. The severity of arteriosclerosis and presence of global infarcts/lacunes were related to mild Alzheimer's dementia (B=0.423, p<0.001; B=0.366, p=0.026), and the effects were significant after adjusting for neuritic plaques and neurofibrillary tangles (B=0.385, p<0.001; B=0.63, p=0.001). When vascular brain injuries were subdivided into old and acute/subacute types, we found that old microinfarcts and old microbleeds were associated with mild Alzheimer's dementia (B=0.754, p=0.007; B=2.331, p=0.032). The old microinfarcts remained significantly associated with mild Alzheimer's dementia after correcting AD pathologies (B=1.31, p<0.001). In addition, the number of microinfarcts in the cerebral cortex had a significant relation with mild Alzheimer's dementia, whether or not the data were corrected for AD pathologies (B=0.616, p=0.016; B=0.884, p=0.005). Atherosclerosis, arteriosclerosis and white matter rarefaction were found to be significantly associated with faster progression of Alzheimer's dementia (B=0.068, p=0.001; B=0.046, p=0.016, B=0.081, p=0.037), but white matter rarefaction no longer had a significant effect after adjusting for AD pathologies. We also found that the severity of atherosclerosis was related to impairment in processing speed (β=-0.112, p=0.006) and executive function (β=-0.092, p=0.023). Arteriosclerosis was significantly associated with language (β=-0.103, p=0.011) and global cognition (β=-0.098, p=0.016) deficits.

Conclusion: Our study found the significant relation of global, old, acute/subacute and regional cerebral vascular pathologies, but not white matter rarefaction, to the onset and severity of Alzheimer's dementia. We also showed that late-life risk factors were found to have no relation with Alzheimer's dementia, and the increased risk of dementia with APOE ε4 is not mediated by CVD. The best interpretation of these findings is that CVD has a potential additive effect with AD pathologies in the development and progression of what is clinically diagnosed as Alzheimer's dementia.
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http://dx.doi.org/10.2174/1567205018666210212160902DOI Listing
January 2020

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 11. Epub 2021 Feb 11.

Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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http://dx.doi.org/10.1002/hbm.25320DOI Listing
February 2021

Organisational aspects and assessment practices of Australian memory clinics: an Australian Dementia Network (ADNeT) Survey.

BMJ Open 2021 02 9;11(2):e038624. Epub 2021 Feb 9.

Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.

Objectives: Conducting a national survey of clinicians and administrators from specialised dementia assessment services (memory clinics) in Australia to examine their current organisational aspects and assessment procedures and inform clinical tool harmonisation as part of the Australian Dementia Network-memory clinics project.

Design: A cross-sectional survey.

Setting: Public and private memory clinics across Australia.

Participants: 150 individual clinicians completed the survey between May and August 2019. Responses could be given anonymously. Most clinics were publicly funded services (83.2%) and in metropolitan regions (70.9%).

Outcome Measures: Descriptive data on organisational aspects of memory clinics (eg, waiting times, staffing); the three most commonly used assessment tools per assessment type (eg, self-report) and cognitive domain (eg, attention).

Results: Since the last national survey in 2009, the number of memory clinics across Australia has increased substantially but considerable variability has remained with respect to funding structure, staffing and assessment procedures. The average clinic employed 2.4 effective full-time staff (range 0.14-14.0). The reported waiting time for an initial assessment ranged from 1 week to 12 months with a median of 7 weeks. While most clinics (97%) offered follow-up assessments for their clients, only a few (31%) offered any form of cognitive intervention. We identified over 100 different cognitive assessment tools that were used at least 'sometimes', with widespread use of well-established core screening tools and a subset of common neuropsychological tests.

Conclusion: This paper presents a current snapshot of Australian memory clinics, showing considerable heterogeneity with some common core elements. These results will inform the development of national memory clinic guidelines. Furthermore, our data make a valuable contribution to the international comparison of clinical practice standards and advocate for greater harmonisation to ensure high-quality dementia care.
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http://dx.doi.org/10.1136/bmjopen-2020-038624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875292PMC
February 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 Apr;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Association of Dilated Perivascular Spaces With Cognitive Decline and Incident Dementia.

Neurology 2021 03 27;96(11):e1501-e1511. Epub 2021 Jan 27.

From the Centre for Healthy Brain Ageing (CHeBA) (M.P., J.D.C., B.C.P.L., W.W., N.A.K., S.M., J.T., B.D., H.B., P.S.S.), School of Psychiatry, UNSW Medicine, University of New South Wales; Neuropsychiatric Institute (P.S.S.), The Prince of Wales Hospital (L.D., B.D., H.B.) ; and Department of Developmental Disability Neuropsychiatry, School of Psychiatry (J.T.), UNSW Sydney, Australia.

Objective: To determine whether severe perivascular space (PVS) dilation is associated with longitudinal cognitive decline and incident dementia over 4 and 8 years, respectively, we analyzed data from a prospective cohort study.

Methods: A total of 414 community-dwelling older adults aged 72-92 years were assessed at baseline and biennially for up to 8 years, with cognitive assessments, consensus dementia diagnoses, and 3T MRI. The numbers of PVS in 2 representative slices in the basal ganglia (BG) and centrum semiovale (CSO) were counted and severe PVS pathology defined as the top quartile. The effects of severe PVS pathology in either region or both regions and those with severe BG PVS and severe CSO PVS were examined. White matter hyperintensity volume, cerebral microbleed number, and lacune number were calculated.

Results: Participants with severe PVS pathology in both regions or in the CSO alone had greater decline in global cognition over 4 years, even after adjustment for the presence of other small vessel disease neuroimaging markers. The presence of severe PVS pathology in both regions was an independent predictor of dementia across 8 years (odds ratio 2.91, 95% confidence interval 1.43-5.95, = 0.003). The presence of severe PVS pathology in all groups examined was associated with greater dementia risk at either year 4 or 6.

Conclusions: Severe PVS pathology is a marker for increased risk of cognitive decline and dementia, independent of other small vessel disease markers. The differential cognitive associations for BG and CSO PVS may represent differences in their underlying pathology.
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http://dx.doi.org/10.1212/WNL.0000000000011537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032377PMC
March 2021

Hypertension and Alzheimer's disease: is the picture any clearer?

Curr Opin Psychiatry 2021 03;34(2):142-148

Faculty of Medicine, University of New South Wales.

Purpose Of Review: The relationship between hypertension and Alzheimer's disease (AD) is complex and varies across the lifespan. Studies have suggested that midlife hypertension is a risk factor for AD, although studies of late life hypertension have suggested that it either has no effect or a weak protective effect.

Recent Findings: Animal models of induced and spontaneous hypertension have found that AD pathological change (β-amyloid plaques and tau tangles) occurs within weeks of a hypertensive insult. Human imaging and autopsy studies indicate that midlife and late life hypertension are associated with increased AD pathological change. Meta-analyses of longitudinal studies indicate that midlife rather than late life hypertension is a risk factor for AD. New areas of research have suggested that rather than mean blood pressure (BP), it is the negative BP trajectories or the variability of BP that contributes to AD. In a number of meta-analyses of antihypertensive medications and their effect on AD, there were weak associations between improved AD outcomes and treatment.

Summary: The combined analysis of animal, human clinical/pathological, epidemiological and drug trial data indicates that hypertension increases the risk of AD and treatment of hypertension may be an appropriate preventive measure.
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http://dx.doi.org/10.1097/YCO.0000000000000684DOI Listing
March 2021

Is Healthy Neuroticism Associated with Health Behaviors? A Coordinated Integrative Data Analysis.

Collabra Psychol 2020 21;6(1). Epub 2020 Jul 21.

Humboldt University, Berlin Germany, Department of Psychology.

Current literature suggests that neuroticism is positively associated with maladaptive life choices, likelihood of disease, and mortality. However, recent research has identified circumstances under which neuroticism is associated with positive outcomes. The current project examined whether "healthy neuroticism", defined as the interaction of neuroticism and conscientiousness, was associated with the following health behaviors: smoking, alcohol consumption, and physical activity. Using a pre-registered multi-study coordinated integrative data analysis (IDA) approach, we investigated whether "healthy neuroticism" predicted the odds of engaging in each of the aforementioned activities. Each study estimated identical models, using the same covariates and data transformations, enabling optimal comparability of results. These results were then meta-analyzed in order to estimate an average (N-weighted) effect and to ascertain the extent of heterogeneity in the effects. Overall, these results suggest that neuroticism alone was not related to health behaviors, while individuals higher in conscientiousness were less likely to be smokers or drinkers, and more likely to engage in physical activity. In terms of the healthy neuroticism interaction of neuroticism and conscientiousness, significant interactions for smoking and physical activity suggest that the association between neuroticism and health behaviors was smaller among those high in conscientiousness. These findings lend credence to the idea that healthy neuroticism may be linked to certain health behaviors and that these effects are generalizable across several heterogeneous samples.
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http://dx.doi.org/10.1525/collabra.266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751766PMC
July 2020

Is Healthy Neuroticism Associated with Longevity? A Coordinated Integrative Data Analysis.

Collabra Psychol 2020 21;6(1). Epub 2020 Jul 21.

Northwestern University, Department of Medical Social Sciences, Chicago, IL, USA.

Individual differences in the Big Five personality traits have emerged as predictors of health and longevity. Although there are robust protective effects for higher levels of conscientiousness, results are mixed for other personality traits. In particular, higher levels of neuroticism have significantly predicted an increased risk of mortality, no-risk at all, and even a reduced risk of dying. The current study hypothesizes that one potential reason for the discrepancy in these findings for neuroticism is that interactions among neuroticism and other key personality traits have largely been ignored. Thus, in the current study we focus on testing whether the personality traits neuroticism and conscientiousness interact to predict mortality. Specifically, we borrow from recent evidence of "healthy neuroticism" to explore whether higher levels of neuroticism are only a risk factor for increased mortality risk when conscientiousness levels are low. We conducted a pre-registered integrative data analysis using 12 different cohort studies (total = 44,702). Although a consistent pattern emerged of higher levels of conscientiousness predicting a reduced hazard of dying, neuroticism did not show a consistent pattern of prediction. Moreover, no study provided statistical evidence of a neuroticism by conscientiousness interaction. The current findings do not support the idea that the combination of high conscientiousness and high neuroticism can be protective for longevity. Future work is needed to explore different protective factors that may buffer the negative effects of higher levels of neuroticism on health, as well as other behaviors and outcomes that may support the construct of healthy neuroticism.
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http://dx.doi.org/10.1525/collabra.268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751763PMC
July 2020

Estimating prevalence of subjective cognitive decline in and across international cohort studies of aging: a COSMIC study.

Alzheimers Res Ther 2020 12 18;12(1):167. Epub 2020 Dec 18.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Background: Subjective cognitive decline (SCD) is recognized as a risk stage for Alzheimer's disease (AD) and other dementias, but its prevalence is not well known. We aimed to use uniform criteria to better estimate SCD prevalence across international cohorts.

Methods: We combined individual participant data for 16 cohorts from 15 countries (members of the COSMIC consortium) and used qualitative and quantitative (Item Response Theory/IRT) harmonization techniques to estimate SCD prevalence.

Results: The sample comprised 39,387 cognitively unimpaired individuals above age 60. The prevalence of SCD across studies was around one quarter with both qualitative harmonization/QH (23.8%, 95%CI = 23.3-24.4%) and IRT (25.6%, 95%CI = 25.1-26.1%); however, prevalence estimates varied largely between studies (QH 6.1%, 95%CI = 5.1-7.0%, to 52.7%, 95%CI = 47.4-58.0%; IRT: 7.8%, 95%CI = 6.8-8.9%, to 52.7%, 95%CI = 47.4-58.0%). Across studies, SCD prevalence was higher in men than women, in lower levels of education, in Asian and Black African people compared to White people, in lower- and middle-income countries compared to high-income countries, and in studies conducted in later decades.

Conclusions: SCD is frequent in old age. Having a quarter of older individuals with SCD warrants further investigation of its significance, as a risk stage for AD and other dementias, and of ways to help individuals with SCD who seek medical advice. Moreover, a standardized instrument to measure SCD is needed to overcome the measurement variability currently dominant in the field.
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http://dx.doi.org/10.1186/s13195-020-00734-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749505PMC
December 2020

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Associations between Alzheimer's disease polygenic risk scores and hippocampal subfield volumes in 17,161 UK Biobank participants.

Neurobiol Aging 2021 02 6;98:108-115. Epub 2020 Nov 6.

Centre for Healthy Brain Aging (CHeBA), School of Psychiatry, University of New South Wales Medicine, Kensington, Sydney, New South Wales, Australia; Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Randwick, Sydney, New South Wales, Australia.

Hippocampal volume is an important biomarker of Alzheimer's disease (AD), and genetic risk of AD is associated with hippocampal atrophy. However, the hippocampus is not a uniform structure and has a number of subfields, the associations of which with age, sex, and polygenic risk score for AD (PRS) have been inadequately investigated. We examined these associations in 17,161 cognitively normal UK Biobank participants (44-80 years). Age was negatively associated with all the hippocampal subfield volumes and females had smaller volumes than men. Higher PRS was associated with lower volumes in the bilateral whole hippocampus, hippocampal-amygdala-transition-area, and hippocampal tail; right subiculum; left cornu ammonis 1, cornu ammonis 4, molecular layer, and granule cell layer of dentate gyrus. Older individuals (median age 63 years, n = 8984) showed greater subfield vulnerability to high PRS compared to the younger group (n = 8177), but the effect did not differ by sex. The pattern of subfield involvement in relation to the PRS in community dwelling healthy individuals sheds additional light on the pathogenesis of AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.11.002DOI Listing
February 2021

Sensorimotor, Cognitive, and Affective Functions Contribute to the Prediction of Falls in Old Age and Neurologic Disorders: An Observational Study.

Arch Phys Med Rehabil 2021 05 27;102(5):874-880. Epub 2020 Nov 27.

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, University of New South Wales, Sydney, Australia; School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia. Electronic address:

Objective: To determine whether impairments across cognitive and affective domains provide additional information to sensorimotor deficits for fall prediction among various populations.

Design: We pooled data from 5 studies for this observational analysis of prospective falls.

Setting: Community or low-level care facility.

Participants: Older people (N=1090; 74.0±9.4y; 579 female); 500 neurologically intact (NI) older people and 3 groups with neurologic disorders (cognitive impairment, n=174; multiple sclerosis (MS), n=111; Parkinson disease, n=305).

Interventions: None.

Main Outcome Measures: Sensorimotor function was assessed with the Physiological Profile Assessment, cognitive function with tests of executive function, affect with questionnaires of depression, and concern about falling with falls efficacy questionnaires. These variables were associated with fall incidence rates, obtained prospectively over 6-12 months.

Results: Poorer sensorimotor function was associated with falls (incidence rate ratio [95% CI], 1.46 [1.28-1.66]). Impaired executive function was the strongest predictor of falls overall (2.91 [2.27-3.73]), followed by depressive symptoms (2.07 [1.56-2.75]) and concern about falling (2.02 [1.61-2.55]). Associations were similar among groups, except for a weaker relationship with executive impairment in NI persons and a stronger relationship with concern about falling in persons with MS. Multivariable analyses showed that executive impairment, poorer sensorimotor performance, depressive symptoms, and concern about falling were independently associated with falls.

Conclusions: Deficits in cognition (executive function) and affect (depressive symptoms) and concern about falling are as important as sensorimotor function for fall prediction. These domains should be included in fall risk assessments for older people and clinical groups.
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http://dx.doi.org/10.1016/j.apmr.2020.10.134DOI Listing
May 2021

Does Antihypertensive Use Moderate the Effect of Blood Pressure on Cognitive Decline in Older People?

J Gerontol A Biol Sci Med Sci 2021 Apr;76(5):859-866

Faculty of Medicine, University of New South Wales, Sydney, Australia.

Background: While midlife hypertension is deleterious, late-life hypertension has been associated with better cognitive outcomes in several studies. Many questions remain, including the relative benefit or harm of a blood pressure (BP) target and antihypertensive therapy of <120 in very old individuals.

Methods: The Sydney Memory and Aging Study (n = 1015) comprises a cohort of 70- to 90-year-olds, who were followed biennially for 8 years. Global cognition was assessed with a battery of 10 neuropsychological tests. Blood pressure was measured at Waves 1 and 2 and classified into 3 systolic groupings: group 1 (≤120 mmHg), group 2 (121-140 mmHg), and group 3 (>140 mmHg). Multiple regression, linear mixed modeling, and Cox regression examined the effect of BP and antihypertensives.

Results: There were no overall significant differences in global cognition or dementia between the disparate BP groups. However, in those not taking antihypertensives, the systolic BP (SBP) > 140 mmHg group had a significantly worse global cognitive trajectory compared to SBP ≤ 120 mmHg (b = -0.067, 95% CI [-0.129, -0.006], p = .030). Within the SBP ≤ 120 mmHg group those taking antihypertensives had significantly worse global cognition trajectories compared to those not taking antihypertensives even when controlling for past history of hypertension (b = -0.077, 95% CI [-0.147, -0.007], p = .030).

Conclusions: Untreated hypertension in old age is related to worse global cognitive decline. However, ongoing treatment at new recommendations of lower SBP targets may be related to poorer cognitive decline and should be considered carefully in older populations.
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http://dx.doi.org/10.1093/gerona/glaa232DOI Listing
April 2021
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