Publications by authors named "Bruno Vellas"

545 Publications

Cross-sectional and longitudinal interaction effects of physical activity and APOE-ε4 on white matter integrity in older adults: The MAPT study.

Maturitas 2021 Oct 30;152:10-19. Epub 2021 Jun 30.

Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalo-Universitaire de Toulouse, 37 allées Jules Guesdes, 31000 Toulouse, France; UMR INSERM, 1027 University of Toulouse III, Toulouse, France, Faculté de Médecine, 37 allées Jules Guesde 31000 Toulouse, France.

Background: Physical activity (PA) has been shown to modulate the detrimental effect of carrying the apolipoprotein-E epsilon 4 (APOE-ɛ4) allele on brain structure. However, the current literature mainly provides cross-sectional data, and longitudinal studies investigating the interaction between genotype and PA on white matter (WM) integrity are lacking.

Objectives: We investigated both the cross-sectional and the longitudinal interactive effects of APOE-ɛ4 and PA on WM integrity in older adults.

Methods: Fractional anisotropy, as well as axial, radial, and mean diffusivity, extracted from brain diffusion tensor imaging (DTI) were used to assess WM integrity in non-demented older adults. They were categorized according to their APOE-ɛ4 status (carriers vs. non-carriers), and their level of total (TPA), moderate to vigorous (MVPA) and light (LPA) PA were assessed using a questionnaire. Mixed model regressions were performed to test the interactive effects of APOE-ɛ4 status and PA on WM integrity at baseline and over a 3-year follow-up.

Results: 190 subjects with a mean age 74.5 years (SD = 3.9) were examined. Despite a lack of cross-sectional associations, sensitivity analyses revealed that, in the carrier group only, higher levels of LPA, but not MVPA, were mainly associated with higher axial and mean diffusivity values over time.

Conclusions: This study partially confirms the previously reported interactive associations between PA, APOE-ɛ4 genotype and WM integrity, supporting the hypothesis that PA may protect against fiber loss in WM tracts containing crossing fibers. Future studies assessing sedentary behaviors in addition to PA could bring relevant contributions to the field. CLINICAL TRIAL REGISTRATION NUMBER FROM CLINICALTRIALS.GOV: NCT00672685.
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http://dx.doi.org/10.1016/j.maturitas.2021.06.010DOI Listing
October 2021

Multidomain interventions: state-of-the-art and future directions for protocols to implement precision dementia risk reduction. A user manual for Brain Health Services-part 4 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):171. Epub 2021 Oct 11.

Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.

Although prevention of dementia and late-life cognitive decline is a major public health priority, there are currently no generally established prevention strategies or operational models for implementing such strategies into practice. This article is a narrative review of available evidence from multidomain dementia prevention trials targeting several risk factors and disease mechanisms simultaneously, in individuals without dementia at baseline. Based on the findings, we formulate recommendations for implementing precision risk reduction strategies into new services called Brain Health Services. A literature search was conducted using medical databases (MEDLINE via PubMed and SCOPUS) to select relevant studies: non-pharmacological multidomain interventions (i.e., combining two or more intervention domains), target population including individuals without dementia, and primary outcomes including cognitive/functional performance changes and/or incident cognitive impairment or dementia. Further literature searches covered the following topics: sub-group analyses assessing potential modifiers for the intervention effect on cognition in the multidomain prevention trials, dementia risk scores used as surrogate outcomes in multidomain prevention trials, dementia risk scores in relation to brain pathology markers, and cardiovascular risk scores in relation to dementia. Multidomain intervention studies conducted so far appear to have mixed results and substantial variability in target populations, format and intensity of interventions, choice of control conditions, and outcome measures. Most trials were conducted in high-income countries. The differences in design between the larger, longer-term trials that met vs. did not meet their primary outcomes suggest that multidomain intervention effectiveness may be dependent on a precision prevention approach, i.e., successfully identifying the at-risk groups who are most likely to benefit. One such successful trial has already developed an operational model for implementing the intervention into practice. Evidence on the efficacy of risk reduction interventions is promising, but not yet conclusive. More long-term multidomain randomized controlled trials are needed to fill the current evidence gaps, especially concerning low- and middle-income countries and integration of dementia prevention with existing cerebrovascular prevention programs. A precision risk reduction approach may be most effective for dementia prevention. Such an approach could be implemented in Brain Health Services.
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http://dx.doi.org/10.1186/s13195-021-00875-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507202PMC
October 2021

Brain Health Services: organization, structure, and challenges for implementation. A user manual for Brain Health Services-part 1 of 6.

Alzheimers Res Ther 2021 Oct 11;13(1):168. Epub 2021 Oct 11.

Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland.

Dementia has a devastating impact on the quality of life of patients and families and comes with a huge cost to society. Dementia prevention is considered a public health priority by the World Health Organization. Delaying the onset of dementia by treating associated risk factors will bring huge individual and societal benefit. Empirical evidence suggests that, in higher-income countries, dementia incidence is decreasing as a result of healthier lifestyles. This observation supports the notion that preventing dementia is possible and that a certain degree of prevention is already in action. Further reduction of dementia incidence through deliberate prevention plans is needed to counteract its growing prevalence due to increasing life expectancy.An increasing number of individuals with normal cognitive performance seek help in the current memory clinics asking an evaluation of their dementia risk, preventive interventions, or interventions to ameliorate their cognitive performance. Consistent evidence suggests that some of these individuals are indeed at increased risk of dementia. This new health demand asks for a shift of target population, from patients with cognitive impairment to worried but cognitively unimpaired individuals. However, current memory clinics do not have the programs and protocols in place to deal with this new population.We envision the development of new services, henceforth called Brain Health Services, devoted to respond to demands from cognitively unimpaired individuals concerned about their risk of dementia. The missions of Brain Health Services will be (i) dementia risk profiling, (ii) dementia risk communication, (iii) dementia risk reduction, and (iv) cognitive enhancement. In this paper, we present the organizational and structural challenges associated with the set-up of Brain Health Services.
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http://dx.doi.org/10.1186/s13195-021-00827-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507194PMC
October 2021

Predictors of drug prescription in nursing home residents: results from the INCUR study.

Intern Emerg Med 2021 Sep 21. Epub 2021 Sep 21.

Geriatric Unit, Fondazione IRCCS Istituti Clinici Scientifici Maugeri, Via Camaldoli 64, 20138, Milan, Italy.

Polypharmacy represents a major clinical and public health issue in older persons. We aimed to measure the prevalence of polypharmacy, and the main predictors of drug prescription in nursing home residents. Post hoc analyses of the "Incidence of pNeumonia and related ConseqUences in nursing home Residents" (INCUR) study were conducted. Polypharmacy was defined as the prescription of 5 or more drugs. A frailty index (FI) was computed according to the model proposed by Rockwood and Mitnitski using 36 health deficits, including diseases, signs, symptoms, and disabilities. Linear regression models were performed to identify the main predictors of the number of prescribed drugs. The INCUR study enrolled 800 patients (mean [SD] age 86.2 [4.1] years, 74.1% women). The mean number of medications prescribed at the baseline was 8.5 (SD 4.1). Prevalence of polypharmacy was found 86.4%. The mean FI was 0.38 (SD 0.10). A fully adjusted linear multivariate regression model found an inverse and independent association between age and number of prescribed drugs (beta - 0.07, 95% CI - 0.13, - 0.02; p = 0.005). Conversely, the FI was independently and positively associated with the number of medications (beta 4.73, 95% CI 1.17, 8.29; p = 0.009). The prevalence of polypharmacy is high among older persons living in nursing home. Age and FI are significantly associated with the number of drugs. The number of prescribed drugs tends to decrease with age, whereas a direct association with frailty is reported.
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http://dx.doi.org/10.1007/s11739-021-02841-6DOI Listing
September 2021

Cognitive decline as an outcome and marker of progression toward dementia, in early preventive trials.

Alzheimers Dement 2021 Sep 5. Epub 2021 Sep 5.

INSERM-University of Toulouse, UMR1027, Toulouse, France.

Introduction: Recent Food and Drug Administration guidance endorses cognitive assessment as a possible primary endpoint for early trials for Alzheimer's disease but emphasizes the need for certainty regarding the relationship with progression to dementia.

Methods: We compared the validity of the 2-year change (Y0-Y2) of 11 markers of neuropsychological and functional abilities for the prediction of incident dementia over the following 3 years (Y2-Y5), in 860 subjects aged 70 years or older, who consulted for memory loss and were included in the "GuidAge" prevention trial.

Results: The Free and Cued Selective Reminding Test-Free Recall (FCSRT-FR) score showed the most predictive 2-year change (area under the curve = 0.72 95% confidence interval = 0.64;0.81). Changes in other subscores of the FCSRT, verbal fluencies tasks, and composite cognitive score were also significantly predictive. Conversely, 2-year change of Mini-Mental State Examination, Trail Making test (TMT)-A, TMT-B, Clinical Dementia Rating Sum of Boxes, and Instrumental Activities of Daily Living scores did not significantly predict occurrence of dementia.

Conclusion: The FCSRT, the Fluency Task, and the composite cognitive score appear to be good cognitive markers of progression toward dementia in early prevention trials.
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http://dx.doi.org/10.1002/alz.12431DOI Listing
September 2021

Screening for intrinsic capacity impairments as markers of increased risk of frailty and disability in the context of integrated care for older people: Secondary analysis of MAPT.

Maturitas 2021 Aug 4;150:1-6. Epub 2021 Jun 4.

Gerontopole of Toulouse, Institute of Aging, Toulouse University Hospital (CHU Toulouse), Toulouse, France; UPS/Inserm UMR1027, University of Toulouse III, Toulouse, France. Electronic address:

Aim: This longitudinal secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) aimed to test whether the Integrated Care for Older People (ICOPE) Step 1 screening tool is able to identify people at risk of developing frailty and disability in basic (ADL) and instrumental (IADL) activities of daily living among community-dwelling older adults.

Participants And Setting: Seven hundred and fifty-nine (n = 759) non-demented participants of the MAPT aged 70-89 years were assessed in memory clinics in France between 2008 and 2013.

Methods: We measured six intrinsic capacity (IC) impairments, adapted from the ICOPE screening tool. We used Cox models to estimate the adjusted hazard ratios of incident frailty and IADL/ADL disability. Incident frailty was defined by Fried's phenotype, and incident disability was measured according to Lawton and Katz for IADLs and ADLs.

Results: Limited mobility (HR= 2.97, 95%CI= 1.85-4.76), depressive symptoms (HR= 2.07, 95%CI= 1.03-4.19), and visual impairment (HR= 1.70, 95%CI 1.01-2.86) were associated with a higher incidence of frailty over 5 years. Each additional IC condition demonstrated a positive association with a higher risk of incident frailty, IADL, ADL disability, with risk increased by 47%, 27%, and 23% over 5 years, respectively.

Conclusion: Screening for IC impairments identifies older adults at higher risk of incident frailty and incident IADL/ADL disability. It is relevant to screen for these impairments together because the risk of frailty and disability increases with each additional one. ClinicalTrials.gov identifier: NCT00672685.
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http://dx.doi.org/10.1016/j.maturitas.2021.05.011DOI Listing
August 2021

Plasma neurofilament light chain is associated with cognitive decline in non-dementia older adults.

Sci Rep 2021 06 28;11(1):13394. Epub 2021 Jun 28.

Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalo-Universitaire de Toulouse, 37 Allées Jules Guesdes, 31000, Toulouse, France.

Neurofilament light chain (NfL) has been associated with cognitive status in multiple neurodegenerative conditions. Studies about plasma NfL and cognitive decline in older adults are still limited. 504 older adults (median age 75 years) who expressed memory complaints were selected from the Multidomain Alzheimer's Preventive Trial (MAPT) and were classified as normal cognition (NC) or mild cognitive impairment (MCI). Cognitive functions were measured as mini mental state examination (MMSE) and composite cognitive score (CCS) over a 4-year period. Plasma NfL was measured at the first or the second year of the MAPT. Mixed-effects linear models were performed to evaluate cross-sectional and longitudinal associations. In the whole population, higher plasma NfL was cross-sectionally associated with lower cognitive functions (MMSE: β =  - 0.007, 95% CI [- 0.013, - 0.001]; CCS: β =  - 0.003, 95% CI [- 0.006, - 0.001]). In adults with MCI, but not NC, higher plasma NfL was associated with lower CCS at the cross-sectional level (β =  - 0.003, 95% CI [- 0.005, - 0.0002]). The upper quartile NfL group further demonstrated more over time decline in CCS (β =  - 0.07, 95% CI [- 0.12, - 0.01]) under the MCI status. Plasma NfL can be a promising biomarker of progressive cognition decline in older adults with MCI.
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http://dx.doi.org/10.1038/s41598-021-91038-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238930PMC
June 2021

Agitation in Alzheimer's disease: Novel outcome measures reflecting the International Psychogeriatric Association (IPA) agitation criteria.

Alzheimers Dement 2021 Jun 16. Epub 2021 Jun 16.

Gerontopole Alzheimer Clinical and Research Center, University Hospital of Toulouse (CHU Toulouse), URM 1295, CERPOP, Inserm, UPS, Université de Toulouse, Toulouse, France.

Introduction: The 2017 European Union-North American Clinical Trials in Alzheimer's Disease Task Force recommended development of clinician-rated primary outcome measures for Alzheimer's disease (AD) agitation trials, incorporating International Psychogeriatric Association (IPA) criteria.

Methods: In a modified Delphi process, Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory-Clinician (NPI-C) items were mapped to IPA agitation domains generating novel instruments, CMAI-IPA and NPI-C-IPA. Validation in the Agitation and Aggression AD Cohort (A3C) assessed minimal clinically important differences (MCIDs), change sensitivity, and predictive validity.

Results: MCID was -17 (odds ratio [OR] = 14.9, 95% confidence interval [CI] = 6.8-32.6) for CMAI; -5 (OR = 9.3, 95% CI = 4.0-21.2) for CMAI-IPA; -3 (OR = 11.9, 95% CI = 4.1-34.8) for NPI-C-A+A; and -5 (OR = 7.8, 95% CI = 3.4-17.9) for NPI-C-IPA at 3 months. Areas under the curve suggested no scale better predicted global clinician ratings. Sensitivity to change for all measures was high.

Conclusion: Internal consistency and reliability analyses demonstrated better accuracy for the NPI-C-IPA than for the CMAI-IPA and can be used for agitation clinical trial inclusion, and for response to intervention.
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http://dx.doi.org/10.1002/alz.12335DOI Listing
June 2021

RETRACTED: Development and Implementation of the Advanced Practice Nurse Worldwide with an Interest in Geriatric Care.

J Am Med Dir Assoc 2021 Jul 8;22(7):1563. Epub 2021 Jun 8.

Gérontopôle, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; Inserm UMR1027, Université de Toulouse III Paul Sabatier, Toulouse, France.

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http://dx.doi.org/10.1016/j.jamda.2021.06.003DOI Listing
July 2021

RETRACTED: Association Between Frailty and Cognitive Impairment: Cross-Sectional Data From Toulouse Frailty Day Hospital.

J Am Med Dir Assoc 2021 Jul 8;22(7):1564. Epub 2021 Jun 8.

Gérontopôle, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; Inserm UMR1027, Université de Toulouse III Paul Sabatier, Toulouse, France.

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http://dx.doi.org/10.1016/j.jamda.2021.06.004DOI Listing
July 2021

Neuroimaging correlates of persistent fatigue in older adults: A secondary analysis from the Multidomain Alzheimer Preventive Trial (MAPT) trial.

Aging Ment Health 2021 Jun 4:1-7. Epub 2021 Jun 4.

Gerontopole of Toulouse, Toulouse University Hospital (CHU Toulouse), Toulouse, France.

Objectives: Fatigue has been suggested as a marker of biological aging. It seems plausible that this symptom might be associated with changes in brain health. The objective of this study was to examine the associations between persistent fatigue and neuroimaging correlates in a non-disease-specific population of community-dwelling older adults.

Methods: We performed a cross-sectional analysis using data from The Multidomain Alzheimer Preventive Trial (MAPT). We included 458 subjects. Persistent fatigue was defined as meeting exhaustion criterion of Fried frailty phenotype in two consecutive clinical visits six months apart between study baseline and one year. Brain imaging correlates, assessed by magnetic resonance imaging (MRI), were the outcomes. The associations between persistent fatigue and brain correlates were explored using mixed model linear regressions with random effect at the center level.

Results: The mean age of the participants was 74.8 ± 4 years old, and 63% of the subjects were women. Forty-seven participants (10%) exhibited a persistent fatigue profile. People with persistent fatigue were older compared to subjects without persistent fatigue (76.2 years ± 4.3 vs.74.7 ± 3.9  = 0.009). Persistent fatigue was associated with higher white matter hyperintensity volume in the fully adjusted analysis. We did not find any cross-sectional association between persistent fatigue and sub-cortical volumes and global and regional cortical thickness.

Conclusion: Persistent fatigue was cross-sectionnally associated with higher white matter hyperintensity volume in older adults. Further longitudinal studies, using an assessment tool specifically designed and validated for measuring fatigue, are needed to confirm our findings.
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http://dx.doi.org/10.1080/13607863.2021.1932737DOI Listing
June 2021

[The digital tool for the prevention of dependency in the elderly].

Soins Gerontol 2021 Mar-Apr;26(148):20-23. Epub 2021 Feb 2.

Plateau ambulatoire de gériatrie, cité de la Santé, place Lange, TSA 60033, 31059 Toulouse cedex 9, France. Electronic address:

Dependency care is a real public health issue. The lengthening of life expectancy and the increase in polypathologies require health policies that are as close as possible to the needs of the elderly. The World Health Organisation has set up a program to encourage healthy ageing. Based on this program, the Toulouse gerontopôle has developed digital tools for the prevention, evaluation, monitoring and management of ageing in order to detect and monitor 200,000 elderly people in Occitania within five years.
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http://dx.doi.org/10.1016/j.sger.2021.01.007DOI Listing
April 2021

Associations Between Physical Activity, Blood-Based Biomarkers of Neurodegeneration, and Cognition in Healthy Older Adults: The MAPT Study.

J Gerontol A Biol Sci Med Sci 2021 07;76(8):1382-1390

Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalo-Universitaire de Toulouse, France.

Physical activity (PA) demonstrated benefits on brain health, but its relationship with blood biomarkers of neurodegeneration remains poorly investigated. We explored the cross-sectional associations of PA with blood concentrations of neurofilament light chain (NFL) and beta amyloid (Aβ)42/40. We further examined whether the interaction between PA and these biomarkers was longitudinally related to cognition. Four-hundred and sixty-five nondemented older adults engaged in an interventional study and who had a concomitant assessment of PA levels and blood measurements of NFL (pg/mL) and Aβ 42/40 were analyzed. A composite Z-score combining 4 cognitive tests was used for cognitive assessment up to a 4-year follow-up. Multiple linear regressions demonstrated that people achieving 500-999 and 2000+ MET-min/week of PA had lower (ln)NFL concentrations than their inactive peers. Logistic regressions revealed that achieving at least 90 MET-min/week of PA was associated with a lower probability of having high NFL concentrations (ie, ≥91.961 pg/mL [third quartile]). PA was not associated with (Aβ)42/40. Mixed-model linear regressions demonstrated that the reverse relationship between PA and cognitive decline tended to be more pronounced as Aβ 42/40 increased, while it was dampened with increasing levels of (ln)NFL concentrations. This study demonstrates that PA is associated with blood NFL but not with Aβ 42/40. Furthermore, it suggests that PA may attenuate the negative association between amyloid load and cognition, while having high NFL levels mitigates the favorable relationship between PA and cognition. More investigations on non demented older adults are required for further validation of the present findings.
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http://dx.doi.org/10.1093/gerona/glab094DOI Listing
July 2021

Visit-to-Visit Blood Pressure Variability and Incident Frailty in Older Adults.

J Gerontol A Biol Sci Med Sci 2021 07;76(8):1369-1375

Gérontopôle de Toulouse, Institut du Vieillissement, CHU de Toulouse, France.

This study aimed to determine whether visit-to-visit blood pressure (BP) variability (BPV) is associated with incident frailty. We included 1 394 nonfrail community-dwelling participants aged ≥70 years from the Multidomain Alzheimer Preventive Trial (MAPT) who underwent repeated clinical examinations, including BP and frailty, over a 5-year follow-up period. Systolic BPV (SBPV), diastolic BPV (DBPV), mean arterial pressure variability (MAPV), and pulse pressure variability (PPV) were evaluated using standard deviation (SD), coefficient of variation (CV), average real variability, successive variation, variation independent of mean, and residual SD. Incident frailty was assessed using the Fried phenotype. Cox proportional hazards models were used for the analyses. Higher SBPV was significantly associated with greater risk of frailty (1-SD increase of CV: hazard ratio [HR] = 1.18, 95% confidence interval [CI]: 1.02-1.36) after adjustment for demographics, systolic BP, antihypertensive drugs, body mass index, diabetes, ischemic heart disease, congestive heart failure, stroke, atrial fibrillation, MAPT randomization group, and frailty status. Similar results were observed with all indicators of variability. Higher PPV was associated with a greater risk of developing frailty over time (1-SD increase of CV: HR = 1.17, 95% CI: 1.01-1.35). DBPV and MAPV were not significantly associated with incident frailty. Higher SBPV and PPV were associated with greater risk of incident frailty. Our findings support the concept of BP physiological dysregulation underlying the frail state and suggest that BP instability could be an early marker of frailty.
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http://dx.doi.org/10.1093/gerona/glab112DOI Listing
July 2021

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

Genome Biol 2021 03 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

Retraction of: Identification of biological markers for better characterization of older subjects with physical frailty and sarcopenia.

Transl Neurosci 2020 11;11(1):334. Epub 2020 Sep 11.

Gérontopôle, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

[This retracts the article DOI: 10.1515/tnsci-2015-0009.].
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http://dx.doi.org/10.1515/tnsci-2020-0142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724002PMC
September 2020

Associations of Omega-3 fatty acids with brain morphology and volume in cognitively healthy older adults: A narrative review.

Ageing Res Rev 2021 05 16;67:101300. Epub 2021 Feb 16.

Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital (CHU Toulouse), Toulouse, France; UPS/Inserm UMR1027, University of Toulouse III, Toulouse, France.

Introduction: Human neurodevelopment is complete by the 4th decade of life at which point brain atrophy ensues with variable rate and regionality into old age. Literally all regions of the brain experience atrophy with older age, however the pattern and rate of atrophy can dictate the behavioral consequences (i.e., cognitive impairment, Alzheimer's disease). Substantial research has aimed to discover the reasons why some people experience greater morphologic changes that produce undesirable consequences with aging and how it may be prevented. One possible explanation is diet, particularly fish consumption and the intake of omega-3 polyunsaturated fatty acids (omega 3) concentrated in fish oil. This narrative review examines the available evidence on the association between omega-3 and brain volume in non-demented older adults.

Methods: A PubMed search of the literature was conducted in search of studies that investigated the associations of omega-3 on brain morphology and volume in cognitively intact older adults. Inclusion criteria were: populations of adults aged 45 years or over, who were cognitively intact, free of any central nervous system disease, and free of advanced structural brain atrophy. Study participants had to have DHA and EPA levels measured either by blood testing or scoring of dietary intake. There were no restrictions to dates of publication. Studies including demented participants, or participants with substantial white or grey matter atrophy visible on magnetic resonance imaging were excluded.

Results And Conclusion: The search identified only 12 studies, 8 of which were cross-sectional observational studies, 3 longitudinal observational studies, and 1 randomized controlled trial published between 2007 and 2019. The largest amount of evidence indicated that the hippocampus was most frequently involved in this association, with a higher volume associated with higher omega-3 levels. Larger total grey matter, total brain volume, and lower white matter lesion volume were also associated with higher omega-3 among four of the reviewed studies. However, most studies reviewed provided mixed findings regarding the presence or absence of the association of interest, and the findings were observed to be brain region-dependent. Current evidence is still insufficient to formulate recommendations for omega-3 intake to support brain health specifically.
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http://dx.doi.org/10.1016/j.arr.2021.101300DOI Listing
May 2021

What day is today? Cognitive capacity and the risk of incident dementia in the context of integrated care for older people (ICOPE Step 1).

Aging Clin Exp Res 2021 Feb 13. Epub 2021 Feb 13.

Gerontopole of Toulouse, Institute of Aging, Toulouse University Hospital (CHU Toulouse), Toulouse, France.

Based on clinical observations, our objective was to test if the older adults who failed to recall the name of the weekday, or had a higher number of mistakes in the word recall were at higher risk of mild cognitive impairment (MCI) or dementia. Longitudinal data of the Multidomain Alzheimer Preventive Trial (MAPT) was used to retrospectively measure the cognitive capacity according to the ICOPE Step 1 tool. Incident dementia was assessed by two multidisciplinary committees independent from each other. MCI was defined as Clinical Dementia Rating scale CDR = 0.5. Failure to recall the name of the weekday had a three-fold risk of incident dementia in the next 5 years (HRa = 3.11, 95%CI: 1.18-8.17). Having two or three mistakes in the word recall carried a higher risk of incident dementia, (HRa for two mistakes = 3.50, 95% CI: 1.49-8.26; HRa for three mistakes = 4.28, 95% CI: 1.60-11.46), but not MCI. People with impaired cognitive capacity according to the ICOPE Step 1 tool deserve further assessment and a closer follow-up.
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http://dx.doi.org/10.1007/s40520-021-01803-4DOI Listing
February 2021

Cross-sectional associations between cortical thickness and physical activity in older adults with spontaneous memory complaints: The MAPT Study.

J Sport Health Sci 2021 Feb 2. Epub 2021 Feb 2.

Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalo-Universitaire de Toulouse, Toulouse 31000, France; Université Paul-Sabatier/Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1027, Faculté de médecine, University of Toulouse III, Toulouse 31000, France.

Background: Age-related changes in brain structure may constitute the starting point for cerebral function alteration. Physical activity (PA) demonstrated favorable associations with total brain volume, but its relationship with cortical thickness (CT) remains unclear. We investigated the cross-sectional associations between PA level and CT in community-dwelling people aged 70 years and older.

Methods: A total of 403 older adults aged 74.8 ± 4.0 years (mean ± SD) who underwent a baseline magnetic resonance imaging examination and who had data on PA and confounders were included. PA was assessed with a questionnaire. Participants were categorized according to PA levels. Multiple linear regressions were used to compare the brain CT (mm) of the inactive group (no PA at all) with 6 active groups (growing PA levels) in 34 regions of interest.

Results: Compared with inactive persons, people who achieved PA at a level of 1500-1999 metabolic equivalent task-min/week (i.e., about 6-7 h of brisk walking for exercise and those who achieved it at 2000-2999 metabolic equivalent task-min/week (i.e., 8-11 h of brisk walking for exercise) had higher CT in the fusiform gyrus and the temporal pole. Additionally, dose-response associations between PA and CT were found in the fusiform gyrus (B = 0.011, SE = 0.004, adj. p = 0.035), the temporal pole (B = 0.026, SE = 0.009, adj. p = 0.048), and the caudal middle frontal gyrus, the entorhinal, medial orbitofrontal, lateral occipital, and insular cortices.

Conclusion: This study demonstrates a positive association between PA level and CT in temporal areas such as the fusiform gyrus, a brain region often associated to Alzheimer's disease in people aged 70 years or older. Future investigations focusing on PA type may help to fulfil remaining knowledge gaps in this field.
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http://dx.doi.org/10.1016/j.jshs.2021.01.011DOI Listing
February 2021

The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease.

Alzheimers Dement 2021 07 25;17(7):1145-1156. Epub 2021 Jan 25.

Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Introduction: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals.

Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants.

Results: Phosphorylated-tau181 (P-tau181), neurofilament light, amyloid-β (Aβ42/40), Total-tau and Glial fibrillary acidic protein were altered in AD dementia but P-tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P-tau181 was increased in MCI converters compared to non-converters. Higher P-tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P-tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals.

Discussion: P-tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P-tau181 as a non-invasive and cost-effective diagnostic and prognostic biomarker in AD.
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http://dx.doi.org/10.1002/alz.12283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359457PMC
July 2021

Physical activity and exercise in the context of SARS-Cov-2: A perspective from geroscience field.

Ageing Res Rev 2021 03 12;66:101258. Epub 2021 Jan 12.

Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital (CHU Toulouse), Toulouse, France; UPS/Inserm UMR1027, University of Toulouse III, Toulouse, France.

The recent pandemics of the SARS-Cov-2 has pushed physical activity (PA) and exercise at the forefront of the discussion, since PA is associated with a reduced risk of developing all the chronic diseases strongly associated with severe cases of SARS-Cov-2 and exercise is considered a complimentary therapeutics for the treatment of these age-related conditions. The mechanisms through which PA and exercise could contribute to reduce the severity of the SARS-Cov-2 infection would be multiple, including their capacity to boost the immune system, but also their global effect on slowing down the progression of the aging process. The present perspective presents a discussion on how PA and exercise might hypothetically be linked with SARS-Cov-2 infection, current scientific gaps and shortcomings as well as recommendations for advancing research in this area, placing the debate in the context of aging and gerosciences.
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http://dx.doi.org/10.1016/j.arr.2021.101258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042847PMC
March 2021

Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer's disease.

Alzheimers Res Ther 2021 01 9;13(1):20. Epub 2021 Jan 9.

UK Dementia Research Institute, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK.

Background: Both serotonergic signalling disruption and systemic inflammation have been associated with the pathogenesis of Alzheimer's disease (AD). The common denominator linking the two is the catabolism of the essential amino acid, tryptophan. Metabolism via tryptophan hydroxylase results in serotonin synthesis, whilst metabolism via indoleamine 2,3-dioxygenase (IDO) results in kynurenine and its downstream derivatives. IDO is reported to be activated in times of host systemic inflammation and therefore is thought to influence both pathways. To investigate metabolic alterations in AD, a large-scale metabolic phenotyping study was conducted on both urine and serum samples collected from a multi-centre clinical cohort, consisting of individuals clinically diagnosed with AD, mild cognitive impairment (MCI) and age-matched controls.

Methods: Metabolic phenotyping was applied to both urine (n = 560) and serum (n = 354) from the European-wide AddNeuroMed/Dementia Case Register (DCR) biobank repositories. Metabolite data were subsequently interrogated for inter-group differences; influence of gender and age; comparisons between two subgroups of MCI - versus those who remained cognitively stable at follow-up visits (sMCI); and those who underwent further cognitive decline (cMCI); and the impact of selective serotonin reuptake inhibitor (SSRI) medication on metabolite concentrations.

Results: Results revealed significantly lower metabolite concentrations of tryptophan pathway metabolites in the AD group: serotonin (urine, serum), 5-hydroxyindoleacetic acid (urine), kynurenine (serum), kynurenic acid (urine), tryptophan (urine, serum), xanthurenic acid (urine, serum), and kynurenine/tryptophan ratio (urine). For each listed metabolite, a decreasing trend in concentrations was observed in-line with clinical diagnosis: control > MCI > AD. There were no significant differences in the two MCI subgroups whilst SSRI medication status influenced observations in serum, but not urine.

Conclusions: Urine and serum serotonin concentrations were found to be significantly lower in AD compared with controls, suggesting the bioavailability of the neurotransmitter may be altered in the disease. A significant increase in the kynurenine/tryptophan ratio suggests that this may be a result of a shift to the kynurenine metabolic route due to increased IDO activity, potentially as a result of systemic inflammation. Modulation of the pathways could help improve serotonin bioavailability and signalling in AD patients.
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http://dx.doi.org/10.1186/s13195-020-00741-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797094PMC
January 2021

Five-Year Lower Extremity Function is Associated with White Matter Abnormality in Older Adults.

J Am Geriatr Soc 2021 04 8;69(4):995-1002. Epub 2021 Jan 8.

Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.

Objective: To explore associations between changes of lower extremity function (LEF) parameters over a 5-year period and diffusion tensor imaging (DTI) parameters of white matter tracts among community-dwelling older adults.

Design: A secondary analysis on image and physical function data collected from the Multidomain Alzheimer's Preventive Trial (MAPT).

Participants: 208 older adults (aged 75 ± 4 years, with spontaneous memory complaint or limited instrumental daily living activity or slow gait speed, 60% female) of the MAPT-magnetic resonance imaging (MRI) ancillary study. The time interval between a participant's enrolment and MRI scan was on average 110 ± 97 days.

Measurements: Forty-eight white matter tracts (WMTs) were measured. LEF parameters (measured after the MRI scan) were assessed as the short physical performance battery (SPPB) score, gait speed, and chair stands time over a 5-year period. Mixed-effects models were performed to explore the associations between baseline DTI values and the progression of LEF parameters. Bonferroni correction was applied for multiple comparison correction.

Results: The progression of LEF was associated with 35 baseline DTI parameters from 24 WMTs. Higher baseline DTI parameter values were related to more decreases in SPPB score and gait speed, and greater increases in chair stands time. Bilateral uncinate fasciculus was associated with all LEF parameters. Other WMTs in cingulum, cerebral and cerebellar peduncle, internal capsule, and corpus callosum also showed close connections with LEF changes.

Conclusions: Our findings show that DTI parameters of some WMTs are associated with the 5-year decline in LEF, suggesting that alterations in WMT integrity (evaluated by DTI parameters) might be used to explore potential causes of impaired mobility in older adults when no clear explanations can be found.
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http://dx.doi.org/10.1111/jgs.16989DOI Listing
April 2021

Assessment of Plasma Amyloid-β42/40 and Cognitive Decline Among Community-Dwelling Older Adults.

JAMA Netw Open 2020 12 1;3(12):e2028634. Epub 2020 Dec 1.

Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital, Toulouse, France.

Importance: Plasma measurement of amyloid-β (Aβ) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce.

Objective: To investigate the associations between plasma Aβ42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns.

Design, Setting, And Participants: This multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020.

Exposure: Plasma Aβ42 and Aβ40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of Aβ assessment was defined as the baseline for this study.

Main Outcomes And Measures: Cognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study-Activities of Daily Living. Mixed-effect linear regressions were performed.

Results: A total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma Aβ42/40 (≤0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ε4 genotype, and MAPT intervention groups, low plasma Aβ42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: -0.20, 95% CI, -0.34 to -0.07; P = .004) and decline in MMSE score (adjusted between-group mean difference: -0.59; 95% CI, -1.07 to -0.11; P = .02) during the follow-up period compared with the group with an Aβ42/40 ratio greater than 0.107.

Conclusions And Relevance: In this study, low plasma Aβ42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma Aβ42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.28634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747018PMC
December 2020

Urinary metabolic phenotyping for Alzheimer's disease.

Sci Rep 2020 12 10;10(1):21745. Epub 2020 Dec 10.

Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.

Finding early disease markers using non-invasive and widely available methods is essential to develop a successful therapy for Alzheimer's Disease. Few studies to date have examined urine, the most readily available biofluid. Here we report the largest study to date using comprehensive metabolic phenotyping platforms (NMR spectroscopy and UHPLC-MS) to probe the urinary metabolome in-depth in people with Alzheimer's Disease and Mild Cognitive Impairment. Feature reduction was performed using metabolomic Quantitative Trait Loci, resulting in the list of metabolites associated with the genetic variants. This approach helps accuracy in identification of disease states and provides a route to a plausible mechanistic link to pathological processes. Using these mQTLs we built a Random Forests model, which not only correctly discriminates between people with Alzheimer's Disease and age-matched controls, but also between individuals with Mild Cognitive Impairment who were later diagnosed with Alzheimer's Disease and those who were not. Further annotation of top-ranking metabolic features nominated by the trained model revealed the involvement of cholesterol-derived metabolites and small-molecules that were linked to Alzheimer's pathology in previous studies.
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http://dx.doi.org/10.1038/s41598-020-78031-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730184PMC
December 2020

Exercise Effects on Falls, Fractures, Hospitalizations, and Mortality in Older Adults With Dementia: An Individual-Level Patient Data Meta-analysis.

J Gerontol A Biol Sci Med Sci 2021 Aug;76(9):e203-e212

Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital (CHU Toulouse), France.

Background: To study the effects of exercise on falls, fractures, hospitalizations, and death in people with dementia.

Method: We conducted an individual-level patient data meta-analysis of 7 randomized controlled trials (RCTs). We looked for studies from the reference list of previous systematic reviews and undertook an electronic search for articles published between 2013 and 2019 in Ageline, CENTRAL, PsycINFO, PubMed, and SportsDiscus. Main (binary) outcome measures were the risk of mortality, hospitalization, faller, multiple faller, injurious faller, and fractures. Secondary (count) outcomes were the incident rates of hospitalizations, falls, and injurious falls.

Results: From the 1314 participants, 771 were allocated to the exercise group and 543 to the control group. The number of cases regarding the main outcome measures in exercisers and controls were, respectively: 45 (5.8%) and 31 (5.7%) deaths; 102 (14.4%) and 65 (13.4%) participants hospitalized; 221 (34.4%) and 175 (41.3%) had at least 1 fall; 128 (20.2%) and 92 (21.7%) had multiple falls; 78 (24.8%) and 92 (29.3%) had injurious falls; and 19 (2.9%) and 15 (3.5%) had suffered a fracture. Two-step meta-analysis found no effects of exercise on any outcome. One-step meta-analysis found exercise reduced the risk of falls (odds ratio 0.75; 95% CI: 0.57-0.99). Exploratory analysis showed exercise decreased the rate of incident falls in participants with the lowest functional ability (incident rate ratio 0.48; 95% CI: 0.30-0.79).

Conclusions: Although the 2-step meta-analysis suggests exercise does not have an effect on the outcomes, 1-step meta-analysis suggested that exercise may reduce fall risk. Data from further high-quality RCTs are still needed.
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http://dx.doi.org/10.1093/gerona/glaa307DOI Listing
August 2021

BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain.

Brain 2020 12;143(12):3816-3826

Merck and Co., Inc., Kenilworth, NJ, USA.

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.
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http://dx.doi.org/10.1093/brain/awaa332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453290PMC
December 2020

Biological and Neuroimaging Markers as Predictors of 5-Year Incident Frailty in Older Adults: A Secondary Analysis of the MAPT Study.

J Gerontol A Biol Sci Med Sci 2021 Oct;76(11):e361-e369

Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital (CHU Toulouse), France.

Background: This study aims to investigate the predictive value of biological and neuroimaging markers to determine incident frailty among older people for a period of 5 years.

Methods: We included 1394 adults aged 70 years and older from the Multidomain Alzheimer Preventive Trial, who were not frail at baseline (according to Fried's criteria) and who had at least 1 post-baseline measurement of frailty. Participants who progressed to frailty during the 5-year follow-up were categorized as "incident frailty" and those who remained non-frail were categorized as "without frailty." The differences of baseline biochemical factors (25-hydroxyvitamin D, homocysteine, omega-3 index, C-reactive protein), other biological markers (Apolipoprotein E genotypes, amyloid-β deposits), and neuroimaging data (gray matter volume, hippocampal volume, white matter hyperintensities) were compared between groups. Cox proportional hazard model was used to evaluate the associations between biomarkers and incident frailty.

Results: A total of 195 participants (14.0%) became frail over 5 years. Although 25-hydroxyvitamin D deficiency, homocysteine levels, low-grade inflammation (persistently increased C-reactive protein 3-10 mg/L), gray matter, and hippocampal volume were significantly associated with incident frailty in unadjusted models, these associations disappeared after adjustment for age, sex, and other confounders. Omega-3 index was the sole marker that presented a trend of association with incident frailty (hazard ratio: 0.92; 95% confidence interval: 0.83-1.01; p = .082).

Conclusions: This study failed to identify biomarkers able to predict frailty incidence in community-dwelling older adults for a period of 5 years. Further longitudinal research with multiple measurements of biomarkers and frailty is needed to evaluate the long-term relationships between changes in biomarkers levels and frailty evolution.
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http://dx.doi.org/10.1093/gerona/glaa296DOI Listing
October 2021

Kidney Function and Cognitive Decline in Older Adults: Examining the Role of Neurodegeneration.

J Am Geriatr Soc 2021 03 20;69(3):651-659. Epub 2020 Nov 20.

Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital (CHU Toulouse), Toulouse, France.

Background/objectives: Cognitive decline associated with impaired kidney function might involve neurodegeneration. Our objectives were to evaluate the longitudinal association between kidney function and cognitive decline in older adults and to assess the involvement of cortical beta-amyloid and hippocampal atrophy (features of Alzheimer's disease (AD)) in this association.

Design: Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial (MAPT).

Settings: Thirteen memory centers (France and Monaco, 2008-2016).

Participants: A total of 1,334 community-dwellers >70 years old without dementia at baseline.

Measurements: We estimated glomerular filtration rate (eGFR) from serum creatinine using CKD-Epi equation. Cognition was assessed at baseline, 6, 12, 24, 36, 48, and 60 months using a composite Z-score designed for MAPT. The Clinical Dementia Rating (CDR) score was used to assess cognition and functional independence. We examined the association between eGFR and (1) evolution of the composite cognitive Z-score using mixed-effect models and (2) progression on CDR using Cox models and mixed-effect models. Adjustments were made for age, sex, education, ApoE genotype, cardiovascular risk factors and disease, hippocampal volume (measured with magnetic resonance), and cortical beta-amyloid (measured with positron emission tomography).

Results: Median (IQR) eGFR was 73(60-84) mL/min/1.73 m . Two hundred sixty-nine participants experienced progression on CDR score during follow-up. eGFR<60 was significantly associated with progression on CDR score (adjusted hazard ratio (aHR) = 1.35, 95% CI 1.01-1.80) and with both the cognitive and functional independence components of CDR, but not with the evolution of the composite cognitive Z-score (adjusted β-coefficient -0.004, 95% CI -0.014; 0.006). Associations were not modified after further adjustment for beta-amyloid (subsample: n = 252) and hippocampal volume (subsample: n = 270).

Conclusions: We did not find a mild to moderate renal insufficiency to be associated with brain imaging features of AD, and our results do not support the involvement of AD mechanisms in the incidence of cognitive impairment and functional decline associated with chronic kidney disease.
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http://dx.doi.org/10.1111/jgs.16954DOI Listing
March 2021

Cross-Sectional and Longitudinal Associations Between Plasma Neurodegenerative Biomarkers and Physical Performance Among Community-Dwelling Older Adults.

J Gerontol A Biol Sci Med Sci 2021 Sep;76(10):1874-1881

Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalo-Universitaire de Toulouse, France.

Background: Plasma amyloid-beta (Aβ), neurofilament light chain (NfL), and progranulin (PGRN) have been related to multiple neurodegenerative conditions that might affect physical performance. The aim of this study was to explore the relationship between these plasma neurodegenerative markers and physical performance among community-dwelling older adults.

Methods: Five hundred and seven older adults (aged 76 ± 5 years) previously recruited in the Multidomain Alzheimer's Preventive Trial, and had received blood and physical performance tests, were included in this study. Plasma Aβ (Aβ 42/Aβ 40 ratio), NfL, and PGRN levels were measured. Physical performance was assessed by handgrip strength and the Short Physical Performance Battery (combining gait speed, chair stands, and balance tests). Physical performance measured at the same time point and after the blood tests were used. Mixed-effect linear models were performed with age, sex, allocation to Multidomain Alzheimer's Preventive Trial group, body mass index, and Mini-Mental State Examination score as covariates.

Results: The mean values of Aβ 42/Aβ 40 ratio, NfL, and PGRN were 0.11, 84.06 pg/mL, and 45.43 ng/mL, respectively. At the cross-sectional level, higher plasma NfL was associated with a lower Short Physical Performance Battery score (β = -0.004, 95% CI [-0.007, -0.001]). At the longitudinal level, higher PGRN levels were associated with decreasing handgrip strength over time (β = -0.02, 95% CI [-0.04, -0.007]). All the other associations were statistically nonsignificant.

Conclusion: Our findings suggest the possibility of using plasma NfL and PGRN as markers of physical performance in older adults.
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http://dx.doi.org/10.1093/gerona/glaa284DOI Listing
September 2021
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