Effects of preventive interventions on neuroimaging biomarkers in subjects at-risk to develop Alzheimer's disease: A systematic review.

Alzheimer's Disease (AD) is a multifactorial and complex neurodegenerative disorder. Some modifiable risk factors have been associated with an increased risk of appearance of the disease and/or cognitive decline. Preventive clinical trials aiming at reducing one or combined risk factors have been implemented and their potential effects assessed on cognitive trajectories and on AD biomarkers. However, the effect of interventions on surrogate markers, in particular imaging biomarkers, remains poorly understood. We conducted a review of the literature and analyzed 43 interventional studies that included physical exercise, nutrition, cognitive training or multidomain interventions, and assessed various brain imaging biomarkers, to determine the effects of preventive interventions on imaging biomarkers for subjects at-risk to develop AD. Deciphering the global and regional brain effect of each and combined interventions will help to better understand the interplay relationship between multimodal interventions, cognition, surrogate brain markers, and to better design primary and secondary outcomes for future preventive clinical trials. Those studies were pondered using generally-admitted quality criteria to reveal that interventions may affect the brain of patients with cognitive impairment rather than those without cognitive impairment thus indicating that particular care should be taken when selecting individuals for interventions. Additionally, a majority of the studies concurred on the effect of the interventions and particularly onto the frontal brain areas.

Sulcal morphology as cognitive decline predictor in older adults with memory complaints.

To determine whether sulcal morphology can predict changes in cognition, we investigated the relationship between width of 20 cerebral sulci and cognitive decline. Sulcal width was measured in T1-weighted MRI images at baseline in 433 adults aged ≥70 years with memory complaints from the MRI-Multidomain Alzheimer Preventive Trial study. Cognition was evaluated at baseline, 6, 12, 24, and 36 months of follow-up with a composite Z score. The composite score variations over time relative to the baseline sulcal width were assessed using linear mixed regression models. We observed a positive association between a greater decline in cognitive composite score and the width of the superior and the anterior inferior temporal sulci, and the cingulate anterior sulcus of the left hemisphere. Sulcal widening in the lateral temporal and the cingulate anterior areas might predict cognitive decline in individuals with memory complaints.

Impact of multidomain preventive strategies on functional brain connectivity in older adults with cognitive complaint: Subset from the Montpellier center of the ancillary MAPT-MRI study.

Introduction: The impact of multi-domain preventive interventions on older adults, in particular on those with higher risk to develop Alzheimer's disease (AD), could be beneficial, as it may delay cognitive decline. However, the precise mechanism of such positive impact is not fully understood and may involve brain reserve and adaptability of brain functional connectivity (FC). Methods: To determine the effect of multidomain interventions (involving physical activity, cognitive training, nutritional counseling alone or in combination with omega-3 fatty acid supplementation and vs. a placebo) on the brain, longitudinal FC changes were assessed after 36 months of intervention on 100 older adults (above 70 year-old) with subjective cognitive complaints. Results: No global change in FC was detected after uni or multidomain preventive interventions. However, an effect of omega-3 fatty acid supplementation dependent on cognitive decline status was underlined for frontoparietal, salience, visual and sensorimotor networks FC. These findings were independent of the cortical thickness and vascular burden. Discussion: These results emphasize the importance of patient stratification, based on risk factors, for preventive interventions.

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

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.

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

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.

Prospective associations between physical activity levels and white matter integrity in older adults: results from the MAPT study.

BACKGROUND: Higher levels of physical activity (PA) are known to be associated with better white matter integrity measured by diffusion tensor imaging (DTI) in older adults in cross-sectional studies. However, no studies have investigated the association between PA levels and the evolution of DTI parameters (fractional anisotropy and mean diffusivity). OBJECTIVES: To examine the cross-sectional associations between PA levels and DTI parameters, then to investigate the association between baseline PA levels and the evolution of DTI parameters in older adults. METHODS: Data on magnetic resonance imaging with DTI method from the Multidomain Alzheimer's Preventive Trial (MAPT) study were used; 228 participants had data on DTI measured at three time-points over five years. Fractional anisotropy and mean diffusivity were acquired for six different brain regions. RESULTS: No significant associations were found in the cross-sectional analyses. Only one association was found: compared with active individuals, a faster worsening in the mean diffusivity of the uncinate fasciculus region was found in inactive individuals (-5.0 × 10-6 (-9.5 × 10-5, 4.9 × 10-6)). CONCLUSIONS: In this study, we found that the condition of the uncinate fasciculus region may be susceptible to changes in PA levels in older adults. Longitudinal studies that assess fitness and PA using objective measurements (e.g. cardiorespiratory fitness and accelerometry) could shed some new light on this topic.

Prospective Associations Between Diffusion Tensor Imaging Parameters and Frailty in Older Adults.

BACKGROUND: Cross-sectional associations have been found between frail individuals and worse white matter (WM) integrity. However, the prospective association between WM integrity and frailty is still unclear. Our objectives were to measure associations between WM integrity using diffusion tensor imaging (DTI) and the 5-year worsening of frailty in community-dwelling older adults. DESIGN: Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial (MAPT). SETTING: Thirteen memory centers in France and Monaco between 2008 and 2011. PARTICIPANTS: Participants (mean age = 74.7 ± 3.9 years) with no dementia at baseline who had functional magnetic resonance imaging performed as part of the MAPT study (n = 227). MEASUREMENTS: Fractional anisotropy and mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) were acquired for 10 different brain regions. Frailty was assessed by the Fried frailty phenotype (score from 0 to 5, higher is worse) at up to seven time points for 5 years. Mixed effect ordinal logistic regression model was used to assess the prospective association between DTI parameters (independent variables) and frailty (dependent variable). All the analyses were adjusted for age, sex, baseline total intracranial volume, and the presence of one of the following cardiovascular risk factors (hypertension, diabetes, and/or hypercholesterolemia). RESULTS: A statistically significant association was found between the RD, AxD, and MD for different brain regions (anterior limb of internal capsule, external capsule, posterior corona radiata, posterior thalamic radiation, superior corona radiata, superior frontal occipital fasciculus, and superior longitudinal fasciculus) and worsening of frailty over 5 years after adjusting for multiple comparisons. CONCLUSIONS: This is the first study to show that WM integrity is associated with frailty in older adults. The mechanisms related to these results require further investigation. J Am Geriatr Soc 68:1050-1055, 2020.