Depressive Symptoms Have Distinct Relationships With Neuroimaging Biomarkers Across the Alzheimer's Clinical Continuum

Background: Depressive and anxiety symptoms are frequent in Alzheimer’s disease and associated with increased risk of developing Alzheimer’s disease in older adults. We sought to examine their relationships to Alzheimer’s disease biomarkers across the preclinical and clinical stages of the disease. Method: Fifty-six healthy controls, 35 patients with subjective cognitive decline and 56 amyloid-positive cognitively impaired patients on the Alzheimer’s continuum completed depression and anxiety questionnaires, neuropsychological tests and neuroimaging assessments. We performed multiple regressions in each group separately to assess within group associations of depressive and anxiety symptoms with either cognition (global cognition and episodic memory) or neuroimaging data (gray matter volume, glucose metabolism and amyloid load). Results: Depressive symptoms, but not anxiety, were higher in patients with subjective cognitive decline and cognitively impaired patients on the Alzheimer’s continuum compared to healthy controls. Greater depressive symptoms were associated with higher amyloid load in subjective cognitive decline patients, while they were related to higher cognition and glucose metabolism, and to better awareness of cognitive difficulties, in cognitively impaired patients on the Alzheimer’s continuum. In contrast, anxiety symptoms were not associated with brain integrity in any group. Conclusion: These data show that more depressive symptoms are associated with greater Alzheimer’s disease biomarkers in subjective cognitive decline patients, while they reflect better cognitive deficit awareness in cognitively impaired patients on the Alzheimer’s continuum. Our findings highlight the relevance of assessing and treating depressive symptoms in the preclinical stages of Alzheimer’s disease

Distinct relationships of self-reported subjective memory decline to neurodegeneration across the Alzheimer's clinical continuum: Neuroimaging/Optimal neuroimaging measures for tracking disease progression

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IC-P-082: ASSOCIATION OF PERCEIVED MEMORY DECLINE WITH MULTIMODAL NEUROIMAGING AT DIFFERENT STAGES OF ALZHEIMER'S DISEASE

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Exposure to negative socio-emotional events induces sustained alteration of resting-state brain networks in older adults

Basic emotional functions seem well preserved in older adults. However, their reactivity to and recovery from socially negative events remain poorly characterized. To address this, we designed a ‘task–rest’ paradigm in which 182 participants from two independent experiments underwent functional magnetic resonance imaging while exposed to socio-emotional videos. Experiment 1 (N = 55) validated the task in young and older participants and unveiled age-dependent effects on brain activity and connectivity that predominated in resting periods after (rather than during) negative social scenes. Crucially, emotional elicitation potentiated subsequent resting-state connectivity between default mode network and amygdala exclusively in older adults. Experiment 2 replicated these results in a large older adult cohort (N = 127) and additionally showed that emotion-driven changes in posterior default mode network–amygdala connectivity were associated with anxiety, rumination and negative thoughts. These findings uncover the neural dynamics of empathy-related functions in older adults and help understand its relationship to poor social stress recovery

Effect of an 18-Month Meditation Training on Regional Brain Volume and Perfusion in Older Adults: The Age-Well Randomized Clinical Trial.

peer reviewedImportance: No lifestyle-based randomized clinical trial directly targets psychoaffective risk factors of dementia. Meditation practices recently emerged as a promising mental training exercise to foster brain health and reduce dementia risk. Objective: To investigate the effects of meditation training on brain integrity in older adults. Design, Setting, and Participants: Age-Well was a randomized, controlled superiority trial with blinded end point assessment. Community-dwelling cognitively unimpaired adults 65 years and older were enrolled between November 24, 2016, and March 5, 2018, in France. Participants were randomly assigned (1:1:1) to (1) an 18-month meditation-based training, (2) a structurally matched non-native language (English) training, or (3) no intervention arm. Analysis took place between December 2020 and October 2021. Interventions: Meditation and non-native language training included 2-hour weekly group sessions, practice of 20 minutes or longer daily at home, and 1-day intensive practices. Main Outcomes and Measures: Primary outcomes included volume and perfusion of anterior cingulate cortex (ACC) and insula. Main secondary outcomes included a global composite score capturing metacognitive, prosocial, and self-regulatory capacities and constituent subscores. Results: Among 137 participants (mean [SD] age, 69.4 [3.8] years; 83 [60.6%] female; 54 [39.4%] male) assigned to the meditation (n = 45), non-native language training (n = 46), or no intervention (n = 46) groups, all but 1 completed the trial. There were no differences in volume changes of ACC (0.01 [98.75% CI, -0.02 to 0.05]; P = .36) or insula (0.01 [98.75% CI, -0.02 to 0.03]; P = .58) between meditation and no intervention or non-native language training groups, respectively. Differences in perfusion changes did not reach statistical significance for meditation compared with no intervention in ACC (0.02 [98.75% CI, -0.01 to 0.05]; P = .06) or compared with non-native language training in insula (0.02 [98.75% CI, -0.01 to 0.05]; P = .09). Meditation was superior to non-native language training on 18-month changes in a global composite score capturing attention regulation, socioemotional, and self-knowledge capacities (Cohen d, 0.52 [95% CI, 0.19-0.85]; P = .002). Conclusions and Relevance: The study findings confirm the feasibility of meditation and non-native language training in elderly individuals, with high adherence and very low attrition. Findings also show positive behavioral effects of meditation that were not reflected on volume, and not significantly on perfusion, of target brain areas. Trial Registration: ClinicalTrials.gov Identifier: NCT02977819

The Effect of Mindfulness-based Programs on Cognitive Function in Adults: A Systematic Review and Meta-analysis.

peer reviewedMindfulness-based programs (MBPs) are increasingly utilized to improve mental health. Interest in the putative effects of MBPs on cognitive function is also growing. This is the first meta-analysis of objective cognitive outcomes across multiple domains from randomized MBP studies of adults. Seven databases were systematically searched to January 2020. Fifty-six unique studies (n = 2,931) were included, of which 45 (n = 2,238) were synthesized using robust variance estimation meta-analysis. Meta-regression and subgroup analyses evaluated moderators. Pooling data across cognitive domains, the summary effect size for all studies favored MBPs over comparators and was small in magnitude (g = 0.15; [0.05, 0.24]). Across subgroup analyses of individual cognitive domains/subdomains, MBPs outperformed comparators for executive function (g = 0.15; [0.02, 0.27]) and working memory outcomes (g = 0.23; [0.11, 0.36]) only. Subgroup analyses identified significant effects for studies of non-clinical samples, as well as for adults aged over 60. Across all studies, MBPs outperformed inactive, but not active comparators. Limitations include the primarily unclear within-study risk of bias (only a minority of studies were considered low risk), and that statistical constraints rendered some p-values unreliable. Together, results partially corroborate the hypothesized link between mindfulness practices and cognitive performance. This review was registered with PROSPERO [CRD42018100904]

Subclinical depressive symptoms in older adults and risk of Alzheimer’s disease : associations with multimodal neuroimaging and blood markers of stress, and evaluation of the impact of the COVID-19 pandemic and a meditation intervention

Les symptômes dépressifs infracliniques chez le sujet âgé sont associés à un risque accru de développer une dépression et une maladie d’Alzheimer. Cependant, les mécanismes cérébraux et biologiques sous-tendant cette association sont encore mal connus. Les objectifs de cette thèse étaient de mieux caractériser les liens entre les symptômes dépressifs infracliniques d’une part et l’intégrité cérébrale en neuroimagerie multimodale, ainsi que des marqueurs sanguins du stress d’autre part, chez des sujets âgés cognitivement sains. Nous avons également évalué l’impact de ces symptômes dépressifs sur la santé mentale lors des confinements liés à la pandémie de COVID-19 et le potentiel effet modérateur de la pratique de la méditation. Nos résultats montrent que les symptômes dépressifs infracliniques sont associés à une plus faible intégrité cérébrale (i.e. volume de substance grise, substance blanche et métabolisme du glucose) dans des régions appartenant principalement au réseau fronto-limbique, dont certaines sont particulièrement sensibles à la maladie d’Alzheimer. De plus, ces symptômes dépressifs sont liés à un taux sanguin d’adrénaline plus élevé et à une connectivité fonctionnelle au repos entre l’hypothalamus et les sous-champs hippocampiques CA1 et Subiculum plus importante – ce qui refléterait une activité plus élevée de l’axe sympatho-medullo-surrénalien lié au stress. Enfin, la présence de ces symptômes avant la pandémie est associée à une détérioration de la santé mentale lors des confinements liés au COVID-19, avec pour facteur prédicteur un niveau de rumination élevé – ce qui n’était pas significativement impacté par l’intervention de méditation du protocole Age-Well. Ces résultats soulignent la nécessité de mettre en place des stratégies préventives et/ou interventionnelles visant à diminuer ces symptômes dépressifs afin d’en limiter les conséquences chez le sujet âgé.Subclinical depressive symptoms in older adults are associated with an increased risk of developing depression and Alzheimer's disease. However, the brain and biological mechanisms underlying this association are still unclear. The objectives of this thesis were to better characterise the links between subclinical depressive symptoms on the one hand and brain integrity using multimodal neuroimaging, as well as blood markers of stress on the other hand, in cognitively unimpaired older adults. We also assessed the impact of these depressive symptoms on mental health during the COVID-19-related confinements and the potential moderating effect of meditation practice. Our results show that subclinical depressive symptoms are associated with lower brain integrity (i.e. grey matter volume, white matter and glucose metabolism) in regions belonging mainly to the fronto-limbic network, some of which being particularly sensitive to Alzheimer's disease. Furthermore, these depressive symptoms are linked to higher blood levels of epinephrine and higher resting state functional connectivity between the hypothalamus and the hippocampal subfields CA1 and Subiculum - likely reflecting higher activity of the sympatho-adrenomedullary axis linked to stress. Finally, the presence of these symptoms prior to the pandemic was associated with poorer mental health during the COVID-19 confinements, with high rumination as a predictor - which was not significantly impacted by the Age-Well meditation intervention. These results highlight the need for preventive and/or interventional strategies to reduce these depressive symptoms in order to limit their consequences in the elderly

Symptômes dépressifs infracliniques chez le sujet âgé et risque de maladie d’Alzheimer : liens avec la neuroimagerie multimodale et les marqueurs sanguins du stress, et évaluation de l’impact de la pandémie de COVID-19 et d’une intervention de méditation

Subclinical depressive symptoms in older adults are associated with an increased risk of developing depression and Alzheimer's disease. However, the brain and biological mechanisms underlying this association are still unclear. The objectives of this thesis were to better characterise the links between subclinical depressive symptoms on the one hand and brain integrity using multimodal neuroimaging, as well as blood markers of stress on the other hand, in cognitively unimpaired older adults. We also assessed the impact of these depressive symptoms on mental health during the COVID-19-related confinements and the potential moderating effect of meditation practice. Our results show that subclinical depressive symptoms are associated with lower brain integrity (i.e. grey matter volume, white matter and glucose metabolism) in regions belonging mainly to the fronto-limbic network, some of which being particularly sensitive to Alzheimer's disease. Furthermore, these depressive symptoms are linked to higher blood levels of epinephrine and higher resting state functional connectivity between the hypothalamus and the hippocampal subfields CA1 and Subiculum - likely reflecting higher activity of the sympatho-adrenomedullary axis linked to stress. Finally, the presence of these symptoms prior to the pandemic was associated with poorer mental health during the COVID-19 confinements, with high rumination as a predictor - which was not significantly impacted by the Age-Well meditation intervention. These results highlight the need for preventive and/or interventional strategies to reduce these depressive symptoms in order to limit their consequences in the elderly.Les symptômes dépressifs infracliniques chez le sujet âgé sont associés à un risque accru de développer une dépression et une maladie d’Alzheimer. Cependant, les mécanismes cérébraux et biologiques sous-tendant cette association sont encore mal connus. Les objectifs de cette thèse étaient de mieux caractériser les liens entre les symptômes dépressifs infracliniques d’une part et l’intégrité cérébrale en neuroimagerie multimodale, ainsi que des marqueurs sanguins du stress d’autre part, chez des sujets âgés cognitivement sains. Nous avons également évalué l’impact de ces symptômes dépressifs sur la santé mentale lors des confinements liés à la pandémie de COVID-19 et le potentiel effet modérateur de la pratique de la méditation. Nos résultats montrent que les symptômes dépressifs infracliniques sont associés à une plus faible intégrité cérébrale (i.e. volume de substance grise, substance blanche et métabolisme du glucose) dans des régions appartenant principalement au réseau fronto-limbique, dont certaines sont particulièrement sensibles à la maladie d’Alzheimer. De plus, ces symptômes dépressifs sont liés à un taux sanguin d’adrénaline plus élevé et à une connectivité fonctionnelle au repos entre l’hypothalamus et les sous-champs hippocampiques CA1 et Subiculum plus importante – ce qui refléterait une activité plus élevée de l’axe sympatho-medullo-surrénalien lié au stress. Enfin, la présence de ces symptômes avant la pandémie est associée à une détérioration de la santé mentale lors des confinements liés au COVID-19, avec pour facteur prédicteur un niveau de rumination élevé – ce qui n’était pas significativement impacté par l’intervention de méditation du protocole Age-Well. Ces résultats soulignent la nécessité de mettre en place des stratégies préventives et/ou interventionnelles visant à diminuer ces symptômes dépressifs afin d’en limiter les conséquences chez le sujet âgé

Symptômes dépressifs infracliniques chez le sujet âgé et risque de maladie d’Alzheimer : liens avec la neuroimagerie multimodale et les marqueurs sanguins du stress, et évaluation de l’impact de la pandémie de COVID-19 et d’une intervention de méditation

Subclinical depressive symptoms in older adults are associated with an increased risk of developing depression and Alzheimer's disease. However, the brain and biological mechanisms underlying this association are still unclear. The objectives of this thesis were to better characterise the links between subclinical depressive symptoms on the one hand and brain integrity using multimodal neuroimaging, as well as blood markers of stress on the other hand, in cognitively unimpaired older adults. We also assessed the impact of these depressive symptoms on mental health during the COVID-19-related confinements and the potential moderating effect of meditation practice. Our results show that subclinical depressive symptoms are associated with lower brain integrity (i.e. grey matter volume, white matter and glucose metabolism) in regions belonging mainly to the fronto-limbic network, some of which being particularly sensitive to Alzheimer's disease. Furthermore, these depressive symptoms are linked to higher blood levels of epinephrine and higher resting state functional connectivity between the hypothalamus and the hippocampal subfields CA1 and Subiculum - likely reflecting higher activity of the sympatho-adrenomedullary axis linked to stress. Finally, the presence of these symptoms prior to the pandemic was associated with poorer mental health during the COVID-19 confinements, with high rumination as a predictor - which was not significantly impacted by the Age-Well meditation intervention. These results highlight the need for preventive and/or interventional strategies to reduce these depressive symptoms in order to limit their consequences in the elderly.Les symptômes dépressifs infracliniques chez le sujet âgé sont associés à un risque accru de développer une dépression et une maladie d’Alzheimer. Cependant, les mécanismes cérébraux et biologiques sous-tendant cette association sont encore mal connus. Les objectifs de cette thèse étaient de mieux caractériser les liens entre les symptômes dépressifs infracliniques d’une part et l’intégrité cérébrale en neuroimagerie multimodale, ainsi que des marqueurs sanguins du stress d’autre part, chez des sujets âgés cognitivement sains. Nous avons également évalué l’impact de ces symptômes dépressifs sur la santé mentale lors des confinements liés à la pandémie de COVID-19 et le potentiel effet modérateur de la pratique de la méditation. Nos résultats montrent que les symptômes dépressifs infracliniques sont associés à une plus faible intégrité cérébrale (i.e. volume de substance grise, substance blanche et métabolisme du glucose) dans des régions appartenant principalement au réseau fronto-limbique, dont certaines sont particulièrement sensibles à la maladie d’Alzheimer. De plus, ces symptômes dépressifs sont liés à un taux sanguin d’adrénaline plus élevé et à une connectivité fonctionnelle au repos entre l’hypothalamus et les sous-champs hippocampiques CA1 et Subiculum plus importante – ce qui refléterait une activité plus élevée de l’axe sympatho-medullo-surrénalien lié au stress. Enfin, la présence de ces symptômes avant la pandémie est associée à une détérioration de la santé mentale lors des confinements liés au COVID-19, avec pour facteur prédicteur un niveau de rumination élevé – ce qui n’était pas significativement impacté par l’intervention de méditation du protocole Age-Well. Ces résultats soulignent la nécessité de mettre en place des stratégies préventives et/ou interventionnelles visant à diminuer ces symptômes dépressifs afin d’en limiter les conséquences chez le sujet âgé

P4-295: ASSOCIATION OF PERCEIVED MEMORY DECLINE WITH MULTIMODAL NEUROIMAGING AT DIFFERENT STAGES OF ALZHEIMER'S DISEASE

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