Brain hemodynamic intermediate phenotype links Vitamin B12 to cognitive profile of healthy and mild cognitive impaired subjects

Vitamin B12, folate, and homocysteine are implicated in pivotal neurodegenerative mechanisms and partake in elders' mental decline. Findings on the association between vitamin-related biochemistry and cognitive abilities suggest that the structural and functional properties of the brain may represent an intermediate biomarker linking vitamin concentrations to cognition. Despite this, no previous study directly investigated whether vitamin B12, folate, and homocysteine levels are sufficient to explain individual neuropsychological profiles or, alternatively, whether the activity of brain regions modulated by these compounds better predicts cognition in elders. Here, we measured the relationship between vitamin blood concentrations, scores at seventeen neuropsychological tests, and brain activity of sixty-five elders spanning from normal to Mild Cognitive Impairment. We then evaluated whether task-related brain responses represent an intermediate phenotype, providing a better prediction of subjects' neuropsychological scores, as compared to the one obtained considering blood biochemistry only. We found that the hemodynamic activity of the right dorsal anterior cingulate cortex was positively associated (p value < 0 05 cluster corrected) with vitamin B12 concentrations, suggesting that elders with higher B12 levels had a more pronounced recruitment of this salience network region. Crucially, the activity of this area significantly predicted subjects' visual search and attention abilities (p value = 0 0023), whereas B12 levels per se failed to do so. Our results demonstrate that the relationship between blood biochemistry and elders' cognitive abilities is revealed when brain activity is included into the equation, thus highlighting the role of brain imaging as intermediate phenotype.Vitamin B12, folate, and homocysteine are implicated in pivotal neurodegenerative mechanisms and partake in elders' mental decline. Findings on the association between vitamin-related biochemistry and cognitive abilities suggest that the structural and functional properties of the brain may represent an intermediate biomarker linking vitamin concentrations to cognition. Despite this, no previous study directly investigated whether vitamin B12, folate, and homocysteine levels are sufficient to explain individual neuropsychological profiles or, alternatively, whether the activity of brain regions modulated by these compounds better predicts cognition in elders. Here, we measured the relationship between vitamin blood concentrations, scores at seventeen neuropsychological tests, and brain activity of sixty-five elders spanning from normal to Mild Cognitive Impairment. We then evaluated whether task-related brain responses represent an intermediate phenotype, providing a better prediction of subjects' neuropsychological scores, as compared to the one obtained considering blood biochemistry only. We found that the hemodynamic activity of the right dorsal anterior cingulate cortex was positively associated (p value < 0 05 cluster corrected) with vitamin B12 concentrations, suggesting that elders with higher B12 levels had a more pronounced recruitment of this salience network region. Crucially, the activity of this area significantly predicted subjects' visual search and attention abilities (p value = 0 0023), whereas B12 levels per se failed to do so. Our results demonstrate that the relationship between blood biochemistry and elders' cognitive abilities is revealed when brain activity is included into the equation, thus highlighting the role of brain imaging as intermediate phenotype

Randomized trial on the effects of a combined physical/cognitive training in aged MCI subjects: the Train the Brain study

Age-related cognitive impairment and dementia are an increasing societal burden. Epidemiological studies indicate that lifestyle factors, e.g. physical, cognitive and social activities, correlate with reduced dementia risk; moreover, positive effects on cognition of physical/cognitive training have been found in cognitively unimpaired elders. Less is known about effectiveness and action mechanisms of physical/cognitive training in elders already suffering from Mild Cognitive Impairment (MCI), a population at high risk for dementia. We assessed in 113 MCI subjects aged 65-89 years, the efficacy of combined physical-cognitive training on cognitive decline, Gray Matter (GM) volume loss and Cerebral Blood Flow (CBF) in hippocampus and parahippocampal areas, and on brain-blood-oxygenation-level-dependent (BOLD) activity elicited by a cognitive task, measured by ADAS-Cog scale, Magnetic Resonance Imaging (MRI), Arterial Spin Labeling (ASL) and fMRI, respectively, before and after 7 months of training vs. usual life. Cognitive status significantly decreased in MCI-no training and significantly increased in MCI-training subjects; training increased parahippocampal CBF, but no effect on GM volume loss was evident; BOLD activity increase, indicative of neural efficiency decline, was found only in MCI-no training subjects. These results show that a non pharmacological, multicomponent intervention improves cognitive status and indicators of brain health in MCI subjects

MÖSSBAUER EFFECT (ME) OF IMPURITIES IN HYDROGEN-LOADED PALLADIUM

Il a déjà été montré [1] que le déplacement isomérique (IS) de l'effet Mössbauer de 197Au, 195Pt, 193Ir et 99Ru dilués dans le palladium présente des variations systématiques quand la matrice est chargée d'hydrogène. La variation de IS correspond toujours à une diminution de la densité électronique au noyau de l'impureté. Dans le présent travail, nous suggérons que deux aspects fondamentaux doivent être soulignés lors de l'interprétation de ces résultats : 1) Pour tous les isotopes, la variation de IS avec la concentration d'hydrogène indique la présence des phases α et β dotées de valeurs différentes de IS. 99Ru semble être l'isotope donnant la meilleure résolution pour étudier des diagrammes de phase. 2) Le problème de l'interprétation de changements systématiques de IS lors du passage de la phase α à la phase β, pour les isotopes ci-dessus. A propos de la deuxième question, nous suggérons qu'un traitement convenable consiste à traiter l'impureté comme un centre de dispersion des électrons de conduction de la matrice. Les données d'entrée sont : a) les différences de structure électronique entre les atomes de l'impureté et de la matrice (effets de charge et de nœud) ; b) la structure des bandes des états de conduction de la matrice (Pd ou Pd-H0.7). Il est important d'observer que l'évaluation du potentiel d'impureté qui détermine les densités électroniques qui contribuent au IS, dépend de la solution des problèmes de dispersion dans lesquels a) et b) sont des conditions initiales. Des modifications de a) (substitution d'une impureté par une autre) ou de b) (modification de la structure de bande en allant de Pd à Pd-H0.7) doivent montrer des variations de IS (observées expérimentalement). Dans un travail récent [2], il a été montré par la technique XPS que les structures de bande de Pd-H et Pd sont différentes. Ainsi par exemple, la phase β (H/Pd = 0,7) présente de nouveaux états situés immédiatement au-dessous du fond des bandes correspondant au Pd. Avec les arguments ci-dessus nous arrivons à la conclusion que la systématique de IS des impuretés dans le Pd et Pd-H reflète l'importance des conditions a) et b). Ces arguments renforcent ainsi notre idée que le même point de vue s'applique à la systématique du IS dans les alliages dilués des métaux de transition [3]. Une formulation théorique générale traitant l'impureté comme un centre de dispersion selon le point de vue ci-dessus, a été précédemment établie [4]. Cependant, des résultats numériques ne peuvent être obtenus qu'au moyen d'approximations importantes, ce qui ne permet pas la comparaison détaillée avec des résultats expérimentaux. En dépit de cela, on peut s'attendre à ce que des tendances générales puissent apparaître même en utilisant des modèles élémentaires et des approximations convenables.Previously [1] it was shown that the Isomer Shift (IS) of ME of 197Au, 195Pt, 193Ir and 99Ru diluted in Palladium exhibited systematic changes when the host is loaded with hydrogen. The IS changes always correspond to a decrease of the electronic density at the impurity nuclei. In this work we suggest that in interpreting these results two basic features should be emphasized : 1) For all isotopes the change of IS with hydrogen content indicates the presence of α and β phases with two distinct values of IS. 99Ru seems to be the isotope of best resolution for the purpose of studying phase diagrams ; 2) The remaining problem of interpreting the systematic changes of IS, in going from α to β phase, for the above mentioned isotopes. Concerning the second question we propose that an appropriate formulation consists in treating the impurity as a scattering center for the matrix conduction electrons. The input data are : a) differences in electronic structure between the impurity and host atoms (charge and node effects) ; b) the band structure of the matrix conduction states (Pd or Pd-H0.7). One should note that the self consistent evaluation of the impurity potential, which determines the electronic densities of interest to IS, depends on the solution of the scattering problems in which a) and b) are initial conditions. Changes in conditions a) (substitution of an impurity for another) or b) (modification of the band structure when one goes from Pd to Pd-H0.7) should give rise to IS variations (experimentally observed). In a recent paper [2] it was shown by XPS technique that the band structure of Pd-H and Pd are différent ; e.g. the β phase (H/Pd 0.7) has new states just below the bottom of the corresponding d bands of Pd. From the above arguments we come to the conclusion that the IS systematics of ME of impurities in Pd and Pd-H reflect the importance of items a) and b). They also reinforce our opinion that the same point of view applies for the systematics of IS in diluted alloys of transition metals [3]. A general theoretical formulation which treats the impurity as a scattering center along the lines above mentioned has previously been done [4]. Numerical results, however, can only be obtained using drastic approximations which rules out detailed comparison with experimental results. Not with standing one would expect that general trends should emerge even using crude models and adequate approximations

MÖSSBAUER STUDY OF TRANSITION METAL IMPURITIES IN HYDROGEN-LOADED PALLADIUM

On a étudié l'influence du chargement d'une matrice de palladium avec de l'hydrogène sur les déplacements isomériques d'impuretés de 197Au, 195Pt, 193Ir et 99Ru. Dans tous ces systèmes on a trouvé que la densité d'électrons aux noyaux des impuretés Mössbauer décroît comme conséquence de l'hydrogénisation. Le décroissement est comparable à la différence des densités d'électrons observée dans des matrices de Pd et de Ag.The influence of hydrogen-loading of a palladium matrix on the isomer shifts for impurities of 197Au, 195Pt, 193Ir and 99Ru has been studied. In all these systems the electron density at the nuclei of the Mossbauer impurity has been found to decrease on hydrogenation. The decrease is comparable to the electron density difference observed between Pd and Ag matrices

CIS controls the functional polarization of GM-CSF-derived macrophages

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the capacity to differentiate monocytes into macrophages (MØs) with opposing functions, namely, proinflammatory M1-like MØs and immunosuppressive M2-like MØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here, we showed that GM-CSF-induced MØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive M2-like MØs. CIS deficiency resulted in hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss- and gain-of-function approaches highlighted IRF8 as a critical regulator of the M1-like polarization program. In vivo, CIS deficiency induced the differentiation of M2-like macrophages, which promoted strong Th2 immune responses characterized by the development of severe experimental asthma. Collectively, our results reveal a CIS-modulated mechanism that clarifies the opposing actions of GM-CSF in MØ differentiation and uncovers the role of GM-CSF in controlling allergic inflammation.Shengbo Zhang ... Naiara G. Bediaga ... et al

Long-term beneficial impact of the randomised trial ‘Train the Brain’, a motor/cognitive intervention in mild cognitive impairment people: effects at the 14-month follow-up

No treatment options are currently available to counteract cognitive deficits and/or delay progression towards dementia in older people with mild cognitive impairment (MCI). The ‘Train the Brain’ programme is a combined motor and cognitive intervention previously shown to markedly improve cognitive functions in MCI individuals compared to non-trained MCI controls, as assessed at the end of the 7-month intervention. Here, we extended the previous analyses to include the long-term effects of the intervention and performed a data disaggregation by gender, education and age of the enrolled participants. We report that the beneficial impact on cognitive functions was preserved at the 14-month follow-up, with greater effects in low-educated compared to high-educated individuals, and in women than in men

Effects of combined training on neuropsychiatric symptoms and quality of life in patients with cognitive decline

Background and aims: Cognitive impairments associated with aging and dementia are major sources of neuropsychiatric symptoms (NPs) and deterioration in quality of life (QoL). Preventive measures to both reduce disease and improve QoL in those affected are increasingly targeting individuals with mild cognitive impairment (MCI) at early disease stage. However, NPs and QoL outcomes are too commonly overlooked in intervention trials. The purpose of this study was to test the effects of physical and cognitive training on NPs and QoL in MCI. Methods: Baseline data from an MCI court (N = 93, mean age 74.9 ± 4.7) enrolled in the Train the Brain (TtB) study were collected. Subjects were randomized in two groups: a group participated to a cognitive and physical training program, while the other sticked to usual standard care. Both groups underwent a follow-up re-evaluation after 7 months from baseline. NPs were assessed using the Neuropsychiatric Inventory (NPI) and QoL was assessed using Quality of Life-Alzheimer’s Disease (QOL-AD) scale. Results: After 7 months of training, training group exhibited a significant reduction of NPs and a significant increase in QOL-AD with respect to no-training group (p = 0.0155, p = 0.0013, respectively). Our preliminary results suggest that a combined training can reduce NPs and improve QoL. Conclusions: Measuring QoL outcomes is a potentially important factor in ensuring that a person with cognitive deficits can ‘live well’ with pathology. Future data from non-pharmacological interventions, with a larger sample and a longer follow-up period, could confirm the results and the possible implications for such prevention strategies for early cognitive decline.Background and aims: Cognitive impairments associated with aging and dementia are major sources of neuropsychiatric symptoms (NPs) and deterioration in quality of life (QoL). Preventive measures to both reduce disease and improve QoL in those affected are increasingly targeting individuals with mild cognitive impairment (MCI) at early disease stage. However, NPs and QoL outcomes are too commonly overlooked in intervention trials. The purpose of this study was to test the effects of physical and cognitive training on NPs and QoL in MCI. Methods: Baseline data from an MCI court (N = 93, mean age 74.9 ± 4.7) enrolled in the Train the Brain (TtB) study were collected. Subjects were randomized in two groups: a group participated to a cognitive and physical training program, while the other sticked to usual standard care. Both groups underwent a follow-up re-evaluation after 7 months from baseline. NPs were assessed using the Neuropsychiatric Inventory (NPI) and QoL was assessed using Quality of Life-Alzheimer’s Disease (QOL-AD) scale. Results: After 7 months of training, training group exhibited a significant reduction of NPs and a significant increase in QOL-AD with respect to no-training group (p = 0.0155, p = 0.0013, respectively). Our preliminary results suggest that a combined training can reduce NPs and improve QoL. Conclusions: Measuring QoL outcomes is a potentially important factor in ensuring that a person with cognitive deficits can ‘live well’ with pathology. Future data from non-pharmacological interventions, with a larger sample and a longer follow-up period, could confirm the results and the possible implications for such prevention strategies for early cognitive decline

Effects of combined training on neuropsychiatric symptoms and quality of life in patients with cognitive decline

BACKGROUND AND AIMS: Cognitive impairments associated with aging and dementia are major sources of neuropsychiatric symptoms (NPs) and deterioration in quality of life (QoL). Preventive measures to both reduce disease and improve QoL in those affected are increasingly targeting individuals with mild cognitive impairment (MCI) at early disease stage. However, NPs and QoL outcomes are too commonly overlooked in intervention trials. The purpose of this study was to test the effects of physical and cognitive training on NPs and QoL in MCI. METHODS: Baseline data from an MCI court (N = 93, mean age 74.9 ± 4.7) enrolled in the Train the Brain (TtB) study were collected. Subjects were randomized in two groups: a group participated to a cognitive and physical training program, while the other sticked to usual standard care. Both groups underwent a follow-up re-evaluation after 7 months from baseline. NPs were assessed using the Neuropsychiatric Inventory (NPI) and QoL was assessed using Quality of Life-Alzheimer's Disease (QOL-AD) scale. RESULTS: After 7 months of training, training group exhibited a significant reduction of NPs and a significant increase in QOL-AD with respect to no-training group (p = 0.0155, p = 0.0013, respectively). Our preliminary results suggest that a combined training can reduce NPs and improve QoL. CONCLUSIONS: Measuring QoL outcomes is a potentially important factor in ensuring that a person with cognitive deficits can 'live well' with pathology. Future data from non-pharmacological interventions, with a larger sample and a longer follow-up period, could confirm the results and the possible implications for such prevention strategies for early cognitive decline