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1. Vascular Function Is Improved After an Environmental Enrichment Program

Author

Bruno, Rosa Maria, Stea, Francesco, Sicari, Rosa, Ghiadoni, Lorenzo, Taddei, Stefano, Ungar, Andrea, Bonuccelli, Ubaldo, Tognoni, Gloria, Cintoli, Simona, Del Turco, Serena, Sbrana, Silverio, Gargani, Luna, D'Angelo, Gennaro, Pratali, Lorenza, Berardi, Nicoletta, Maffei, Lamberto, Picano Eugenio, on behalf of Train the Brain Consortium. Full list of consortium members: Maffei L, Picano E, Andreassi MG, Angelucci A, Baldacci F, Baroncelli L, Begenisic T, Bellinvia PF, Berardi N, Biagi L, Bonaccorsi J, Bonanni E, Bonuccelli U, Borghini A, Braschi C, Broccardi M, Bruno RM, Caleo M, Carlesi C, Carnicelli L, Cartoni G, Cecchetti L, Cenni MC, Ceravolo R, Chico L, Cintoli S, Cioni G, Costa M, D’Angelo G, D’Ascanio P, De Nes M, Del Turco S, Di Coscio E, Di Galante M, di Lascio N, Faita F, Falorni I, Faraguna U, Fenu A, Fortunato L, Franco R, Gargani L, Gargiulo R, Ghiadoni L, Giorgi FS, Iannarella R, Iofrida C, Kusmic C, Limongi F, Maestri M, Maffei M, Maggi S, Mainardi M, Mammana L, Marabotti A, Mariotti V, Melissari E, Mercuri A, Molinaro S, Narducci R, Navarra T, Noale M, Pagni C, Palumbo S, Pasquariello R, Pellegrini S, Pietrini P, Pizzorusso T, Poli A, Pratali L, Retico A, Ricciardi E, Rota G, Sale A, Sbrana S, Scabia G, Scali M, Scelfo D, Sicari R, Siciliano G, Stea F, Taddei S, Tognoni G, Tonacci A, Tosetti M, Turchi S, Volpi L, Bruno, Rosa Maria, Stea, Francesco, Sicari, Rosa, Ghiadoni, Lorenzo, Taddei, Stefano, Ungar, Andrea, Bonuccelli, Ubaldo, Tognoni, Gloria, Cintoli, Simona, Del Turco, Serena, Sbrana, Silverio, Gargani, Luna, D'Angelo, Gennaro, Pratali, Lorenza, Berardi, Nicoletta, Maffei, Lamberto, Picano, Eugenio, on behalf of Train the Brain Consortium., Full list of consortium members: Maffei L, Picano, E, Andreassi, Mg, Angelucci, A, Baldacci, F, Baroncelli, L, Begenisic, T, Bellinvia, Pf, Berardi, N, Biagi, L, Bonaccorsi, J, Bonanni, E, Bonuccelli, U, Borghini, A, Braschi, C, Broccardi, M, Bruno, Rm, Caleo, M, Carlesi, C, Carnicelli, L, Cartoni, G, Cecchetti, L, Cenni, Mc, Ceravolo, R, Chico, L, Cintoli, S, Cioni, G, Costa, M, D’Angelo, G, D’Ascanio, P, De Nes, M, Del Turco, S, Di Coscio, E, Di Galante, M, di Lascio, N, Faita, F, Falorni, I, Faraguna, U, Fenu, A, Fortunato, L, Franco, R, Gargani, L, Gargiulo, R, Ghiadoni, L, Giorgi, F, Iannarella, R, Iofrida, C, Kusmic, C, Limongi, F, Maestri, M, Maffei, M, Maggi, S, Mainardi, M, Mammana, L, Marabotti, A, Mariotti, V, Melissari, E, Mercuri, A, Molinaro, S, Narducci, R, Navarra, T, Noale, M, Pagni, C, Palumbo, S, Pasquariello, R, Pellegrini, S, Pietrini, P, Pizzorusso, T, Poli, A, Pratali, L, Retico, A, Ricciardi, E, Rota, G, Sale, A, Sbrana, S, Scabia, G, Scali, M, Scelfo, D, Sicari, R, Siciliano, G, Stea, F, Taddei, S, Tognoni, G, Tonacci, A, Tosetti, M, Turchi, S, and Volpi, L

Subjects
Male, control groups, medicine.medical_specialty, Brachial Artery, Pulse Wave Analysis, 030204 cardiovascular system & hematology, 03 medical and health sciences, endothelial progenitor cell, 0302 clinical medicine, cognitive dysfunction, Internal medicine, medicine.artery, Internal Medicine, medicine, human, Brachial artery, Cognitive decline, humans, Pulse wave velocity, Aged, endothelial progenitor cells, Aged, 80 and over, Environmental enrichment, business.industry, control group, Area under the curve, Neuropsychology, Brain, vascular stiffness, Cognition, Middle Aged, medicine.disease, Exercise Therapy, Vasodilation, Cross-Sectional Studies, Cardiovascular Diseases, Cardiology, Female, Endothelium, Vascular, Alzheimer's disease, business, 030217 neurology & neurosurgery
Abstract

Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65–89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow-mediated dilation, carotid–femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97±2.14% versus 3.73±2.06%; P =0.03) and hyperemic stimulus (shear rate area under the curve, 19.1±15.7 versus 25.7±15.1×10 −3 ; P =0.009); only the latter remained significant after adjustment for confounders ( P =0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0±4.8 to 13.1±5.5; nontraining, 12.1±3.9 to 13.2±4.8; P for interaction visit×training=0.02), flow-mediated dilation (2.82±2.19% to 3.40±1.81%, 3.05±2.08% to 2.24±1.59%; P =0.006; P =0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34 + cells and prevented the decline in carotid distensibility (18.4±5.3 to 20.0±6.6, 23.9±11.0 to 19.5±7.1 Pa −1 ; P =0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34 + cells, and preserved carotid distensibility. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01725178.

Published
2018
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2. Brain Hemodynamic Intermediate Phenotype Links Vitamin B12 to Cognitive Profile of Healthy and Mild Cognitive Impaired Subjects

Author

Cecchetti L., Lettieri G., Handjaras G., Leo A., Ricciardi E., Pietrini P., Pellegrini S., Andreassi M. G., Angelucci A., Baldacci F., Baroncelli L., Begenisic T., Bellinvia P. F., Biagi L., Bonaccorsi J., Bonanni E., Borghini A., Braschi C., Broccardi M., Caleo M., Carlesi C., Carnicelli L., Cartoni G., Cenni M. C., Ceravolo R., Chico L., Cioni G., Costa M., D'Ascanio P., De Nes M., Di Coscio E., Di Galante M., di Lascio N., Faita F., Falorni I., Faraguna U., Fenu A., Fortunato L., Franco R., Gargiulo R., Giorgi F. S., Iannarella R., Iofrida C., Kusmic C., Limongi F., Maestri M., Maffei M., Maggi S., Mainardi M., Mammana L., Marabotti A., Mariotti V., Melissari E., Mercuri A., Molinaro S., Narducci R., Navarra T., Noale M., Pagni C., Palumbo S., Pasquariello R., Pizzorusso T., Poli A., Retico A., Rota G., Sale A., Scabia G., Scali M., Scelfo D., Siciliano G., Tonacci A., Tosetti M., Turchi S., Volpi L., Cecchetti, L., Lettieri, G., Handjaras, G., Leo, A., Ricciardi, E., Pietrini, P., Pellegrini, S., Andreassi, M. G., Angelucci, A., Baldacci, F., Baroncelli, L., Begenisic, T., Bellinvia, P. F., Biagi, L., Bonaccorsi, J., Bonanni, E., Borghini, A., Braschi, C., Broccardi, M., Caleo, M., Carlesi, C., Carnicelli, L., Cartoni, G., Cenni, M. C., Ceravolo, R., Chico, L., Cioni, G., Costa, M., D'Ascanio, P., De Nes, M., Di Coscio, E., Di Galante, M., di Lascio, N., Faita, F., Falorni, I., Faraguna, U., Fenu, A., Fortunato, L., Franco, R., Gargiulo, R., Giorgi, F. S., Iannarella, R., Iofrida, C., Kusmic, C., Limongi, F., Maestri, M., Maffei, M., Maggi, S., Mainardi, M., Mammana, L., Marabotti, A., Mariotti, V., Melissari, E., Mercuri, A., Molinaro, S., Narducci, R., Navarra, T., Noale, M., Pagni, C., Palumbo, S., Pasquariello, R., Pizzorusso, T., Poli, A., Retico, A., Rota, G., Sale, A., Scabia, G., Scali, M., Scelfo, D., Siciliano, G., Tonacci, A., Tosetti, M., Turchi, S., and Volpi, L.

Subjects
Vitamin, Male, medicine.medical_specialty, Article Subject, Homocysteine, Brain activity and meditation, Longitudinal Studie, Settore BIO/09 - Fisiologia, lcsh:RC321-571, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cognition, Neuroimaging, Internal medicine, medicine, Humans, Cognitive Dysfunction, Vitamin B12, Hemodynamic, Longitudinal Studies, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Anterior cingulate cortex, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, business.industry, Neuropsychology, Hemodynamics, Brain, Vitamin B 12, medicine.anatomical_structure, Endocrinology, Phenotype, Neurology, chemistry, Female, Neurology (clinical), Cohort Studie, business, 030217 neurology & neurosurgery, Human, Research Article
Abstract

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.

Published
2019

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

Author

Cintoli, S., Radicchi, C., Noale, M., Maggi, S., Meucci, G., Tognoni, G., Bonuccelli, U., Sale, A., Berardi, N., Maffei, L., Picano, E., Andreassi, M. G., Angelucci, A., Baldacci, F., Baroncelli, L., Begenisic, T., Bellinvia, P. F., Biagi, L., Bonaccorsi, J., Bonanni, E., Borghini, A., Braschi, C., Broccardi, M., Bruno, R. M., Caleo, M., Carlesi, C., Carnicelli, L., Cartoni, G., Cecchetti, L., Cenni, M. C., Ceravolo, R., Chico, L., Cioni, G., Coscia, M., Costa, M., D'Angelo, G., D'Ascanio, P., Denes, M., Delturco, S., Dicoscio, E., Digalante, M., Dilascio, N., Faita, F., Falorni, I., Faraguna, U., Fenu, A., Fortunato, L., Franco, R., Gargani, L., Gargiulo, R., Ghiadoni, L., Giorgi, F. S., Iannarella, R., Iofrida, C., Kusmic, C., Limongi, F., Maestri, M., Maffei, M., Mainardi, M., Mammana, L., Marabotti, A., Mariotti, V., Melissari, E., Mercuri, A., Micera, S., Molinaro, S., Narducci, R., Navarra, T., Pagni, C., Palumbo, S., Pasquariello, R., Pellegrini, S., Pietrini, P., Pizzorusso, T., Poli, A., Pratali, L., Retico, A., Ricciardi, E., Rota, G., Sbrana, S., Scabia, G., Scali, M., Scelfo, D., Sicari, R., Siciliano, G., Stea, F., Taddei, S., Tonacci, A., Tosetti, M., Turchi, S., Volpi, L., Cintoli, S., Radicchi, C., Noale, M., Maggi, S., Meucci, G., Tognoni, G., Bonuccelli, U., Sale, A., Berardi, N., Maffei, L., Picano, E., Andreassi, M. G., Angelucci, A., Baldacci, F., Baroncelli, L., Begenisic, T., Bellinvia, P. F., Biagi, L., Bonaccorsi, J., Bonanni, E., Borghini, A., Braschi, C., Broccardi, M., Bruno, R. M., Caleo, M., Carlesi, C., Carnicelli, L., Cartoni, G., Cecchetti, L., Cenni, M. C., Ceravolo, R., Chico, L., Cioni, G., Coscia, M., Costa, M., D'Angelo, G., D'Ascanio, P., Denes, M., Delturco, S., Dicoscio, E., Digalante, M., Dilascio, N., Faita, F., Falorni, I., Faraguna, U., Fenu, A., Fortunato, L., Franco, R., Gargani, L., Gargiulo, R., Ghiadoni, L., Giorgi, F. S., Iannarella, R., Iofrida, C., Kusmic, C., Limongi, F., Maestri, M., Maffei, M., Mainardi, M., Mammana, L., Marabotti, A., Mariotti, V., Melissari, E., Mercuri, A., Micera, S., Molinaro, S., Narducci, R., Navarra, T., Pagni, C., Palumbo, S., Pasquariello, R., Pellegrini, S., Pietrini, P., Pizzorusso, T., Poli, A., Pratali, L., Retico, A., Ricciardi, E., Rota, G., Sbrana, S., Scabia, G., Scali, M., Scelfo, D., Sicari, R., Siciliano, G., Stea, F., Taddei, S., Tonacci, A., Tosetti, M., Turchi, S., and Volpi, L.

Subjects
Quality of life, medicine.medical_specialty, Aging, education, Psychological intervention, Neuropsychiatric symptom, Disease, Neuropsychological Tests, Settore BIO/09 - Fisiologia, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, mental disorders, Medicine, Dementia, Humans, Mild cognitive impairment, Neuropsychiatric symptoms, Non-pharmacological interventions, Physical and cognitive training, In patient, Cognitive Dysfunction, 030212 general & internal medicine, Cognitive decline, Aged, business.industry, Non-pharmacological intervention, Cognition, medicine.disease, Cognitive training, humanities, Physical therapy, Neuropsychological Test, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Human
Abstract

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 7months 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 7months 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.

Published
2019

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

Author

Cintoli, Simona, Radicchi, Claudia, Noale, Marianna, Maggi, Stefania, Meucci, Giuseppe, Tognoni, Gloria, Bonuccelli, Ubaldo, Sale, Alessandro, Berardi, Nicoletta, Maffei, Lamberto, Train the Brain Consortium, Maffei, L., Picano, E., Andreassi, M. G., Angelucci, A., Baldacci, F., Baroncelli, L., Begenisic, T., Bellinvia, P. F., and Berardi, N.

Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2021
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5. Randomized trial on the effects of a combined physical/cognitive training in aged MCI subjects: the Train the Brain study

Author

Maffei, L., Picano, E., Andreassi, M. G., Angelucci, A., Baldacci, F., Baroncelli, L., Begenisic, T., Bellinvia, P. F., Berardi, N., Biagi, L., Bonaccorsi, J., Bonanni, E., Bonuccelli, U., Borghini, A., Braschi, C., Broccardi, M., Bruno, R. M., Caleo, M., Carlesi, C., Carnicelli, L., Cartoni, G., Cecchetti, L., Cenni, M. C., Ceravolo, R., Chico, L., Cintoli, S., Cioni, G., Coscia, M., Costa, M., D’Angelo, G., D’Ascanio, P., Nes, M. De, Turco, S. Del, Coscio, E. Di, Galante, M. Di, Lascio, N. di, Faita, F., Falorni, I., Faraguna, U., Fenu, A., Fortunato, L., Franco, R., Gargani, L., Gargiulo, R., Ghiadoni, L., Giorgi, F. S., Iannarella, R., Iofrida, C., Kusmic, C., Limongi, F., Maestri, M., Maffei, M., Maggi, S., Mainardi, Marco, Mammana, L., Marabotti, A., Mariotti, V., Melissari, E., Mercuri, A., Micera, S., Molinaro, S., Narducci, R., Navarra, T., Noale, M., Pagni, C., Palumbo, S., Pasquariello, R., Pellegrini, S., Pietrini, P., Pizzorusso, T., Poli, A., Pratali, L., Retico, A., Ricciardi, E., Rota, G., Sale, A., Sbrana, S., Scabia, G., Scali, M., Scelfo, D., Sicari, R., Siciliano, G., Stea, F., Taddei, S., Tognoni, G., Tonacci, A., Tosetti, M., Turchi, S., Volpi, L., Mainardi, Marco (ORCID:0000-0003-2001-1287), Maffei, L., Picano, E., Andreassi, M. G., Angelucci, A., Baldacci, F., Baroncelli, L., Begenisic, T., Bellinvia, P. F., Berardi, N., Biagi, L., Bonaccorsi, J., Bonanni, E., Bonuccelli, U., Borghini, A., Braschi, C., Broccardi, M., Bruno, R. M., Caleo, M., Carlesi, C., Carnicelli, L., Cartoni, G., Cecchetti, L., Cenni, M. C., Ceravolo, R., Chico, L., Cintoli, S., Cioni, G., Coscia, M., Costa, M., D’Angelo, G., D’Ascanio, P., Nes, M. De, Turco, S. Del, Coscio, E. Di, Galante, M. Di, Lascio, N. di, Faita, F., Falorni, I., Faraguna, U., Fenu, A., Fortunato, L., Franco, R., Gargani, L., Gargiulo, R., Ghiadoni, L., Giorgi, F. S., Iannarella, R., Iofrida, C., Kusmic, C., Limongi, F., Maestri, M., Maffei, M., Maggi, S., Mainardi, Marco, Mammana, L., Marabotti, A., Mariotti, V., Melissari, E., Mercuri, A., Micera, S., Molinaro, S., Narducci, R., Navarra, T., Noale, M., Pagni, C., Palumbo, S., Pasquariello, R., Pellegrini, S., Pietrini, P., Pizzorusso, T., Poli, A., Pratali, L., Retico, A., Ricciardi, E., Rota, G., Sale, A., Sbrana, S., Scabia, G., Scali, M., Scelfo, D., Sicari, R., Siciliano, G., Stea, F., Taddei, S., Tognoni, G., Tonacci, A., Tosetti, M., Turchi, S., Volpi, L., and Mainardi, Marco (ORCID:0000-0003-2001-1287)

Abstract

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.

Published
2017

7. Vascular Function Is Improved After an Environmental Enrichment Program: The Train the Brain-Mind the Vessel Study.

Author

Ungar, Andrea, on behalf of the Train the Brain Consortium*, Andreassi, M.G., Angelucci, A., Baldacci, F., Baroncelli, L., Begenisic, T., Bellinvia, P.F., Biagi, L., Bonaccorsi, J., Bonanni, E., Borghini, A., Braschi, C., Broccardi, M., Caleo, M., Carlesi, C., Carnicelli, L., Cartoni, G., Cecchetti, L., and Cenni, M.C.

Abstract

Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65-89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow-mediated dilation, carotid-femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97±2.14% versus 3.73±2.06%; P=0.03) and hyperemic stimulus (shear rate area under the curve, 19.1±15.7 versus 25.7±15.1×10-3; P=0.009); only the latter remained significant after adjustment for confounders (P=0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0±4.8 to 13.1±5.5; nontraining, 12.1±3.9 to 13.2±4.8; P for interaction visit×training=0.02), flow-mediated dilation (2.82±2.19% to 3.40±1.81%, 3.05±2.08% to 2.24±1.59%; P=0.006; P=0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34+ cells and prevented the decline in carotid distensibility (18.4±5.3 to 20.0±6.6, 23.9±11.0 to 19.5±7.1 Pa-1; P=0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34+ cells, and preserved carotid distensibility.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01725178. [ABSTRACT FROM AUTHOR]

Published
2018
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10. Nurturing brain plasticity: impact of environmental enrichment.

Author

Baroncelli, L., Braschi, C., Spolidoro, M., Begenisic, T., Sale, A., and Maffei, L.

Subjects
CENTRAL nervous system, MENTAL illness, NUCLEOPROTEINS, NEUROPLASTICITY, CEREBRAL cortex
Abstract

Environmental enrichment (EE) is known to profoundly affect the central nervous system (CNS) at the functional, anatomical and molecular level, both during the critical period and during adulthood. Recent studies focusing on the visual system have shown that these effects are associated with the recruitment of previously unsuspected neural plasticity processes. At early stages of brain development, EE triggers a marked acceleration in the maturation of the visual system, with maternal behaviour acting as a fundamental mediator of the enriched experience in both the foetus and the newborn. In adult brain, EE enhances plasticity in the cerebral cortex, allowing the recovery of visual functions in amblyopic animals. The molecular substrate of the effects of EE on brain plasticity is multi-factorial, with reduced intracerebral inhibition, enhanced neurotrophin expression and epigenetic changes at the level of chromatin structure. These findings shed new light on the potential of EE as a non-invasive strategy to ameliorate deficits in the development of the CNS and to treat neurological disorders. [ABSTRACT FROM AUTHOR]

Published
2010
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11. Quantification and prospective evaluation of serum NfL and GFAP as blood-derived biomarkers of outcome in acute ischemic stroke patients.

Author

Ferrari F, Rossi D, Ricciardi A, Morasso C, Brambilla L, Albasini S, Vanna R, Fassio C, Begenisic T, Loi M, Bossi D, Zaliani A, Alberici E, Lisi C, Morotti A, Cavallini A, Mazzacane F, Nardone A, Corsi F, and Truffi M

Subjects
Humans, Glial Fibrillary Acidic Protein, Intermediate Filaments, Biomarkers, Ischemic Stroke, Stroke
Abstract

Identification of reliable and accessible biomarkers to characterize ischemic stroke patients' prognosis remains a clinical challenge. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are markers of brain injury, detectable in blood by high-sensitive technologies. Our aim was to measure serum NfL and GFAP after stroke, and to evaluate their correlation with functional outcome and the scores in rehabilitation scales at 3-month follow-up. Stroke patients were prospectively enrolled in a longitudinal observational study within 24 hours from symptom onset (D1) and monitored after 7 (D7), 30 ± 3 (M1) and 90 ± 5 (M3) days. At each time-point serum NfL and GFAP levels were measured by Single Molecule Array and correlated with National Institute of Health Stroke Scale (NIHSS), modified Rankin scale (mRS), Trunk Control Test (TCT), Functional Ambulation Classification (FAC) and Functional Independence Measure (FIM) scores. Serum NfL and GFAP showed different temporal profiles: NfL increased after stroke with a peak value at D7; GFAP showed an earlier peak at D1. NfL and GFAP concentrations correlated with clinical/rehabilitation outcomes both longitudinally and prospectively. Multivariate analysis revealed that NfL-D7 and GFAP-D1 were independent predictors of 3-month NIHSS, TCT, FAC and FIM scores, with NfL being the biomarker with the best predictive performance.

Published
2023
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14. Dynamics of biomarkers across the stages of traumatic spinal cord injury - implications for neural plasticity and repair.

Author

Begenisic T, Pavese C, Aiachini B, Nardone A, and Rossi D

Subjects
Animals, Biomarkers, Neuronal Plasticity physiology, Recovery of Function physiology, Spinal Cord pathology, MicroRNAs metabolism, Spinal Cord Injuries pathology
Abstract

Background: Traumatic spinal cord injury (SCI) is a complex medical condition causing significant physical disability and psychological distress. While the adult spinal cord is characterized by poor regenerative potential, some recovery of neurological function is still possible through activation of neural plasticity mechanisms. We still have limited knowledge about the activation of these mechanisms in the different stages after human SCI., Objective: In this review, we discuss the potential role of biomarkers of SCI as indicators of the plasticity mechanisms at work during the different phases of SCI., Methods: An extensive review of literature related to SCI pathophysiology, neural plasticity and humoral biomarkers was conducted by consulting the PubMed database. Research and review articles from SCI animal models and SCI clinical trials published in English until January 2021 were reviewed. The selection of candidates for humoral biomarkers of plasticity after SCI was based on the following criteria: 1) strong evidence supporting involvement in neural plasticity (mandatory); 2) evidence supporting altered expression after SCI (optional)., Results: Based on selected findings, we identified two main groups of potential humoral biomarkers of neural plasticity after SCI: 1) neurotrophic factors including: Brain derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Neurotrofin-3 (NT-3), and Insulin-like growth factor 1 (IGF-1); 2) other factors including: Tumor necrosis factor-alpha (TNF-α), Matrix Metalloproteinases (MMPs), and MicroRNAs (miRNAs). Plasticity changes associated with these biomarkers often can be both adaptive (promoting functional improvement) and maladaptive. This dual role seems to be influenced by their concentrations and time-window during SCI., Conclusions: Further studies of dynamics of biomarkers across the stages of SCI are necessary to elucidate the way in which they reflect the remodeling of neural pathways. A better knowledge about the mechanisms underlying plasticity could guide the selection of more appropriate therapeutic strategies to enhance positive spinal network reorganization.

Published
2021
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15. Preservation of Visual Cortex Plasticity in Retinitis Pigmentosa.

Author

Begenisic T, Mazziotti R, Sagona G, Lupori L, Sale A, Galli L, and Baroncelli L

Subjects
Animals, Electroretinography methods, Female, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Retina physiopathology, Retinitis Pigmentosa genetics, Neuronal Plasticity physiology, Retinitis Pigmentosa physiopathology, Visual Cortex physiology
Abstract

Retinitis Pigmentosa (RP) is a class of inherited disorders caused by the progressive death of photoreceptors in the retina. RP is still orphan of an effective treatment, with increasing optimism deriving from research aimed at arresting neurodegeneration or replacing light-responsive elements. All these therapeutic strategies rely on the functional integrity of the visual system downstream of photoreceptors. Whereas the inner retinal structure and optic radiation are known to be considerably preserved at least in early stages of RP, very little is known about the visual cortex. Remarkably, it remains completely unclear whether visual cortex plasticity is still present in RP. Using a well-established murine model of RP, the rd10 mouse, we report that visual cortical circuits retain high levels of plasticity, preserving their capability of input-dependent remodelling even at a late stage of retinal degeneration., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Published
2020
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16. Early impoverished environment delays the maturation of cerebral cortex.

Author

Narducci R, Baroncelli L, Sansevero G, Begenisic T, Prontera C, Sale A, Cenni MC, Berardi N, and Maffei L

Subjects
Animals, Axons metabolism, Biomarkers, Body Weight, Cerebral Cortex growth & development, Cerebral Cortex metabolism, Evoked Potentials, Visual, Female, Insulin-Like Growth Factor I metabolism, Male, Memory, Motor Activity, Myelin Sheath metabolism, Neurons metabolism, Phosphorylation, Rats, Visual Acuity, Visual Cortex, Cerebral Cortex physiology, Maternal-Fetal Relations, Neurogenesis
Abstract

The influence of exposure to impoverished environments on brain development is unexplored since most studies investigated how environmental impoverishment affects adult brain. To shed light on the impact of early impoverishment on developmental trajectories of the nervous system, we developed a protocol of environmental impoverishment in which dams and pups lived from birth in a condition of reduced sensory-motor stimulation. Focusing on visual system, we measured two indexes of functional development, that is visual acuity, assessed by using Visual Evoked Potentials (VEPs), and VEP latency. In addition, we assessed in the visual cortex levels of Insulin-Like Growth Factor 1 (IGF-1) and myelin maturation, together with the expression of the GABA biosynthetic enzyme GAD67. We found that early impoverishment strongly delays visual acuity and VEP latency development. These functional changes were accompanied by a significant reduction of IGF-1 protein and GAD67 expression, as well as by delayed myelination of nerve fibers, in the visual cortex of impoverished pups. Thus, exposure to impoverished living conditions causes a significant alteration of developmental trajectories leading to a prominent delay of brain maturation. These results underscore the significance of adequate levels of environmental stimulation for the maturation of central nervous system.

Published
2018
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17. Experience-dependent reduction of soluble β-amyloid oligomers and rescue of cognitive abilities in middle-age Ts65Dn mice, a model of Down syndrome.

Author

Sansevero G, Begenisic T, Mainardi M, and Sale A

Subjects
Aging, Amyloid beta-Peptides immunology, Amyloid beta-Peptides metabolism, Animals, Antibodies pharmacology, Antibodies therapeutic use, Disease Models, Animal, Humans, Maze Learning drug effects, Maze Learning physiology, Memory Disorders etiology, Memory Disorders therapy, Mice, Mice, Transgenic, Neprilysin immunology, Statistics, Nonparametric, Swimming psychology, Time Factors, Amyloid beta-Peptides chemistry, Cognition Disorders etiology, Cognition Disorders therapy, Down Syndrome complications, Environment, Morpholinos therapeutic use
Abstract

Down syndrome (DS) is the most diffused genetic cause of intellectual disability and, after the age of forty, is invariantly associated with Alzheimer's disease (AD). In the last years, the prolongation of life expectancy in people with DS renders the need for intervention paradigms aimed at improving mental disability and counteracting AD pathology particularly urgent. At present, however, there are no effective therapeutic strategies for DS and concomitant AD in mid-life people. The most intensively studied mouse model of DS is the Ts65Dn line, which summarizes the main hallmarks of the DS phenotype, included severe learning and memory deficits and age-dependent AD-like pathology. Here we report for the first time that middle-age Ts65Dn mice display a marked increase in soluble Aβ oligomer levels in their hippocampus. Moreover, we found that long-term exposure to environmental enrichment (EE), a widely used paradigm that increases sensory-motor stimulation, reduces Aβ oligomers and rescues spatial memory abilities in trisomic mice. Our findings underscore the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes in DS subjects., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2016
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18. Early environmental therapy rescues brain development in a mouse model of Down syndrome.

Author

Begenisic T, Sansevero G, Baroncelli L, Cioni G, and Sale A

Subjects
Animals, Brain-Derived Neurotrophic Factor metabolism, Disease Models, Animal, Down Syndrome psychology, Environment, Evoked Potentials, Visual, Female, Hippocampus growth & development, Long-Term Potentiation physiology, Male, Maternal Behavior, Mice, Inbred C57BL, Mice, Transgenic, Recognition, Psychology physiology, Tissue Culture Techniques, Vesicular Inhibitory Amino Acid Transport Proteins metabolism, Visual Acuity, Visual Pathways growth & development, gamma-Aminobutyric Acid metabolism, Down Syndrome physiopathology, Down Syndrome therapy, Hippocampus physiopathology, Visual Pathways physiopathology
Abstract

Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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19. Fluoxetine in adulthood normalizes GABA release and rescues hippocampal synaptic plasticity and spatial memory in a mouse model of Down syndrome.

Author

Begenisic T, Baroncelli L, Sansevero G, Milanese M, Bonifacino T, Bonanno G, Cioni G, Maffei L, and Sale A

Subjects
Analysis of Variance, Animals, Antidepressive Agents, Second-Generation pharmacology, Biophysics, Disease Models, Animal, Down Syndrome complications, Down Syndrome genetics, Electric Stimulation, Fluoxetine pharmacology, Hippocampus drug effects, In Vitro Techniques, Maze Learning drug effects, Mice, Mice, Inbred C57BL, Mice, Transgenic, Recognition, Psychology drug effects, Synaptosomes drug effects, Synaptosomes metabolism, Antidepressive Agents, Second-Generation therapeutic use, Down Syndrome pathology, Fluoxetine therapeutic use, Hippocampus pathology, Memory Disorders drug therapy, Neuronal Plasticity drug effects, Space Perception drug effects, gamma-Aminobutyric Acid metabolism
Abstract

Down syndrome (DS) is the most common genetic disorder associated with mental retardation. It has been repeatedly shown that Ts65Dn mice, the major animal model for DS, have severe cognitive and synaptic plasticity dysfunctions caused by excessive inhibition in their temporal lobe structures. Here we employed a multidisciplinary approach spanning from the behavioral to the electrophysiological and molecular level to investigate the effects elicited by fluoxetine on cognitive abilities, hippocampal synaptic plasticity and GABA release in adult Ts65Dn mice. We report that a chronic treatment with fluoxetine administered in the drinking water normalizes GABA release and promotes recovery of spatial memory abilities, spatial working memory for alternation, and hippocampal synaptic plasticity in adult Ts65Dn mice. Our findings might encourage new experimental attempts aimed at investigating the potential of fluoxetine for application in the treatment of major functional deficits in adult people with DS., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Published
2014
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20. Fluoxetine treatment promotes functional recovery in a rat model of cervical spinal cord injury.

Author

Scali M, Begenisic T, Mainardi M, Milanese M, Bonifacino T, Bonanno G, Sale A, and Maffei L

Subjects
Animals, Disease Models, Animal, Fluoxetine administration & dosage, Gait drug effects, Male, Motor Activity drug effects, Motor Cortex drug effects, Neuronal Plasticity drug effects, Psychomotor Performance drug effects, Rats, Selective Serotonin Reuptake Inhibitors administration & dosage, Spinal Cord drug effects, Spinal Cord pathology, Spinal Cord physiopathology, Time Factors, Fluoxetine pharmacology, Recovery of Function drug effects, Selective Serotonin Reuptake Inhibitors pharmacology, Spinal Cord Injuries rehabilitation, Spinal Cord Injuries therapy
Abstract

Spinal cord injury (SCI) is a severe condition leading to enduring motor deficits. When lesions are incomplete, promoting spinal cord plasticity might be a useful strategy to elicit functional recovery. Here we investigated whether long-term fluoxetine administration in the drinking water, a treatment recently demonstrated to optimize brain plasticity in several pathological conditions, promotes motor recovery in rats that received a C4 dorsal funiculus crush. We show that fluoxetine administration markedly improved motor functions compared to controls in several behavioral paradigms. The improved functional effects correlated positively with significant sprouting of intact corticospinal fibers and a modulation of the excitation/inhibition balance. Our results suggest a potential application of fluoxetine treatment as a non invasive therapeutic strategy for SCI-associated neuropathologies.

Published
2013
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21. Environmental enrichment decreases GABAergic inhibition and improves cognitive abilities, synaptic plasticity, and visual functions in a mouse model of Down syndrome.

Author

Begenisic T, Spolidoro M, Braschi C, Baroncelli L, Milanese M, Pietra G, Fabbri ME, Bonanno G, Cioni G, Maffei L, and Sale A

Abstract

Down syndrome (DS) is the most common genetic disorder associated with mental retardation. It has been repeatedly shown that Ts65Dn mice, the prime animal model for DS, have severe cognitive and neural plasticity defects due to excessive inhibition. We report that increasing sensory-motor stimulation in adulthood through environmental enrichment (EE) reduces brain inhibition levels and promotes recovery of spatial memory abilities, hippocampal synaptic plasticity, and visual functions in adult Ts65Dn mice.

Published
2011
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22. Brain plasticity and disease: a matter of inhibition.

Author

Baroncelli L, Braschi C, Spolidoro M, Begenisic T, Maffei L, and Sale A

Subjects
Autistic Disorder physiopathology, Down Syndrome physiopathology, Humans, Rett Syndrome physiopathology, Brain physiology, Neural Inhibition physiology, Neuronal Plasticity physiology, Neurons physiology, gamma-Aminobutyric Acid physiology
Abstract

One major goal in Neuroscience is the development of strategies promoting neural plasticity in the adult central nervous system, when functional recovery from brain disease and injury is limited. New evidence has underscored a pivotal role for cortical inhibitory circuitries in regulating plasticity both during development and in adulthood. This paper summarizes recent findings showing that the inhibition-excitation balance controls adult brain plasticity and is at the core of the pathogenesis of neurodevelopmental disorders like autism, Down syndrome, and Rett syndrome.

Published
2011
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