Authors: D’Amelio, Marcello | Serra, Laura | Bozzali, Marco
Article Type: Article Commentary
Abstract: Alzheimer’s disease (AD) is a progressive neurological disorder characterized by several cognitive and non-cognitive symptoms, with episodic memory being the earliest and most prominently impaired cognitive function. Dopaminergic signals are required for encoding hippocampal memory for new events and the ventral tegmental area (VTA), together with the locus coeruleus, are the primary sources of dopamine acting on dopaminergic receptors in the hippocampus. With this in mind, a recent study on a validated mouse model of AD highlighted on the hippocampal dysfunction and its correlation with an early degeneration of dopaminergic neurons in the VTA. In this issue, De Marco and …Venneri test the hypothesis that the volume of the VTA nucleus in humans might be associated with cognitive features of AD. Show more
Keywords: Alzheimer’s disease, dopamine, hippocampus, memory, midbrain, ventral tegmental area
DOI: 10.3233/JAD-180094
Citation: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 181-183, 2018
Authors: Serra, Laura | Gelfo, Francesca | Petrosini, Laura | Di Domenico, Carlotta | Bozzali, Marco | Caltagirone, Carlo
Article Type: Review Article
Abstract: The concept of brain, cognitive , and neural reserves has been introduced to account for the apparent discrepancies between neurological damage and clinical manifestations. However, these ideas are yet theoretical suggestions that are not completely assimilated in the clinical routine. The mechanisms of the reserves have been extensively studied in neurodegenerative pathologies, in particular in Alzheimer’s disease. Both human and animal studies addressed this topic by following two parallel pathways. The specific aim of the present review is to attempt to combine the suggestions derived from the two different research fields to deepen the knowledge about reserves. In fact, the …achievement of a comprehensive theoretical framework on reserve mechanisms is an essential step to propose well-timed interventions tailored to the clinical characteristics of patients. The present review highlights the importance of addressing three main aspects: the definition of reserve proxy measures, the interaction between reserve level and therapeutic interventions, and the specific time-window of reserve efficacy. Show more
Keywords: Alzheimer’s disease, animal studies, environmental enrichment, human studies, MRI, reserve mechanisms
DOI: 10.3233/JAD-180609
Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1065-1078, 2018
Authors: Makovac, Elena | Serra, Laura | Di Domenico, Carlotta | Marra, Camillo | Caltagirone, Carlo | Cercignani, Mara | Bozzali, Marco
Article Type: Research Article
Abstract: Patients with amnestic mild cognitive impairment (aMCI) have higher probability to develop Alzheimer’s disease (AD) than elderly controls. The detection of subtle changes in brain structure associated with disease progression and the development of tools to identify patients at high risk for dementia in a short time is crucial. Here, we used probabilistic white matter (WM) tractography to explore microstructural alterations within the main association, limbic, and commissural pathways in aMCI patients who converted to AD after 1 year follow-up (MCIconverters ) and those who remained stable (MCIstable ). Both diffusion tensor imaging (DTI) and quantitative magnetization transfer (qMT) parameters …have been considered for a comprehensive pathophysiological characterization of the WM damage. Overall, tract-specific parameters derived from qMT and DTI at baseline were able to differentiate aMCI patients who converted to AD from those who remained stable in time. In particular, the qMT exchange rate, RMB 0 , of the right uncinate fasciculus was significantly decreased in MCIconverters , whereas fractional anisotropy was significantly decreased in the bilateral superior cingulum in MCIconverters compared to MCIstable . These results confirm the involvement of WM and particularly of association fibers in the progression of AD, highlighting disconnection as a potential mechanism. Show more
Keywords: Diffusion tensor imaging, mild cognitive impairment, probabilistic tractography, quantitative magnetization transfer, white matter
DOI: 10.3233/JAD-170995
Citation: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 561-575, 2018
Authors: Rodini, Marta | Bonarota, Sabrina | Serra, Laura | Caltagirone, Carlo | Carlesimo, Giovanni Augusto
Article Type: Research Article
Abstract: Background: Recently, subjective cognitive decline (SCD) was proposed as an early risk factor for future Alzheimer’s disease (AD). Objective: In this study, we investigated whether accelerated long-term forgetting (ALF), assessed with extended testing intervals than those adopted in clinical practice, might be a cognitive feature of SCD. Using an explorative MRI analysis of the SCD sample, we attempted to investigate the areas most likely involved in the ALF pattern. Methods: We recruited 31 individuals with SCD from our memory clinic and subdivided them based on their rate of memory complaints into mild SCDs (n = 18) and severe SCDs (n = 13). …A long-term forgetting procedure, involving the recall of verbal and visuo-spatial material at four testing delays (i.e., immediate, 30 min, 24 h, and 7 days post-encoding) was used to compare the two sub-groups of SCDs with a healthy control group (HC; n = 16). Results: No significant between-group difference was found on the standard neuropsychological tests, nor in the immediate and 30 min recall of the experimental procedure. By contrast, on the verbal test severe SCDs forgot significantly more than HCs in the prolonged intervals (i.e., 24 h and 7 days), with the greatest decline between 30 min and 24 h. Finally, in the whole SCD sample, we found significant associations between functional connectivity values within some cortical networks involved in memory (default mode network, salience network, and fronto-parietal network) and verbal long-term measures. Conclusions: Our preliminary findings suggest that long-term forgetting procedures could be a sensitive neuropsychological tool for detecting memory concerns in SCDs, contributing to early AD detection. Show more
Keywords: Accelerated long-term forgetting, Alzheimer’s disease, functional connectivity, subjective cognitive decline
DOI: 10.3233/JAD-240218
Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2024
Authors: Serra, Laura | Petrosini, Laura | Salaris, Andrea | Pica, Lorenzo | Bruschini, Michela | Di Domenico, Carlotta | Caltagirone, Carlo | Marra, Camillo | Bozzali, Marco
Article Type: Research Article
Abstract: Background: Cognitive reserve (CR) explains the individual resilience to neurodegeneration. Years of formal education express the static measure of reserve (sCR). A dynamic aspect of CR (dCR) has been recently proposed. Objective: The aim of the study was to compare sCR and dCR indexes, respectively, to detect brain abnormalities in Alzheimer’s disease (AD) patients. Methods: 117 individuals [39 AD, 40 amnestic mild cognitive impairment (aMCI), 38 healthy subjects (HS)] underwent neuropsychological evaluation and a 3T-MRI. T1-weighted volumes were used for manual segmentation of the hippocampus and of the parahippocampal cortices. Years of formal education were used as an index of …sCR. Partial Least Square analysis was used to decompose the variance of individual MMSE scores, considered as a dCR index. In aMCI and AD patients, the brain abnormalities have been assessed comparing individuals with high and low levels of sCR and dCR in turn. Moreover, we investigated the effect of the different CR indexes in mediating the relationship between changes in brain volumes and memory performances. Results: sCR and dCR indexes classified differently individuals having high or low levels of CR. Smaller hippocampal and parahippocampal volumes in high dCR patients were found. The sCR and dCR indexes mediated significantly the relationship between brain abnormalities and memory in patients. Conclusions: CR mediated the relationship between brain and memory dysfunctions. We hypothesized that sCR and dCR indexes are a representation of different warehouses of reserve not operating in parallel but forming a complex system, in which crystalized cognitive abilities and actual cognitive efficiency interact with brain atrophy impacting on memory. Show more
Keywords: Alzheimer’s disease, dynamic and static cognitive reserve, hippocampus, mild cognitive impairment, parahippocampal gyrus
DOI: 10.3233/JAD-190716
Citation: Journal of Alzheimer's Disease, vol. 72, no. 1, pp. 111-126, 2019
Cerebellar White Matter Disruption in Alzheimer’s Disease Patients: A Diffusion Tensor Imaging Study
Authors: Toniolo, Sofia | Serra, Laura | Olivito, Giusy | Caltagirone, Carlo | Mercuri, Nicola Biagio | Marra, Camillo | Cercignani, Mara | Bozzali, Marco
Article Type: Research Article
Abstract: The cognitive role of the cerebellum has recently gained much attention, and its pivotal role in Alzheimer’s disease (AD) has now been widely recognized. Diffusion tensor imaging (DTI) has been used to evaluate the disruption of the microstructural milieu in AD, and though several white matter (WM) tracts such as corpus callosum, inferior and superior longitudinal fasciculus, cingulum, fornix, and uncinate fasciculus have been evaluated in AD, data on cerebellar WM tracts are currently lacking. We performed a tractography-based DTI reconstruction of the middle cerebellar peduncle (MCP), and the left and right superior cerebellar peduncles separately (SCPL and SCPR) and …addressed the differences in fractional anisotropy (FA), axial diffusivity (Dax), radial diffusivity (RD), and mean diffusivity (MD) in the three tracts between 50 patients with AD and 25 healthy subjects. We found that AD patients showed a lower FA and a higher RD compared to healthy subjects in MCP, SCPL, and SCPR. Moreover, higher MD was found in SCPR and SCPL and higher Dax in SCPL. This result is important as it challenges the traditional view that WM bundles in the cerebellum are unaffected in AD and might identify new targets for therapeutic interventions. Show more
Keywords: Alzheimer’s disease, cerebellum, diffusion tensor imaging, probabilistic tractography, white matter
DOI: 10.3233/JAD-191125
Citation: Journal of Alzheimer's Disease, vol. 74, no. 2, pp. 615-624, 2020
Authors: Serra, Laura | Bonarota, Sabrina | Di Domenico, Carlotta | Caruso, Giulia | Giulietti, Giovanni | Caltagirone, Carlo | Cercignani, Mara | Bozzali, Marco
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia worldwide. Currently there are no disease modifying treatments available. Detecting subjects with increased risk to develop dementia is essential for future clinical trials. Subjective cognitive decline (SCD) is a condition defining individuals who perceive a decrease in their own cognitive functioning in the absence of any detectable deficit on neuropsychological testing. SCD individuals show AD-related biomarkers abnormalities in cerebrospinal fluid. Objective: The aim of the present study was to assess brain functional connectivity (FC) changes in SCD individuals. Methods: 23 SCD and 33 healthy subjects (HS) underwent an extensive …neuropsychological assessment and 3T-MRI scanning including a T1-w volume and resting-state fMRI (RS-fMRI) to assess brain atrophy and brain FC. Results: No between-group differences in grey matter volumes were detected. SCD subjects compared to HS showed both increased and decreased FC in the executive and parietal networks. Associations between cognitive measures, mainly assessing working memory, and FC within brain networks were found both in SCD and HS separately. Conclusions: SCD individuals showed FC abnormalities in networks involving fronto-parietal areas that may account for their lower visuo-spatial working memory performances. Dysfunctions in executive-frontal networks may be responsible for the cognitive decline subjectively experienced by SCD individuals despite the normal scores observed by formal neuropsychological assessment. The present study contributes to consider SCD individuals in an early AD stage with an increased risk of developing the disease in the long term. Show more
Keywords: Alzheimer’s disease, brain functional connectivity, cognitive functions, magnetic resonance imaging, subjective cognitive decline
DOI: 10.3233/JAD-230536
Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1119-1131, 2023
Authors: Gelfo, Francesca | Petrosini, Laura | Mandolesi, Laura | Landolfo, Eugenia | Caruso, Giulia | Balsamo, Francesca | Bonarota, Sabrina | Bozzali, Marco | Caltagirone, Carlo | Serra, Laura
Article Type: Review Article
Abstract: Evidence in the literature indicates that aerobic physical activity may have a protective role in aging pathologies. However, it has not been clarified whether different types of aerobic exercise produce different effects. In particular, these potential differences have not been explored in patients with Alzheimer’s disease (AD). The present narrative review has the specific aim of evaluating whether land (walking/running) and water (swimming) aerobic activities exert different effects on cognitive functions and neural correlates in AD patients. In particular, the investigation is carried out by comparing the evidence provided from studies on AD animal models and on patients. On the …whole, we ascertained that both human and animal studies documented beneficial effects of land and water aerobic exercise on cognition in AD. Also, the modulation of numerous biological processes is documented in association with structural modifications. Remarkably, we found that aerobic activity appears to improve cognition per se , independently from the specific kind of exercise performed. Aerobic exercise promotes brain functioning through the secretion of molecular factors from skeletal muscles and liver. These molecular factors stimulate neuroplasticity, reduce neuroinflammation, and inhibit neurodegenerative processes leading to amyloid-β accumulation. Additionally, aerobic exercise improves mitochondrial activity, reducing oxidative stress and enhancing ATP production. Aerobic activities protect against AD, but implementing exercise protocols for patients is challenging. We suggest that health policies and specialized institutions should direct increasing attention on aerobic activity as lifestyle modifiable factor for successful aging and age-related conditions. Show more
Keywords: Aerobic activity, Alzheimer’s disease, animal models, brain/cognitive/neural reserve, cognition, humans, neural plasticity, physical exercise
DOI: 10.3233/JAD-231279
Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1181-1197, 2024
Authors: Serra, Laura | D’Amelio, Marcello | Esposito, Sharon | Di Domenico, Carlotta | Koch, Giacomo | Marra, Camillo | Mercuri, Nicola Biagio | Caltagirone, Carlo | Artusi, Carlo Alberto | Lopiano, Leonardo | Cercignani, Mara | Bozzali, Marco
Article Type: Research Article
Abstract: Background: Recent cross-sectional studies highlighted the loss of dopaminergic neurons in the ventral tegmental area (VTA) as an early pathophysiological event in Alzheimer’s disease (AD). Objective: In this study, we longitudinally investigated by resting-state fMRI (rs-fMRI) a cohort of patients with mild cognitive impairment (MCI) due to AD to evaluate the impact of VTA disconnection in predicting the conversion to AD. Methods: A cohort of 35 patients with MCI due to AD were recruited and followed-up for 24 months. They underwent cognitive evaluation and rs-fMRI to assess VTA connectivity at baseline and at follow-up. Results: At 24-month follow-up, 16 out …of 35 patients converted to AD. Although converters and non-converters to AD did not differ in demographic and behavioral characteristics at baseline, the first group showed a significant reduction of VTA-driven connectivity in the posterior cingulate and precentral cortex. This pattern of additional disconnection in MCI-Converters compared to non-converters remained substantially unchanged at 24-month follow-up. Conclusion: This study reinforces the hypothesis of an early contribution of dopaminergic dysfunction to AD evolution by targeting the default-mode network. These results have potential implications for AD staging and prognosis and support new opportunities for therapeutic interventions to slow down disease progression. Show more
Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, dopaminergic system, functional connectivity, restingstate MRI, ventral tegmental area
DOI: 10.3233/JAD-210171
Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 985-1000, 2021
Authors: Serra, Laura | Giancaterino, Giulia | Giulietti, Giovanni | Petrosini, Laura | Di Domenico, Carlotta | Marra, Camillo | Caltagirone, Carlo | Bassi, Andrea | Cercignani, Mara | Bozzali, Marco
Article Type: Research Article
Abstract: Background: Cognitive reserve (CR) explains the individual resilience to neurodegeneration. Objective: The present study investigated the effect of CR in modulating brain cortical architecture. Methods: 278 individuals [110 Alzheimer’s disease (AD), 104 amnestic mild cognitive impairment (aMCI) due to AD, 64 healthy subjects (HS)] underwent a neuropsychological evaluation and 3T-MRI. Cortical thickness (CTh) and fractal dimension (FD) were assessed. Years of formal education were used as an index of CR by which participants were divided into high and low CR (HCR and LCR ). Within-group differences in cortical architecture were assessed as a function of CR. Associations between cognitive scores …and cortical measures were also evaluated. Results: aMCI-HCR compared to aMCI-LCR patients showed significant decrease of CTh in the right temporal and in the left prefrontal lobe. Moreover, they showed increased FD in the right temporal and in the left temporo-parietal lobes. Patients with AD-HCR showed reduced CTh in several brain areas and reduced FD in the left temporal cortices when compared with AD-LCR subjects. HS-HCR showed a significant increase of CTh in prefrontal areas bilaterally, and in the right parieto-occipital cortices. Finally, aMCI-HCR showed significant positive associations between brain measures and memory and executive performance. Conclusion: CR modulates the cortical architecture at pre-dementia stage only. Indeed, only patients with aMCI showed both atrophy (likely due to neurodegeneration) alongside richer brain folding (likely due to reserve mechanisms) in temporo-parietal areas. This opposite trend was not observed in AD and HS. Our data confirm the existence of a limited time-window for CR modulation at the aMCI stage. Show more
Keywords: Alzheimer’s disease, cognitive reserve, cortical thickness, fractal dimension, mild cognitive impairment
DOI: 10.3233/JAD-220377
Citation: Journal of Alzheimer's Disease, vol. 89, no. 3, pp. 811-824, 2022