Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography.

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor-evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not-evocable motor-evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first-ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age-matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS-evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics.

Amyloid PET as a marker of normal-appearing white matter early damage in multiple sclerosis: correlation with CSF ß-amyloid levels and brain volumes.

PURPOSE: The disease course of multiple sclerosis (MS) is unpredictable, and reliable prognostic biomarkers are needed. Positron emission tomography (PET) with ß-amyloid tracers is a promising tool for evaluating white matter (WM) damage and repair. Our aim was to investigate amyloid uptake in damaged (DWM) and normal-appearing WM (NAWM) of MS patients, and to evaluate possible correlations between cerebrospinal fluid (CSF) ß-amyloid1-42 (Aß) levels, amyloid tracer uptake, and brain volumes. METHODS: Twelve MS patients were recruited and divided according to their disease activity into active and non-active groups. All participants underwent neurological examination, neuropsychological testing, lumbar puncture, brain magnetic resonance (MRI) imaging, and 18F-florbetapir PET. Aß levels were determined in CSF samples from all patients. MRI and PET images were co-registered, and mean standardized uptake values (SUV) were calculated for each patient in the NAWM and in the DWM. To calculate brain volumes, brain segmentation was performed using statistical parametric mapping software. Nonparametric statistical analyses for between-group comparisons and regression analyses were conducted. RESULTS: We found a lower SUV in DWM compared to NAWM (p < 0.001) in all patients. Decreased NAWM-SUV was observed in the active compared to non-active group (p < 0.05). Considering only active patients, NAWM volume correlated with NAWM-SUV (p = 0.01). Interestingly, CSF Aß concentration was a predictor of both NAWM-SUV (r = 0.79; p = 0.01) and NAWM volume (r = 0.81, p = 0.01). CONCLUSIONS: The correlation between CSF Aß levels and NAWM-SUV suggests that the predictive role of ß-amyloid may be linked to early myelin damage and may reflect disease activity and clinical progression.

CSF ß-amyloid predicts prognosis in patients with multiple sclerosis.

BACKGROUND: The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognized, and hence reliable biomarkers are needed. OBJECTIVES: To investigate the prognostic role of cerebrospinal fluid (CSF) amyloid beta1-42 (Aß) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white matter (WM) and grey matter (GM) damage at early disease stages. METHODS: Sixty patients were recruited and followed up for 3-5 years. Patients underwent clinical assessment, brain magnetic resonance imaging (MRI; at baseline and after 1 year), and CSF analysis to determine Aß levels. T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads. RESULTS: Lower CSF Aß levels were observed in patients with a worse follow-up Expanded Disability Status Scale (EDSS; r = -0.65, p < 0.001). The multiple regression analysis confirmed CSF Aß concentration as a predictor of patients' EDSS increase (r = -0.59, p < 0.0001). Generating a receiver operating characteristic curve, a cut-off value of 813 pg/mL was determined as the threshold able to identify patients with worse prognosis (95% confidence interval (CI): 0.690-0.933, p = 0.0001). No differences in CSF tau and neurofilament light chain (NfL) levels were observed (p > 0.05). CONCLUSION: Low CSF Aß levels may represent a predictive biomarker of disease progression in MS.

Introducing axonal myelination in connectomics: A preliminary analysis of g-ratio distribution in healthy subjects.

Microstructural imaging and connectomics are two research areas that hold great potential for investigating brain structure and function. Combining these two approaches can lead to a better and more complete characterization of the brain as a network. The aim of this work is characterizing the connectome from a novel perspective using the myelination measure given by the g-ratio. The g-ratio is the ratio of the inner to the outer diameters of a myelinated axon, whose aggregated value can now be estimated in vivo using MRI. In two different datasets of healthy subjects, we reconstructed the structural connectome and then used the g-ratio estimated from diffusion and magnetization transfer data to characterize the network structure. Significant characteristics of g-ratio weighted graphs emerged. First, the g-ratio distribution across the edges of the graph did not show the power-law distribution observed using the number of streamlines as a weight. Second, connections involving regions related to motor and sensory functions were the highest in myelin content. We also observed significant differences in terms of the hub structure and the rich-club organization suggesting that connections involving hub regions present higher myelination than peripheral connections. Taken together, these findings offer a characterization of g-ratio distribution across the connectome in healthy subjects and lay the foundations for further investigating plasticity and pathology using a similar approach.

CSF ß-amyloid and white matter damage: a new perspective on Alzheimer's disease.

OBJECTIVE: To assess the connection between amyloid pathology and white matter (WM) macrostructural and microstructural damage in demented patients compared with controls. METHODS: Eighty-five participants were recruited: 65 with newly diagnosed Alzheimer's disease (AD), non-AD dementia or mild cognitive impairment and 20 age-matched and sex-matched healthy controls. ß-amyloid1-42 (Aß) levels were determined in cerebrospinal fluid (CSF) samples from all patients and five controls. Among patients, 42 had pathological CSF Aß levels (Aß(+)), while 23 had normal CSF Aß levels (Aß(-)). All participants underwent neurological examination, neuropsychological testing and brain MRI. We used T2-weighted scans to quantify WM lesion loads (LLs) and diffusion-weighted images to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses. RESULTS: We found an increased WM-LL in Aß(+) compared with both, healthy controls (p=0.003) and Aß(-) patients (p=0.02). Interestingly, CSF Aß concentration was the best predictor of patients' WM-LL (r=-0.30, p<0.05) when using age as a covariate. Lesion apparent diffusion coefficient value was higher in all patients than in controls (p=0.0001) and correlated with WM-LL (r=0.41, p=0.001). In Aß(+), WM-LL correlated with WM microstructural damage in the left peritrigonal WM (p<0.0001). CONCLUSIONS: WM damage is crucial in AD pathogenesis. The correlation between CSF Aß levels and WM-LL suggests a direct link between amyloid pathology and WM macrostructural and microstructural damage.

Whole brain white matter histogram analysis of diffusion tensor imaging data detects microstructural damage in mild cognitive impairment and alzheimer's disease patients.

BACKGROUND: Amnestic mild cognitive impairment (MCI) is a transitional stage between normal aging and Alzheimer's disease (AD). However, the clinical conversion from MCI to AD is unpredictable. Hence, identification of noninvasive biomarkers able to detect early changes induced by dementia is a pressing need. PURPOSE: To explore the added value of histogram analysis applied to measures derived from diffusion tensor imaging (DTI) for detecting brain tissue differences between AD, MCI, and healthy subjects (HS). STUDY TYPE: Prospective. POPULATION/SUBJECTS: A local cohort (57 AD, 28 MCI, 23 HS), and an Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (41 AD, 58 MCI, 41 HS). FIELD STRENGTH: 3T. Dual-echo turbo spin echo (TSE); fluid-attenuated inversion recovery (FLAIR); modified-driven-equilibrium-Fourier-transform (MDEFT); inversion-recovery spoiled gradient recalled (IR-SPGR); diffusion tensor imaging (DTI). ASSESSMENT: Normal-appearing white matter (NAWM) masks were obtained using the T1 -weighted volumes for tissue segmentation and T2 -weighted images for removal of hyperintensities/lesions. From DTI images, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AXD), and radial diffusivity (RD) were obtained. NAWM histograms of FA, MD, AXD, and RD were derived and characterized estimating: peak height, peak location, mean value (MV), and quartiles (C25, C50, C75), which were compared between groups. Receiver operating characteristic (ROC) and area under ROC curves (AUC) were calculated. To confirm our results, the same analysis was repeated on the ADNI dataset. STATISTICAL TESTS: One-way analysis of variance (ANOVA), post-hoc Student's t-test, multiclass ROC analysis. RESULTS: For the local cohort, C25 of AXD had the maximum capability of group discrimination with AUC of 0.80 for "HS vs. patients" comparison and 0.74 for "AD vs. others" comparison. For the ADNI cohort, MV of AXD revealed the maximum group discrimination capability with AUC of 0.75 for "HS vs. patients" comparison and 0.75 for "AD vs. others" comparison. DATA CONCLUSION: AXD of NAWM might be an early marker of microstructural brain tissue changes occurring during the AD course and might be useful for assessing disease progression. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017.

Negative emotions enhance memory-guided attention in a visual search task by increasing frontoparietal, insular, and parahippocampal cortical activity.

Previous literature demonstrated that long-term memory representations guide spatial attention during visual search in real-world pictures. However, it is currently unknown whether memory-guided visual search is affected by the emotional content of the picture. During functional magnetic resonance imaging (fMRI), participants were asked to encode the position of high-contrast targets embedded in emotional (negative or positive) or neutral pictures. At retrieval, they performed a visual search for targets presented at the same location as during encoding, but at a much lower contrast. Behaviorally, participants detected more accurately targets presented in negative pictures compared to those in positive or neutral pictures. They were also faster in detecting targets presented at encoding in emotional (negative or positive) pictures than in neutral pictures, or targets not presented during encoding (i.e., memory-guided attention effect). At the neural level, we found increased activation in a large circuit of regions involving the dorsal and ventral frontoparietal cortex, insular and parahippocampal cortex, selectively during the detection of targets presented in negative pictures during encoding. We propose that these regions might form an integrated neural circuit recruited to select and process previously encoded target locations (i.e., memory-guided attention sustained by the frontoparietal cortex) embedded in emotional contexts (i.e., emotional contexts recollection supported by the parahippocampal cortex and emotional monitoring supported by the insular cortex). Ultimately, these findings reveal that negative emotions can enhance memory-guided visual search performance by increasing neural activity in a large-scale brain circuit, contributing to disentangle the complex relationship between emotion, attention, and memory.

Distinct grey and white matter changes are associated with the phenomenology of visual hallucinations in Lewy Body Disease.

Visual hallucinations in Lewy body disease (LBD) can be differentiated based on phenomenology into minor phenomena (MVH) and complex hallucinations (CVH). MVH include a variety of phenomena, such as illusions, presence and passage hallucinations occurring at early stages of LBD. The neural mechanisms of visual hallucinations are largely unknown. The hodotopic model posits that the hallucination state is due to abnormal activity in specialized visual areas, that occurs in the context of wider network connectivity alterations and that phenomenology of VH, including content and temporal characteristics, may help identify brain regions underpinning these phenomena. Here we investigated both the topological and hodological neural basis of visual hallucinations integrating grey and white matter imaging analyses. We studied LBD patients with VH and age matched healthy controls (HC). VH were assessed using a North-East-Visual-Hallucinations-Interview that captures phenomenological detail. Then we applied voxel-based morphometry and tract based spatial statistics approaches to identify grey and white matter changes. First, we compared LBD patients and HC. We found a reduced grey matter volume and a widespread damage of white tracts in LBD compared to HC. Then we tested the association between CVH and MVH and grey and white matter indices. We found that CVH duration was associated with decreased grey matter volume in the fusiform gyrus suggesting that LBD neurodegeneration-related abnormal activity in this area is responsible for CVH. An unexpected finding was that MVH severity was associated with a greater integrity of white matter tracts, specifically those connecting dorsal, ventral attention networks and visual areas. Our results suggest that networks underlying MVH need to be partly intact and functional for MVH experiences to occur, while CVH occur when cortical areas are damaged. The findings support the hodotopic view and the hypothesis that MVH and CVH relate to different neural mechanisms, with wider implications for the treatment of these symptoms in a clinical context.

Brain tissue modifications induced by cholinergic therapy in Alzheimer's disease.

A previous preliminary investigation based on a novel MRI approach to map anatomical connectivity revealed areas of increased connectivity in Alzheimer's disease (AD) but not in mild cognitive impairment patients. This prompted the hypothesis tested here, that these areas might reflect phenomena of brain plasticity driven by acetylcholinesterase inhibitors (AChEIs). Thirty-eight patients with probable AD (19 under medication with AChEIs and 19 drug-naïve) were recruited together with 11 healthy controls. All subjects had MRI scanning at 3T, including volumetric and diffusion-weighted scans. Probabilistic tractography was used to initiate streamlines from all parenchymal voxels, and anatomical connectivity maps (ACMs) were obtained by counting, among the total number of streamlines initiated, the fraction passing through each brain voxel. After normalization into standard space, ACMs were used to test for between-group comparisons, and for interactions between the exposure to AChEIs and global level of cognition. Patients with AD had reduced ACM values in the fornix, cingulum, and supramarginal gyri. The ACM value was strongly associated with the AChEI dosage-x-duration product in the anterior limb (non-motor pathway) of the internal capsule. Tractography from this region identified the anterior thalamic radiation as the main white matter (WM) tract passing through it. The reduced connectivity in WM bundles connecting the hippocampi with the rest of the brain (fornix/cingulum) suggests a possible mechanism for the spread of AD pathology. An intriguing explanation for the interaction between AChEIs and ACM is related to the mechanisms of brain plasticity, partially driven by neurotrophic properties of acetylcholine replacement.

Preclinical Brain Network Abnormalities in Patients with Subjective Cognitive Decline.

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.

Quality assessment, variability and reproducibility of anatomical measurements derived from T1-weighted brain imaging: The RIN-Neuroimaging Network case study.

Initiatives for the collection of harmonized MRI datasets are growing continuously, opening questions on the reliability of results obtained in multi-site contexts. Here we present the assessment of the brain anatomical variability of MRI-derived measurements obtained from T1-weighted images, acquired according to the Standard Operating Procedures, promoted by the RIN-Neuroimaging Network. A multicentric dataset composed of 77 brain T1w acquisitions of young healthy volunteers (mean age = 29.7 ± 5.0 years), collected in 15 sites with MRI scanners of three different vendors, was considered. Parallelly, a dataset of 7 "traveling" subjects, each undergoing three acquisitions with scanners from different vendors, was also used. Intra-site, intra-vendor, and inter-site variabilities were evaluated in terms of the percentage standard deviation of volumetric and cortical thickness measures. Image quality metrics such as contrast-to-noise and signal-to-noise ratio in gray and white matter were also assessed for all sites and vendors. The results showed a measured global variability that ranges from 11% to 19% for subcortical volumes and from 3% to 10% for cortical thicknesses. Univariate distributions of the normalized volumes of subcortical regions, as well as the distributions of the thickness of cortical parcels appeared to be significantly different among sites in 8 subcortical (out of 17) and 21 cortical (out of 68) regions of i nterest in the multicentric study. The Bland-Altman analysis on "traveling" brain measurements did not detect systematic scanner biases even though a multivariate classification approach was able to classify the scanner vendor from brain measures with an accuracy of 0.60 ± 0.14 (chance level 0.33).

Normative values of the topological metrics of the structural connectome: A multi-site reproducibility study across the Italian Neuroscience network.

PURPOSE: The use of topological metrics to derive quantitative descriptors from structural connectomes is receiving increasing attention but deserves specific studies to investigate their reproducibility and variability in the clinical context. This work exploits the harmonization of diffusion-weighted acquisition for neuroimaging data performed by the Italian Neuroscience and Neurorehabilitation Network initiative to obtain normative values of topological metrics and to investigate their reproducibility and variability across centers. METHODS: Different topological metrics, at global and local level, were calculated on multishell diffusion-weighted data acquired at high-field (e.g. 3 T) Magnetic Resonance Imaging scanners in 13 different centers, following the harmonization of the acquisition protocol, on young and healthy adults. A "traveling brains" dataset acquired on a subgroup of subjects at 3 different centers was also analyzed as reference data. All data were processed following a common processing pipeline that includes data pre-processing, tractography, generation of structural connectomes and calculation of graph-based metrics. The results were evaluated both with statistical analysis of variability and consistency among sites with the traveling brains range. In addition, inter-site reproducibility was assessed in terms of intra-class correlation variability. RESULTS: The results show an inter-center and inter-subject variability of <10%, except for "clustering coefficient" (variability of 30%). Statistical analysis identifies significant differences among sites, as expected given the wide range of scanners' hardware. CONCLUSIONS: The results show low variability of connectivity topological metrics across sites running a harmonised protocol.

Quantitative magnetization transfer provides information complementary to grey matter atrophy in Alzheimer's disease brains.

Preliminary studies, based on a region-of-interest approach, suggest that quantitative magnetization transfer (qMT), an extension of magnetization transfer imaging, provides complementary information to conventional magnetic resonance imaging (MRI) in the characterisation of Alzheimer's disease (AD). The aim of this study was to extend these findings to the whole brain, using a voxel-wise approach. We recruited 19AD patients and 11 healthy subjects (HS). All subjects had an MRI acquisition at 3.0T including a T(1)-weighted volume, 12 MT-weighted volumes for qMT, and data for computing T(1) and B(1) maps. The T(1)-weighted volumes were processed to yield grey matter (GM) volumetric maps, while the other sequences were used to compute qMT parametric maps of the whole brain. qMT maps were warped to standard space and smoothed, and subsequently compared between groups. Of all the qMT parameters considered, only the forward exchange rate, RM(0)(B), showed significant group differences. These images were therefore retained for the multimodal statistical analysis, designed to locate brain regions of RM(0)(B) differences between AD and HS groups, adjusting for local GM atrophy. Widespread areas of reduced RM(0)(B) were found in AD patients, mainly located in the hippocampus, in the temporal lobe, in the posterior cingulate and in the parietal cortex. These results indicate that, among qMT parameters, RM(0)(B) is the most sensitive to AD pathology. This quantity is altered in the hippocampus of patients with AD (as found by previous works) but also in other brain areas, that PET studies have highlighted as involved with both, reduced glucose metabolism and amyloid ß deposition. RM(0)(B) might reflect, through the measurement of the efficiency of MT exchange, some information with a specific pathological counterpart. Given previous evidence of a strict relationship between RM(0)(B) and intracellular pH, an intriguing speculation is that our findings might reflect metabolic changes related to mitochondrial dysfunction, which has been proposed as a contributor to neurodegeneration in AD.

Damage to the cingulum contributes to Alzheimer's disease pathophysiology by deafferentation mechanism.

This study investigates the differential contribution of gray matter (GM) atrophy and deafferentation through white matter (WM) damage in the clinical progression of Alzheimer's disease (AD). Thirty-one patients with probable AD, 23 with amnestic mild cognitive impairment (a-MCI), and 14 healthy subjects underwent MRI scanning at 3T. Voxel-based morphometry was used to assess regional GM atrophy in AD and a-MCI patients. Diffusion tensor-MRI tractography was used to reconstruct the cingulum bilaterally, and to quantify, voxel-by-voxel, its fractional anisotropy (FA) and mean diffusivity (MD) (measures of microscopic WM integrity). Atrophy of the cinguli was also assessed by means of jacobian determinants (JD) of local transformations. In AD patients, four clusters of reduced GM were found nearby the cinguli, in the posterior (PCC) and anterior cingulate cortex, and in the hippocampal/parahippocampal areas. Widespread areas of reduced FA and increased MD were found in the cinguli of both, AD and a-MCI patients. A region of macroscopic atrophy was detectable in AD patients only. Strong associations were found between local GM densities in the four identified clusters, and measures of micro- and (to a lesser extent) macroscopic damage of patients' cinguli. Linear regression analyses revealed that MD in the cinguli predicts patients' measures of episodic memory in combination with GM density of hippocampal/parahippocampal areas, and measures of global cognition in combination with GM density of the PCC. This study indicates that brain deafferentation though the cingulum is likely to play a remarkable role in progressive development of cognitive impairment in AD.

Left egocentric neglect in early subacute right-stroke patients is related to damage of the superior longitudinal fasciculus.

A typical consequence of stroke in the right hemisphere is unilateral spatial neglect. Distinct forms of neglect have been described, such as space-based (egocentric) and object-based (allocentric) neglect. However, the relationship between these two forms of neglect is still far from being understood, as well as their neural substrates. Here, we further explore this issue by using voxel lesion symptoms mapping (VLSM) analyses on a large sample of early subacute right-stroke patients assessed with the Apples Cancellation Test. This is a sensitive test that simultaneously measures both egocentric and allocentric neglect. Behaviourally, we found no correlation between egocentric and allocentric performance, indicating independent mechanisms supporting the two forms of neglect. This was confirmed by the VLSM analysis that pointed out a link between a damage in the superior longitudinal fasciculus and left egocentric neglect. By contrast, no association was found between brain damage and left allocentric neglect. These results indicate a higher probability to observe egocentric neglect as a consequence of white matter damages in the superior longitudinal fasciculus, while allocentric neglect appears more "globally" related to the whole lesion map. Overall, these findings on early subacute right-stroke patients highlight the role played by white matter integrity in sustaining attention-related operations within an egocentric frame of reference.

Cognitive Reserve Modulates Brain Structure and Cortical Architecture in the Alzheimer's Disease.

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.

Multi-centre and multi-vendor reproducibility of a standardized protocol for quantitative susceptibility Mapping of the human brain at 3T.

Quantitative Susceptibility Mapping (QSM) is an MRI-based technique allowing the non-invasive quantification of iron content and myelination in the brain. The RIN - Neuroimaging Network established an optimized and harmonized protocol for QSM across ten sites with 3T MRI systems from three different vendors to enable multicentric studies. The assessment of the reproducibility of this protocol is crucial to establish susceptibility as a quantitative biomarker. In this work, we evaluated cross-vendor reproducibility in a group of six traveling brains. Then, we recruited fifty-one volunteers and measured the variability of QSM values in a cohort of healthy subjects scanned at different sites, simulating a multicentric study. Both voxelwise and Region of Interest (ROI)-based analysis on cortical and subcortical gray matter were performed. The traveling brain study yielded high structural similarity (∼0.8) and excellent reproducibility comparing maps acquired on scanners from two different vendors. Depending on the ROI, we reported a quantification error ranging from 0.001 to 0.017 ppm for the traveling brains. In the cohort of fifty-one healthy subjects scanned at nine different sites, the ROI-dependent variability of susceptibility values, of the order of 0.005-0.025 ppm, was comparable to the result of the traveling brain experiment. The harmonized QSM protocol of the RIN - Neuroimaging Network provides a reliable quantification of susceptibility in both cortical and subcortical gray matter regions and it is ready for multicentric and longitudinal clinical studies in neurological and pychiatric diseases.

Cognitive profile and brain morphological changes in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is accompanied by neurocognitive impairment, likely mediated by injury to various brain regions. We evaluated brain morphological changes in patients with OSA and their relationship to neuropsychological and oximetric data. Sixteen patients affected by moderate-severe OSA (age: 55.8±6.7 years, 13 males) and fourteen control subjects (age: 57.6±5.1 years, 9 males) underwent 3.0 Tesla brain magnetic resonance imaging (MRI) and neuropsychological testing evaluating short- and long-term memory, executive functions, language, attention, praxia and non-verbal learning. Volumetric segmentation of cortical and subcortical structures and voxel-based morphometry (VBM) were performed. Patients and controls differed significantly in Rey Auditory-Verbal Learning test (immediate and delayed recall), Stroop test and Digit span backward scores. Volumes of cortical gray matter (GM), right hippocampus, right and left caudate were smaller in patients compared to controls, with also brain parenchymal fraction (a normalized measure of cerebral atrophy) approaching statistical significance. Differences remained significant after controlling for comorbidities (hypertension, diabetes, smoking, hypercholesterolemia). VBM analysis showed regions of decreased GM volume in right and left hippocampus and within more lateral temporal areas in patients with OSA. Our findings indicate that the significant cognitive impairment seen in patients with moderate-severe OSA is associated with brain tissue damage in regions involved in several cognitive tasks. We conclude that OSA can increase brain susceptibility to the effects of aging and other clinical and pathological occurrences.

Highly superior autobiographical memory in aging: A single case study.

Whilst countless studies have shown that aging is associated with cognitive decline in the general population, near to nothing is known about this association in elderly individuals naturally exhibiting enhanced memory capabilities. The identification of a 75 years old individual (GC) with highly superior autobiographical memory (HSAM), and his willingness to volunteer to our study over a period of five years, allowed us to investigate this issue in a single case study. At the age of 75 years, GC was screened for HSAM with the Public Events Quiz and the Random Dates Quiz, with a positive outcome. GC's memory performance was extraordinarily higher than normal-memory control subjects (>3 standard deviations), and comparable to a group of younger HSAM individuals (mean age of 32.5 years; Santangelo et al., 2018). GC underwent general neuropsychological (Mini-Mental State Examination), personality (Personality Assessment Inventory), and brain morphological (brain volumes and lesions) assessments, showing no deviation from normal ranges. To gain insight into the brain mechanisms underlying his memory performance, GC underwent functional brain imaging during the retrieval of memories associated with random dates. The latter were also rated in terms of reliving quality and emotional valence. Similar to younger HSAM individuals, GC's access to past memories recruited a wide network of prefrontal and temporo-parietal regions, especially during the recollection of memories associated with a lower reliving rating, suggesting a compensatory mechanism in HSAM. Increased activity in the insula was instead associated with emotionally-positive memories. Five years later, GC was tested again for HSAM and showed no sign of memory decline, whereby his memory performance was indistinguishable from the tests he performed five years earlier. GC's case suggests that highly superior memory performance can manifest without apparent decline in physiological aging. Implications of the current findings for the extant models of autobiographical memory are discussed.

Lesion distribution and substrate of white matter damage in myotonic dystrophy type 1: Comparison with multiple sclerosis.

Myotonic Dystrophy type 1 (DM1) is an autosomal dominant condition caused by expansion of the CTG triplet repeats within the myotonic dystrophy protein of the kinase (DMPK) gene. The central nervous system is involved in the disease, with multiple symptoms including cognitive impairment. A typical feature of DM1 is the presence of widespread white matter (WM) lesions, whose total volume is associated with CTG triplet expansion. The aim of this study was to characterize the distribution and pathological substrate of these lesions as well as the normal appearing WM (NAWM) using quantitative magnetization transfer (qMT) MRI, and comparing data from DM1 patients with those from patients with multiple sclerosis (MS). Twenty-eight patients with DM1, 29 patients with relapsing-remitting MS, and 15 healthy controls had an MRI scan, including conventional and qMT imaging. The average pool size ratio (F), a proxy of myelination, was computed within lesions and NAWM for every participant. The lesion masks were warped into MNI space and lesion probability maps were obtained for each patient group. The lesion distribution, total lesion load and the tissue-specific mean F were compared between groups. The supratentorial distribution of lesions was similar in the 2 patient groups, although mean lesion volume was higher in MS than DM1. DM1 presented higher prevalence of anterior temporal lobe lesions, but none in the cerebellum and brainstem. Significantly reduced F values were found within DM1 lesions, suggesting a loss of myelin density. While F was reduced in the NAWM of MS patients, it did not differ between DM1 and controls. Our results provide further evidence for a need to compare histology and imaging using new MRI techniques in DM1 patients, in order to further our understanding of the underlying disease process contributing to WM disease.