The role of the dorsal striatum in the recognition of emotions expressed by voice in Parkinson's disease.

BACKGROUND AND PURPOSE: Non-motor impairment such as emotion recognition deficit in both facial and vocal expressions has been previously reported in Parkinson's disease (PD). We investigated whether the decoding of emotional prosody is impaired in PD and whether this deficit is related to striatal damage. METHODS: Fifteen PD patients and 15 healthy controls (HCs) were requested to listen to six audio tracks and to recognize the emotions expressed by a professional actor while reading a meaning-neutral sentence. All subjects also received a structural MRI examination. Volumetric measurements were extracted for the striatum, a key region involved in emotional processing and typically impaired in PD. RESULTS: Decoding sadness conveyed by voice was impaired in PD compared with HC and was related to the volume of the dorsal striatum bilaterally. CONCLUSIONS: The dorsal striatum is involved in the decoding of vocal negative emotions in PD.

High avidity HSV-1 antibodies correlate with absence of amnestic Mild Cognitive Impairment conversion to Alzheimer's disease.

Amnestic Mild Cognitive Impairment (aMCI) is an alteration in cognitive abilities that can progress to Alzheimer's disease (AD), a condition in which herpes simplex type 1 (HSV-1) infection might play a pathogenetic role. Prognostic indexes capable of predicting aMCI conversion to AD are only partially understood. The objective of the present work is to verify whether HSV-1 immune responses is involved in conversion of aMCI to AD and correlate with grey matter brain morphometry. Two homogeneous groups of individuals who did or did not convert to AD over a 24-months period were selected after retrospective analysis of a cohort of patients with a diagnosis of aMCI. The selection of subjects was based on: a) clinical follow-up; b) neurocognitive evaluation at baseline and after 24months; c) availability of serum and DNA samples at baseline. 36 aMCI individuals, 21 of whom did (aMCI-converters) and 15 of whom did not (aMCI-non-converters) convert to AD, were included in the study. HSV-1 antibody (Ab) titers, avidity index and APOE genotyping were performed in all the enrolled individuals at baseline. Brain magnetic resonance imaging (MRI) by 1.5T scanner results at baseline were available as well in most (29/36) of these individuals. HSV-1-specific Ab titers were increased at baseline in aMCI-non-converters, and the avidity of these Ab was significantly higher in aMCI-non-converter compared to aMCI-converter (p=0.0018). Receiver operating characteristics analysis showed that HSV-1 avidity had a predictive value in distinguishing between aMCI-non-converters and aMCI-converters (p<0.0001). Notably, a positive correlation was detected as well between HSV-1 antibody titers and MRI-evaluated cortical volumes in the left hippocampus and amigdala (pcorr<0.05). In conclusion, stronger HSV-1-specific humoral responses associate with protection against AD conversion and better-preserved cortical volumes. These results reinforce the hypothesis for a role for HSV-1 in the pathogenesis of AD.

The mirror neuron system and the strange case of Broca's area.

Mirror neurons, originally described in the monkey premotor area F5, are embedded in a frontoparietal network for action execution and observation. A similar Mirror Neuron System (MNS) exists in humans, including precentral gyrus, inferior parietal lobule, and superior temporal sulcus. Controversial is the inclusion of Broca's area, as homologous to F5, a relevant issue in light of the mirror hypothesis of language evolution, which postulates a key role of Broca's area in action/speech perception/production. We assess "mirror" properties of this area by combining neuroimaging and intraoperative neurophysiological techniques. Our results show that Broca's area is minimally involved in action observation and has no motor output on hand or phonoarticulatory muscles, challenging its inclusion in the MNS. The presence of these functions in premotor BA6 makes this area the likely homologue of F5 suggesting that the MNS may be involved in the representation of articulatory rather than semantic components of speech.

Cognitive Reserve proxies can modulate motor and non-motor basal ganglia circuits in early Parkinson's Disease.

Parkinson's Disease (PD) is hallmarked by dysfunctional circuitry between the basal ganglia and dorsolateral-prefrontal cortex. Recently progress has been made in understanding factors contributing to differential susceptibility to pathology mitigating disease-related cognitive decline. Cognitive reserve, the brain processing resources accumulated throughout life while engaged in mentally stimulating activities, can play an important protective role in cognitive performance. We tested the hypothesis that Cognitive Reserve proxies may exert an impact on the basal ganglia and dorsolateral-prefrontal atrophy in early PD. Forty-five early patients with PD and 20 age-gender-matched healthy controls (HC) completed the Cognitive Reserve Index questionnaire to quantify Cognitive Reserve proxies by three indexes (CRI-Education, CRI-Working Activity, CRI-Leisure Time) and a structural MRI examination (3T). Morphometrical indexes for basal ganglia (bilateral putamen, caudate, pallidum volume) and dorsolateral-prefrontal cortex (cortical thickness) were computed. Significant differences between HC and PD were tested by direct comparisons in demographics, cognitive level, and cognitive reserve proxies indexes. Then two multiple regression analyses were performed to identify predictors of the basal ganglia and dorsolateral-prefrontal cortex structural integrity. Regression analysis revealed that basal ganglia volume was significantly predicted by CRI-Education (pFDR = 0.029), sex (pFDR = 0.029), and Total Intracranial Volume (pFDR < 0.001). Instead, the dorsolateral-prefrontal thickness was predicted by CRI-Leisure Time (pFDR = 0.030) and age (pFDR = 0.010). Cognitive Reserve proxies, especially education and leisure-time activities, can play a protective role on the structural integrity of the basal ganglia and dorsolateral-prefrontal cortex, respectively, critical regions hallmarking brain status of early phases of PD.

Biomarkers of neural integrity and immunoglobulin genes influence neurodegeneration in Alzheimer's disease.

Compelling evidence has been presented in favor of herpes simplex virus type 1 (HSV1) being one of the causative agents of Alzheimer's disease (AD). The success of HSV1 as a pathogen relates to its sophisticated strategies to evade host immunosurveillance. One strategy involves encoding a decoy Fcγ receptor (FcγR) that thwarts the Fcγ-mediated effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), a potent host immunosurveillance mechanism against virally infected cells. The decoy FcγR binds to antibodies of all IgG subclasses, except IgG3; therefore, IgG3 would be expected to play an important role in viral clearance by neutralization and ADCC, and thus contribute to protection from HSV1-spurred diseases. Previous studies have shown significant association between anti-HSV1 IgG3 antibodies and cortical thinning of the areas of the brain typically altered in AD and also targeted by HSV1. The aim of the present investigation was to determine whether GM (γ marker) 5 and GM 21 allotypes, hereditary allelic determinants expressed on IgG3, together with brain biomarkers of neural integrity, contributed to neurodegeneration-as measured by mini-mental state examination (MMSE) score-in patients with AD. Multiple regression analyses showed that the homozygous GM 5/5 genotype, preserved right hippocampus, and right insula thickness were associated with higher MMSE scores (p < 0.001), whereas the opposite pattern and GM 5/21 genotype were associated with worse clinical profiles. Influence of GM 5/21-expressing IgG3 antibodies on the ADCC of HSV1-infected neurons could, at least partially, explain these results.

Exploring cognitive reserve's influence: unveiling the dynamics of digital telerehabilitation in Parkinson's Disease Resilience.

Telerehabilitation is emerging as a promising digital method for delivering rehabilitation to Parkinson's Disease (PD) patients, especially in the early stages to promote brain resilience. This study explores how cognitive reserve (CR), the brain's ability to withstand aging and disease, impacts the effectiveness of telerehabilitation. It specifically examines the influence of lifelong cognitive activities on the relationship between neural reserve and improved functional abilities following rehabilitation. In the study, 42 PD patients underwent a 4-month neuromotor telerehabilitation program. CR proxies were assessed using the Cognitive Reserve Index questionnaire (CRIq), brain changes via 3T-MRI, and functional response through changes in the 6-Minute Walk Distance (6MWD). Participants were divided into responders (n = 23) and non-responders (n = 19) based on their 6MWD improvement. A multiple regression model was run to test significant predictors of 6MWD after treatment in each group. The results revealed a significant correlation between 6MWD and CRIq scores, but only among responders. Notably, the CRIq Leisure-Time sub-index, along with baseline 6MWD, were predictors of post-treatment 6MWD. These findings highlight CR's role in enhancing the benefits of telerehabilitation on PD patients' neuromotor functions. Clinically, these results suggest that neurologists and clinicians should consider patients' lifestyles and cognitive engagement as important factors in predicting and enhancing the outcomes of telerehabilitation. The study underscores the potential of CR as both a predictor and booster of telerehabilitation's effects, advocating for a personalized approach to PD treatment that takes into account individual CR levels.

Differential Roles of Neural Integrity, Physical Activity and Depression in Frailty: Sex-Related Differences.

The frailty sex paradox has recently gained attention. At all ages, females are more likely to be frail and show a more severe phenotype but have a higher survival rate compared to males. The main aim was to test sex-specific differences in frailty syndrome using a multimodal evaluation from clinical and imaging data to deepen the understanding of different underlying mechanisms involved in the two sexes, and thus understand the association with different risk factors. Ninety-six community-dwelling older adults were characterized by clinical underpinnings (Fried's frailty indicators: comorbidity, depression, global cognitive level, physical activity, autonomy), and neural integrity (T1-weighted brain 3T MRI). The frailty × sex interaction in clinical and neural profiles was tested. Additionally, frailty risk factors were identified in the two sexes separately. Results showed that fragility was associated with an increment of depressive symptomatology in females, while a decrement in physical activity was observed already in the pre-frail stage in males. Finally, different risk factors were observed in the two groups: significant frailty predictors were neural integrity and physical activity in males, and age and depression in females. These data support the starting hypothesis of at least partially different mechanisms involved in the frailty phenotype between men and women.

Production of emotions conveyed by voice in Parkinson's disease: Association between variability of fundamental frequency and gray matter volumes of regions involved in emotional prosody.

OBJECTIVE: Parkinson's disease (PD) is associated with impairment in producing emotions conveyed by voice which could depend on motor limitations of the vocal apparatus and/or alterations in emotional processing. This study explores the relationship between the standard deviation of fundamental frequency (F0SD) of emotional speech and the volume of specific gray matter regions. METHOD: Fifteen PD patients and 15 healthy controls (HC) were asked to produce different emotions vocally elicited by reading short stories. For each vocal track, the F0SD was calculated as index of variability. All subjects underwent a structural magnetic resonance imaging and a voxel-based morphometry analysis. An ad hoc mask of brain regions implicated in emotional prosody was constructed to test the relationship between F0SD and the level of brain atrophy. RESULTS: PD patients showed lower F0SD values than HC in the expression of anger. Neuroimaging results showed brain atrophy in PD patients in a widespread bilateral network, including frontal areas, left cingulate cortex, parietal areas as well as occipital cortices. In the PD group, a positive correlation was observed between F0SD values of anger and volumes of the bilateral supramarginal gyrus, left thalamus, right inferior frontal gyrus, and amygdala. CONCLUSIONS: The lower F0SD values observed in PD patients in anger production are consistent with their lower ability to express anger effectively through voice compared to HC. Our data demonstrated the involvement of right-lateralized areas, such as the inferior frontal gyrus and amygdala, which are typically involved in emotional prosody. Disturbances in emotion processing might contribute to speech production deficits in PD, probably in addition to the motor impairment of the articulatory system. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A digital health home intervention for people within the Alzheimer's disease continuum: results from the Ability-TelerehABILITation pilot randomized controlled trial.

PURPOSE: This study tested the efficacy of digital-health home intervention for people within the Alzheimer's disease (AD)-continuum. METHODS: Thirty people within the AD continuum were randomly assigned to a telerehabilitation (ABILITY; 6 males, Mage=78.2 ± 3.95) or treatment as usual (TAU; 8 males, Mage=77.13 ± 6.38), performing cognitive and physical activities at home for six weeks. The ABILITY intervention additionally included a digital platform enabling communication between the hospital and the patient's home. Efficiency, such as adherence, perceived fit of demands and skills, usability, and effectiveness measures, including neuropsychological level, neuropsychiatric symptoms, and autonomy in daily living, were collected before (T0), after the treatment (T1), and at the 1-year-follow-up (T2). RESULTS: The ABILITY program was efficient, with a higher adherence (81% vs. 62%), a higher perceived fit of demands and skills than TAU (p<.05), and a good level of technology usability. In terms of effectiveness, a treatment effect (ABILITY > TAU) emerged on the global cognitive level, especially in language, executive functions, and memory domains. Moreover, a treatment carry-over effect (1-year follow-up) was observed in global cognitive functions (especially language) (ABILITY > TAU), behavioral symptoms, and caregiver distress (TAU > ABILITY). CONCLUSIONS: Our preliminary findings suggest that ABILITY is a promising eHealth intervention to improve at-home treatment adherence and to preserve cognitive and behavioral abilities.

People in the Alzheimer's Disease continuum facing chronic cognitive disabilities represent an emergency for the healthcare system given the substantial need for long-term rehabilitation;This study evaluates a new model of rehabilitation in the continuity of care for people with cognitive disabilities, adopting an asynchronous approach;The asynchronous telerehabilitation model may be considered a new frontier for continuity of care, capable of answering the unmet need of scaling up rehabilitation services to the broad population.

The key role of depression and supramarginal gyrus in frailty: a cross-sectional study.

Background: The age-related decrease in reserve and resistance to stressors is recognized as frailty, one of the most significant challenges identified in recent years. Despite a well-acknowledged association of frailty with cognitive impairment, depression, and gray matter morphology, no clear data are available regarding the nature of this relationship. This cross-sectional study aims to disentangle the role of the behavioral, neuropsychological, and neural components as predictors or moderators of frailty. Methods: Ninety-six older adults (mean age = 75.49 ± 6.62) were consecutively enrolled and underwent a clinical and MRI (3 T) evaluation to assess frailty, physical activity, global cognitive level, depression, wellbeing, autonomy in daily living, cortical thickness, and subcortical volumes. Results: Results showed a full mediation of depression on the link between cortical thickness and frailty, while the cognitive level showed no significant mediating role. In particular, left supramarginal thickness had a predicting role on depression, that in turn impacted frailty occurrence. Finally, handgrip weakness was an early key indicator of frailty in this study's cohort. Conclusion: These data substantiate the role of depression in mediating the link between neural integrity of the supramarginal gyrus and frailty. In the complexity of frailty, handgrip weakness seems to be an early key indicator. These results are relevant for the design of rehabilitation interventions aimed at reversing the frail condition.

Affective Theory of Mind as a residual ability to preserve mentalizing in amnestic Mild Cognitive Impairment: A 12-months longitudinal study.

Introduction: Theory of Mind (ToM) decline has been outlined in people with amnestic Mild Cognitive Impairment (aMCI), but evidence from longitudinal studies is lacking. This longitudinal study aims to investigate changes in cognitive and affective ToM performance in an aMCI sample (n = 28; 14 females, mean age = 76.54 ± 4.35). Method: Participants underwent two steps of neurocognitive evaluation, at the baseline (T1) and 12-month follow-up (T2), to obtain their global cognitive level and both affective (Reading the Mind in the Eyes test, ET) and cognitive (Strange Stories, SS) ToM profile. Then, participants were categorized into two groups based on ToM changes: people who worsened (ETΔ < 0; SSΔ < 0) and people who did not (ETΔ≥0; SSΔ≥0) at follow-up. Differences between groups in cognitive functions and ToM profiles at baseline have been investigated. Results: Our results showed that 46% of subjects worsened in affective (ET) and 28% in cognitive (SS) ToM at follow-up. People who worsened in ET reported a statistically significantly higher performance in ET at baseline (p = 0.002) but not at follow-up than people who did not worsen. In contrast, subjects who worsened in SS showed a lower Immediate Free Recall (IFR, p = 0.026) and Delayed Free Recall (DFR, p = 0.028) score of the Free and Cued Selective Reminding test at baseline and at follow-up, a lower ET (p = 0.020) baseline score, a lower SS and MMSE level at follow-up than people who not worsened. About 71% of MCI subjects showed the same trend of evolution of the Mini-Mental State Examination and SS. Variables that significantly differed between groups have been inserted in a stepwise logistic regression to pilot explore predictors of affective and cognitive ToM evolution. Logistic regression showed ET at baseline (p = 0.015) as the only significant predictor of affective ToM evolution (R2 = 0.450), while both ET (p = 0.044) and memory performance (p = 0.045) at baseline significantly predicted cognitive ToM evolution (R2 = 0.746). Discussion: In conclusion, our results support the role of affective ToM as a residual mentalizing ability in preserving the mentalizing level in people with aMCI.

Development and Testing of SPIDER-NET: An Interactive Tool for Brain Connectogram Visualization, Sub-Network Exploration and Graph Metrics Quantification.

Brain connectomics consists in the modeling of human brain as networks, mathematically represented as numerical connectivity matrices. However, this representation may result in difficult interpretation of the data. To overcome this limitation, graphical representation by connectograms is currently used via open-source tools, which, however, lack user-friendly interfaces and options to explore specific sub-networks. In this context, we developed SPIDER-NET (Software Package Ideal for Deriving Enhanced Representations of brain NETworks), an easy-to-use, flexible, and interactive tool for connectograms generation and sub-network exploration. This study aims to present SPIDER-NET and to test its potential impact on pilot cases. As a working example, structural connectivity (SC) was investigated with SPIDER-NET in a group of 17 healthy controls (HCs) and in two subjects with stroke injury (Case 1 and Case 2, both with a focal lesion affecting part of the right frontal lobe, insular cortex and subcortical structures). 165 parcels were determined from individual structural magnetic resonance imaging data by using the Destrieux atlas, and defined as nodes. SC matrices were derived with Diffusion Tensor Imaging tractography. SC matrices of HCs were averaged to obtain a single group matrix. SC matrices were then used as input for SPIDER-NET. First, SPIDER-NET was used to derive the connectogram of the right hemisphere of Case 1 and Case 2. Then, a sub-network of interest (i.e., including gray matter regions affected by the stroke lesions) was interactively selected and the associated connectograms were derived for Case 1, Case 2 and HCs. Finally, graph-based metrics were derived for whole-brain SC matrices of Case 1, Case 2 and HCs. The software resulted effective in representing the expected (dis) connectivity pattern in the hemisphere affected by the stroke lesion in Cases 1 and 2. Furthermore, SPIDER-NET allowed to test an a priori hypothesis by interactively extracting a sub-network of interest: Case 1 showed a sub-network connectivity pattern different from Case 2, reflecting the different clinical severity. Global and local graph-based metrics derived with SPIDER-NET were different between cases with stroke injury and HCs. The tool proved to be accessible, intuitive, and interactive in brain connectivity investigation and provided both qualitative and quantitative evidence.

Mid-term MRI evaluation reveals microstructural white matter alterations in COVID-19 fully recovered subjects with anosmia presentation.

Background: Little is still known about the mid/long-term effects of coronavirus disease 2019 (COVID-19) on the brain, especially in subjects who have never been hospitalized due to the infection. In this neuroimaging exploratory study, we analyzed the medium-term effect of COVID-19 on the brain of people who recovered from COVID-19, experienced anosmia during the acute phase of the disease, and have never been hospitalized due to SARS-Co-V-2 infection. Methods: Forty-three individuals who had (COV+, n = 22) or had not (COV-, n = 21) been infected with SARS-Co-V-2 were included in the study; the two groups were age- and sex-matched and were investigated using 3T magnetic resonance imaging (MRI). Gray matter (GM) volume, white matter (WM) hyperintensity volume, WM microstrutural integrity (i.e. fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], radial diffusivity [RD]) and cerebral blood flow (CBF) differences between the two groups were tested with either analysis of covariance or voxel-wise analyses. Results were family wise error (FWE) corrected. Results: No significant differences between COV+ and COV- groups were observed in terms of GM volume, WM hyperintensity volume, and CBF. Conversely, local WM microstructural alterations were detected in COV+ when compared with COV- with tract-based spatial statistics. Specifically, COV+ showed lower FA (pFWE-peak = 0.035) and higher RD (pFWE-peak = 0.038) than COV- in several WM regions. Conclusion: COVID-19 may produce mid/long-term microstructural effect on the brain, even in case of mild-to-moderate disease not requiring hospitalization. Further investigation and additional follow-ups are warranted to assess if the alterations reported in this study totally recover over time. As brain alterations could increase the risk of cognitive decline, greater knowledge of their trajectories is crucial to aid neurorehabilitation treatments.

How Do We Motorically Resonate in Aging? A Compensatory Role of Prefrontal Cortex.

Aging is the major risk factor for chronic age-related neurological diseases such as neurodegenerative disorders and neurovascular injuries. Exploiting the multimodal nature of the Mirror Neuron System (MNS), rehabilitative interventions have been proposed based on motor-resonance mechanisms in recent years. Despite the considerable evidence of the MNS' functionality in young adults, further investigation of the action-observation matching system is required in aging, where well-known structural and functional brain changes occur. Twenty-one healthy young adults (mean age 26.66y) and 19 healthy elderly participants (mean age 71.47y) underwent a single MRI evaluation including a T1-3D high-resolution and functional MRI (fMRI) with mirror task. Morphological and functional BOLD data were derived from MRI images to highlight cortical activations associated with the task; to detect differences between the two groups (Young, Elderly) in the two MRI indexes (BOLD and thickness z-scores) using mixed factorial ANOVA (Group∗Index analyses); and to investigate the presence of different cortical lateralization of the BOLD signal in the two groups. In the entire sample, the activation of a bilateral MNS fronto-parietal network was highlighted. The mixed ANOVA (pFDR-corr < 0.05) revealed significant interactions between BOLD signal and cortical thickness in left dorsal premotor cortex, right ventral premotor and prefrontal cortices. A different cortical lateralization of the BOLD signal in frontal lobe activity between groups was also found. Data herein reported suggest that age-related cortical thinning of the MNS is coupled with increased interhemispheric symmetry along with premotor and prefrontal cortex recruitment. These physiological changes of MNS resemble the aging of the motor and cognitive neural systems, suggesting specific but also common aging and compensatory mechanisms.

An SPRi-based biosensor pilot study: Analysis of multiple circulating extracellular vesicles and hippocampal volume in Alzheimer's disease.

One of the main hurdles in the study of Alzheimer's Disease (AD) is the lack of easily accessible and sensitive biomarkers for the diagnosis, the prediction of the disease progression rate and the evaluation of rehabilitative and pharmacological treatments. Extracellular Vesicles (EVs) are nanoscale particles released by body cells, studied as promising biomarkers of AD as they are involved in the onset and progression of the disease. In the strive for a reliable and sensitive method to analyze EVs, we applied our recently developed biosensor based on Surface Plasmon Resonance imaging (SPRi) technology for the identification and profiling of neural EVs populations circulating in the plasma of 10 AD patients and 10 healthy subjects. The SPRi-array was designed to separate simultaneously EVs released by neurons, astrocytes, microglia and oligodendrocytes, and to evaluate the presence and the relative amount of specific surface molecules related to pathological processes including translocator protein (TSPO), ß-Amyloid and ganglioside M1. As results, significant variations in the relative amount and cargoes of specific brain-derived populations of EVs were observed comparing EVs coming from AD patients and healthy subjects, finding the main differences in the activation phenotype of microglia EVs, in the lipid moieties on generic EVs and in the ß-Amyloid expression on surfaces of neuronal EVs. Besides, the demonstrated correlation of SPRi data with Magnetic Resonance Imaging analysis, provided support for using the SPRi-based biosensor for the evaluation of neurodegeneration detecting and characterizing circulating EVs as peripheral biomarkers for the diagnosis and monitoring of progression and rehabilitation treatments in AD patients.

Neuroimaging Biomarkers Predicting the Efficacy of Multimodal Rehabilitative Intervention in the Alzheimer's Dementia Continuum Pathology.

In this work we aimed to identify neural predictors of the efficacy of multimodal rehabilitative interventions in AD-continuum patients in the attempt to identify ideal candidates to improve the treatment outcome. Subjects in the AD continuum who participated in a multimodal rehabilitative treatment were included in the analysis [n = 82, 38 Males, mean age = 76 ± 5.30, mean education years = 9.09 ± 3.81, Mini Mental State Examination (MMSE) mean score = 23.31 ± 3.81]. All subjects underwent an MRI acquisition (1.5T) at baseline (T0) and a neuropsychological evaluation before (T0) and after intervention (T1). All subjects underwent an intensive multimodal cognitive rehabilitation (8-10 weeks). The MMSE and Neuropsychiatric Inventory (NPI) scores were considered as the main cognitive and behavioral outcome measures, and Delta change scores (T1-T0) were categorized in Improved (ΔMMSE > 0; ΔNPI < 0) and Not Improved (ΔMMSE ≤ 0; ΔNPI ≥ 0). Logistic Regression (LR) and Random Forest classification models were performed including neural markers (Medial Temporal Brain; Posterior Brain (PB); Frontal Brain (FB), Subcortical Brain indexes), neuropsychological (MMSE, NPI, verbal fluencies), and demographical variables (sex, age, education) at baseline. More than 50% of patients showed a positive effect of the treatment (ΔMMSE > 0: 51%, ΔNPI < 0: 52%). LR model on ΔMMSE (Improved vs. Not Improved) indicate a predictive role for MMSE score (p = 0.003) and PB index (p = 0.005), especially the right PB (p = 0.002) at baseline. The Random Forest analysis correctly classified 77% of cognitively improved and not improved AD patients. Concerning the NPI, LR model on ΔNPI (Improved vs. Not Improved) showed a predictive role of sex (p = 0.002), NPI (p = 0.005), PB index (p = 0.006), and FB index (p = 0.039) at baseline. The Random Forest reported a classification accuracy of 86%. Our data indicate that cognitive and behavioral status alone are not sufficient to identify best responders to a multidomain rehabilitation treatment. Increased neural reserve, especially in the parietal areas, is also relevant for the compensatory mechanisms activated by rehabilitative treatment. These data are relevant to support clinical decision by identifying target patients with high probability of success after rehabilitative programs on cognitive and behavioral functioning.

SNAP-25 Single Nucleotide Polymorphisms, Brain Morphology and Intelligence in Children With Borderline Intellectual Functioning: A Mediation Analysis.

Borderline intellectual functioning (BIF) is a multifactorial condition in which both genetic and environmental factors are likely to contribute to the clinical outcome. Abnormal cortical development and lower IQ scores were shown to be correlated in BIF children, but the genetic components of this condition and their possible connection with intelligence and brain morphology have never been investigated in BIF. The synaptosomal-associated protein of 25 kD (SNAP-25) is involved in synaptic plasticity, neural maturation, and neurotransmission, affecting intellectual functioning. We investigated SNAP-25 polymorphisms in BIF and correlated such polymorphisms with intelligence and cortical thickness, using socioeconomic status and environmental stress as covariates as a good proxy of the variables that determine intellectual abilities. Thirty-three children with a diagnosis of BIF were enrolled in the study. SNAP-25 polymorphisms rs363050, rs363039, rs363043, rs3746544, and rs1051312 were analyzed by genotyping; cortical thickness was studied by MRI; intelligence was measured using the WISC-III/IV subscales; environmental stressors playing a role in neuropsychiatric development were considered as covariate factors. Results showed that BIF children carrying the rs363043(T) minor allele represented by (CT + TT) genotypes were characterized by lower performance Perceptual Reasoning Index and lower full-scale IQ scores (p = 0.04) compared to those carrying the (CC) genotype. This association was correlated with a reduced thickness of the left inferior parietal cortex (direct effect = 0.44) and of the left supramarginal gyrus (direct effect = 0.56). These results suggest a link between SNAP-25 polymorphism and intelligence with the mediation role of brain morphological features in children with BIF.

Diagnostic Validity of the Smart Aging Serious Game: An Innovative Tool for Digital Phenotyping of Mild Neurocognitive Disorder.

BACKGROUND: The Smart Aging Serious Game (SASG) is an ecologically-based digital platform used in mild neurocognitive disorders. Considering the higher risk of developing dementia for mild cognitive impairment (MCI) and vascular cognitive impairment (VCI), their digital phenotyping is crucial. A new understanding of MCI and VCI aided by digital phenotyping with SASG will challenge current differential diagnosis and open the perspective of tailoring more personalized interventions. OBJECTIVE: To confirm the validity of SASG in detecting MCI from healthy controls (HC) and to evaluate its diagnostic validity in differentiating between VCI and HC. METHODS: 161 subjects (74 HC: 37 males, 75.47±2.66 mean age; 60 MCI: 26 males, 74.20±5.02; 27 VCI: 13 males, 74.22±3.43) underwent a SASG session and a neuropsychological assessment (Montreal Cognitive Assessment (MoCA), Free and Cued Selective Reminding Test, Trail Making Test). A multi-modal statistical approach was used: receiver operating characteristic (ROC) curves comparison, random forest (RF), and logistic regression (LR) analysis. RESULTS: SASG well captured the specific cognitive profiles of MCI and VCI, in line with the standard neuropsychological measures. ROC analyses revealed high diagnostic sensitivity and specificity of SASG and MoCA (AUCs > 0.800) in detecting VCI versus HC and MCI versus HC conditions. An acceptable to excellent classification accuracy was found for MCI and VCI (HC versus VCI; RF: 90%, LR: 91%. HC versus MCI; RF: 75%; LR: 87%). CONCLUSION: SASG allows the early assessment of cognitive impairment through ecological tasks and potentially in a self-administered way. These features make this platform suitable for being considered a useful digital phenotyping tool, allowing a non-invasive and valid neuropsychological evaluation, with evident implications for future digital-health trails and rehabilitation.

The shape of motor resonance: right- or left-handed?

The human mirror neuron system is a fronto-parietal neural pathway which, when activated by action observation, gives rise to an internal simulation of the observed action (motor resonance). Here we demonstrate how handedness shapes the resonant response, by engaging right-handed (RH) and left-handed (LH) subjects in observation and execution of actions preferentially performed by the dominant hand. We hypothesize that since motor resonance reproduces subliminally the specific motor program for the observed action, it should be subject to motor constraints, such as handedness. A conjunction analysis for observed and executed actions revealed that handedness determines a lateralized activation of the areas engaged in motor resonance. Premotor-BA6 and parietal-BA40 are strongly left lateralized in RH subjects observing or moving their right hand, and to a lesser degree their left hand. Extremely LH subjects show a similar pattern of lateralization on the right, while more ambidextrous LH subjects show a more bilateral activation. The activation of a cortical network outside the mirror neuron system is also discussed.

HSV-1-Specific IgG3 Titers Correlate with Brain Cortical Thinning in Individuals with Mild Cognitive Impairment and Alzheimer's Disease.

Repeated reactivations of latent herpes simplex virus type-1 (HSV-1) in the central nervous system (CNS) may contribute to neurodegeneration in Alzheimer's disease (AD) patients. Immune response is a key element for the control of viral reactivation. HSV-1 uses a number of strategies to evade immune recognition, Immunoglobulin G 3 (IgG3) alone counteracts humoral immunoevasion, as it is the only IgG subclass that is not blocked by the HSV-1 Fc receptor, a protein that protects virion and infected cells from antibody-mediated effector mechanisms. We examined HSV-1-specific IgG3 titers in serum of AD (n = 70) and mild cognitive impairment (MCI) (n = 61) subjects comparing the results to those of 67 age- and sex-matched healthy controls (HC); associations between MRI-determined brain cortical health and HSV-1-specific IgG3 were analyzed in a subgroup of AD and MCI subjects. HSV-1-specific IgG3 were more frequently detected in MCI compared to AD and HC subjects. Significant inverse correlations were found between IgG3 titers and brain cortical thickness in areas typically involved in dementia and HSV-1 encephalitis in AD patients; interestingly, this negative correlation was much less important in MCI subjects. All together these results suggest that in AD an inefficient IgG3 humoral immune response, failing to block viral replication, contributes to progressive neurodegeneration.