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To address the impact of COVID‐19 olfactory loss on the brain, we analyzed the neural connectivity of the central olfactory system in recently SARS‐CoV‐2 infected subjects with persisting olfactory impairment (hyposmia). Twenty‐seven previously SARS‐CoV‐2 infected subjects (10 males, mean age ± SD 40.0 ± 7.6 years) with clinically confirmed COVID‐19 related hyposmia, and eighteen healthy, never SARS‐CoV‐2 infected, normosmic subjects (6 males, mean age ± SD 36.0 ± 7.1 years), were recruited in a 3 Tesla MRI study including high angular resolution diffusion and resting‐state functional MRI acquisitions. Specialized metrics of structural and functional connectivity were derived from a standard parcellation of olfactory brain areas and a previously validated graph‐theoretic model of the human olfactory functional network. These metrics were compared between groups and correlated to a clinical index of olfactory impairment. On the scanning day, all subjects were virus‐free and cognitively unimpaired. Compared to control, both structural and functional connectivity metrics were found significantly increased in previously SARS‐CoV‐2 infected subjects. Greater residual olfactory impairment was associated with more segregated processing within regions more functionally connected to the anterior piriform cortex. An increased neural connectivity within the olfactory cortex was associated with a recent SARS‐CoV‐2 infection when the olfactory loss was a residual COVID‐19 symptom. The functional connectivity of the anterior piriform cortex, the largest cortical recipient of afferent fibers from the olfactory bulb, accounted for the inter‐individual variability in the sensory impairment. Albeit preliminary, these findings could feature a characteristic brain connectivity response in the presence of COVID‐19 related residual hyposmia. A structural and functional neural connectivity analysis of the central olfactory system was performed in previously SARS‐CoV‐2 infected subjects with persisting olfactory impairment. An increased neural connectivity within the olfactory cortex was associated with a recent SARS‐CoV‐2 infection. The functional connectivity of the anterior piriform cortex accounted for the inter‐individual variability in the sensory impairment, suggesting a characteristic brain connectivity response in the presence of COVID‐19 related residual hyposmia.

BackgroundSubjective complaints of cognitive deficits are not necessarily consistent with objective evidence of cognitive impairment in Parkinson’s disease (PD). Here we examined the factors associated with the objective-subjective cognitive discrepancy.MethodsWe consecutively enrolled 90 non-demented patients with PD who completed the Parkinson’s Disease Cognitive Functional Rating Scale (subjective cognitive measure) and the Montreal Cognitive Assessment (MoCA; objective cognitive measure). The patients were classified as “Overestimators”, “Accurate estimators”, and “Underestimators” on the basis of the discrepancy between the objective vs. subjective cognitive measures. To identify the factors distinguishing these groups from each other, we used chi-square tests or one-way analyses of variance, completed by logistic and linear regression analyses.ResultsForty-nine patients (54.45%) were classified as “Accurate estimators”, 29 (32.22%) as “Underestimators”, and 12 (13.33%) as “Overestimators”. Relative to the other groups, the “Underestimators” scored higher on the Fatigue Severity Scale (FSS), Beck Depression Inventory (BDI), and Parkinson Anxiety Scale (p < 0.01). Logistic regression confirmed that FSS and BDI scores distinguished the “Underestimators” group from the others (p < 0.05). Linear regression analyses also indicated that FSS and BDI scores positively related to objective-subjective cognitive discrepancy (p < 0.01). “Overestimators” scored lower than other groups on the MoCA’s total score and attention and working memory subscores (p < 0.01).ConclusionIn more than 45% of consecutive non-demented patients with PD, we found a ‘mismatch’ between objective and subjective measures of cognitive functioning. Such discrepancy, which was related to the presence of fatigue and depressive symptoms and frontal executive impairments, should be carefully evaluated in clinical setting.

IntroductionParkinson’s disease (PD) patients in chronic levodopa treatment may experience motor and non-motor fluctuations, which may affect their quality of life. Safinamide is a new monoamine oxidase B inhibitor, also exerting a non-dopaminergic effect, recently approved as add-on therapy in fluctuating PD patients.MethodsWe performed a longitudinal prospective study in a cohort of 20 fluctuating PD patients, to test whether safinamide 50 mg may improve non-motor, cognitive, and behavioral symptoms over a 6-month treatment period. At each timepoint, clinical features were assessed by means of validated PD-specific scales. Neuropsychological assessment was performed by exploring all five cognitive domains.ResultsCompared to baseline, significant improvement was found in PD patients at 6-month follow-up in items investigating interest (p = 0.02), motivation (p = 0.02), and urinary disturbances (p = 0.03). Moreover, neuropsychiatric assessment showed a significant decrease in fatigue and apathy scores (p = 0.02 and p = 0.01, respectively). Motor assessment revealed a significant reduction in the total wake-up time spent in OFF state (p = 0.01). Follow-up neuropsychological evaluation did not reveal any change compared to baseline.ConclusionsOur data reveal that, along with motor fluctuation improvement, treatment with safinamide 50 mg may significantly decrease non-motor symptom burden in PD patients. Interestingly, non-dopaminergic mechanisms, such as glutamatergic overdrive, have been demonstrated to play a role in many pathways underlying these symptoms. Thus, we hypothesize that the neurotransmitter receptor-binding profile of safinamide may explain our findings.

ObjectivesTo investigate the effects of cholecalciferol supplementation on the progression of motor disability in a cohort of amyotrophic lateral sclerosis (ALS) patients with low blood 25-hydroxyvitamin D3 [25(OH)D] levels, on the basis of the hypothesis of potential neuroprotective effects of vitamin D supplementation.MethodsForty-eight ALS patients, 34 with deficient (<20 ng/mL) and 14 with insufficient (20–29 ng/mL) serum levels of 25(OH)D, were randomized and treated by 3 different doses of cholecalciferol [50.000, 75.000 and 100.000 international units (IU) /month] and evaluated after 6-months. Assessment of motor dysfunction at baseline and after 6 months included ALS Functional Rating Scale-Revised (ALFRS-R) and upper motor neuron (UMN) scores and blood samples for 25(OH)D levels.ResultsClinical data of 33 patients were available after 6 months. Analysis of Covariance (ANCOVA), with pre-treatment measurements included as covariate, did not show statistically significant differences in the ALSFRS-R (p > 0.05) and UMN (p > 0.05) among the patient groups who underwent 3 different doses of cholecalciferol. Conversely, the treatment with 75.000 IU/month or 100.000 IU/month induced a significant increase in serum levels of 25(OH)D in comparison with the supplementation with 50.000 IU/month; no significant differences were found between 75.000 IU/month and 100.000 IU/month.ConclusionsOur findings highlighted that 6-month supplementation of vitamin D in ALS patients had no significant effects on motor dysfunction. However, it is recommended to prevent medical complications of vitamin D deficiency in ALS patients as well as in other populations of neurodegenerative patients, characterized by low mobility and decreased sun exposure.

Background Cognitive deficits related to frontotemporal dysfunction are common in Amyotrophic Lateral Sclerosis (ALS). Visuospatial deficits, related to posterior cerebral regions, are often underestimated in ALS, though they play a crucial role in attending daily living activities. Our pilot study aims at assessing visuospatial abilities using a domain-specific tool in ALS patients compared to healthy controls (HC). Methods Twenty-three patients with early ALS and 23 age- and education-matched HC underwent the Battery for Visuospatial Abilities (BVA), including 4 visuo-perceptual and 4 visuo-representational subtests. Results When compared to HC, ALS scored worse in 2 visuo-perceptual subtests (i.e., Line Length Judgment and Line Orientation Judgment) and 1 visuo-representational tasks (i.e., Hidden Figure Identification, HFI) ( p  < 0.01). No correlations arose between ALS clinical features and BVA performance. More than 80% of the ALS cohort obtained abnormal scores in the HFI subtest. Conclusions Our findings revealed that patients with ALS scored worse (compared to HC) on selective tests tapping “perceptual” and “representational” visuospatial abilities, since the early stages of disease. In clinical practice, our findings highlight the need for multi-domain neuropsychological assessment, for monitoring disease courses and properly organizing care management of patients with ALS.

Background Parkinson’s disease (PD) affects brain networks across multiple anatomical scales, but it is unclear how correctly machine learning (ML) would classify the (altered) topology of functional connectomes in single PD cases at an early clinical stage. Leveraging network graph theory (NGT) for multi-scale topological feature extraction, here we determined (i) which features (across scales, lobes and types) are relatively more important, and (ii) which current state-of-the-art ML classifiers provide better performances, when discriminating newly diagnosed, drug-naive PD patients vs. healthy control (HC) subjects in a single-center MRI study. Methods Resting-state functional MRI was consecutively performed in 112 drug-naïve PD patients and 17 HC subjects. Following standard (automated) preprocessing, the Brainnetome atlas (210/36 cortical/subcortical areas) was applied to reconstruct individual functional connectomes. NGT features were extracted at global, lobar/cortical and lobar/subcortical scales. Feature importance was assessed as the information gain (IG) criterion. The synthetic minority oversampling technique (SMOTE) was used to augment HC datasets. Nine different ML classifiers were trained on discriminating PD vs. HC (balanced) classes and validated via repeated stratified cross-validation. Results Among global NGT features, characteristic path length (IG = 20.3%) was more important than global (IG ~ 14%) and average local (IG ~ 14%) efficiency. Basal ganglia (IG = 18.5%), parietal cortex (IG = 17.7%) and thalamus (IG = 15.6%) cumulatively contributed the most informative NGT features. The “extra-tree classifier” achieved the best performances (F1-score = 95.8 ± 3.8%; AUCROC = 99.3 ± 1.8%). Conclusions Both global and local NGT features are important for the topological classification of functional connectomes in drug-naïve PD patients. Combining multi-scale functional connectomics with ML may contribute to the design of health information technologies (for decision-making) and for the definition of early, accurate and interpretable, non-invasive neuroimaging PD biomarkers.

Emerging evidence suggests that memory deficit in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with varying impairment of motor abilities and cognitive profile, may be independent from executive dysfunction. Our multimodal magnetic resonance imaging (MRI) approach, including resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM), aimed to investigate structural and functional changes within and beyond the Papez circuit in non-demented ALS patients (n = 32) compared with healthy controls (HCs, n = 21), and whether these changes correlated with neuropsychological measures of verbal and non-verbal memory. We revealed a decreased functional connectivity between bilateral hippocampus, bilateral parahippocampal gyri and cerebellum in ALS patients compared with HCs. Between-group comparisons revealed white matter abnormalities in the genu and body of the corpus callosum and bilateral cortico-spinal tracts, superior longitudinal and uncinate fasciculi in ALS patients (p < .05, family-wise error corrected). Interestingly, changes of Digit Span forward performance were inversely related to RS-fMRI signal fluctuations in the cerebellum, while changes of both episodic and visual memory scores were inversely related to mean and radial diffusivity abnormalities in several WM fiber tracts, including middle cerebellar peduncles. Our findings revealed that ALS patients showed significant functional and structural connectivity changes across the regions comprising the Papez circuit, as well as more extended areas including cerebellum and frontal, temporal and parietal areas, supporting the theory of a multi-system pathology in ALS that spreads from cortical to subcortical structures.

Family caregivers of people with amyotrophic lateral sclerosis (ALS), a severely disabling neurodegenerative disease due to the degeneration of both upper and lower motor neurons, have a very demanding role in managing their relatives, thereby often experiencing heavy care burden. Previous literature has widely highlighted that this situation reduces caregivers’ quality of life and increases their psychological distress and risk of health problems, but there are relatively few studies that focus on psychological interventions for these situations. Family support is more—not less—important during crisis. However, during the COVID-19 pandemic, maintaining public safety has required restricting the physical presence of families for hospitalized patients. Caregivers of ALS patients felt increased sense of loneliness and experienced greater difficulties in the access to both hospital and home assistance. In response, health systems rapidly adapted family-centric procedures and tools to circumvent restrictions on physical presence. In this regard, internet-based and telehealth solutions have been adopted to facilitate the routine, predictable, and structured communication, crucial to family-centered care. This narrative review aims at addressing more current matters on support needs and interventions for improving wellbeing of caregivers of ALS patients. In particular, we aimed at highlighting several gaps related to the complex needs of caregivers of ALS patients, to the interventions carried out in order to respond to these needs, and to the changes that COVID-19 pandemic caused from 2020 to nowadays in clinical managing of ALS patients. Finally, we report ongoing experiences of psychological support for family caregivers of ALS patients through telehealth solutions, which have been reinforced in case of needing of physical distancing during the COVID-19 pandemic.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that is increasingly used as a nonpharmacological intervention against cognitive impairment in Alzheimer’s disease (AD) and other dementias. Although rTMS has been shown to modify cognitive performances and brain functional connectivity (FC) in many neurological and psychiatric diseases, there is still no evidence about the possible relationship between executive performances and resting-state brain FC following rTMS in patients with mild cognitive impairment (MCI). In this preliminary study, we aimed to evaluate the possible effects of rTMS of the bilateral dorsolateral prefrontal cortex (DLPFC) in 27 MCI patients randomly assigned to two groups: one group received high-frequency (10 Hz) rTMS (HF-rTMS) for four weeks (n = 11), and the other received sham stimulation (n = 16). Cognitive and psycho-behavior scores, based on the Repeatable Battery for the Assessment of Neuropsychological Status, Beck Depression Inventory-II, Beck Anxiety Inventory, Apathy Evaluation Scale, and brain FC, evaluated by independent component analysis of resting state functional MRI (RS-fMRI) networks, together with the assessment of regional atrophy measures, evaluated by whole-brain voxel-based morphometry (VBM), were measured at baseline, after five weeks, and six months after rTMS stimulation. Our results showed significantly increased semantic fluency (p = 0.026) and visuo-spatial (p = 0.014) performances and increased FC within the salience network (p ≤ 0.05, cluster-level corrected) at the short-term timepoint, and increased FC within the left fronto-parietal network (p ≤ 0.05, cluster-level corrected) at the long-term timepoint, in the treated group but not in the sham group. Conversely, regional atrophy measures did not show significant longitudinal changes between the two groups across six months. Our preliminary findings suggest that targeting DLPFC by rTMS application may lead to a significant long-term increase in FC in MCI patients in a RS network associated with executive functions, and this process might counteract the progressive cortical dysfunction affecting this domain.

The structural connectivity from the primary olfactory cortex to the main secondary olfactory areas was previously reported as relatively increased in the medial orbitofrontal cortex in a cohort of 27 recently SARS-CoV-2-infected (COV+) subjects, of which 23/27 had clinically confirmed olfactory loss, compared to 18 control (COV-) normosmic subjects, who were not previously infected. To complement this finding, here we report the outcome of an identical high angular resolution diffusion MRI analysis on follow-up data sets collected in 18/27 COV+ subjects (10 males, mean age±SD: 38.7±8.1 years) and 10/18 COV- subjects (5 males, mean age±SD: 33.1±3.6 years) from the previous samples who repeated both the olfactory functional assessment and the MRI examination after ~1 year. By comparing the newly derived subgroups, we observed that the increase in the structural connectivity index of the medial orbitofrontal cortex was not significant at follow-up, despite 10/18 COV+ subjects were still found hyposmic after ~1 year from SARS-CoV-2 infection. We concluded that the relative hyperconnectivity of the olfactory cortex to the medial orbitofrontal cortex could be, at least in some cases, an acute or reversible phenomenon linked to the recent SARS-CoV-2 infection with associated olfactory loss.