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Background: The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation., Objective: To evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and [ 18 F]FDG-PET measures of neural dysfunction., Methods: We retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and [ 18 F]FDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For [ 18 F]FDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC)., Results: Based on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the [ 18 F]FDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC., Conclusion: This study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

The conversion from mild cognitive impairment (MCI) to dementia is influenced by several factors, including comorbid conditions such as metabolic and vascular diseases. Understanding the impact of these comorbidities can help in the disease management of patients with a higher risk of progressing to dementia, improving outcomes. In the current study, we aimed to analyze data from a large cohort of MCI (n = 188) by principal component analysis (PCA) and cluster analysis (CA) to classify patients into distinct groups based on their comorbidity profile and to predict the risk of conversion to dementia. From our analysis, four clusters emerged. CA showed a significantly higher rate of disease progression for Cluster 1, which was predominantly characterized by extremely high obesity and diabetes compared to other clusters. In contrast, Cluster 3, which was defined by a lower prevalence of all comorbidities, had a lower conversion rate. Cluster 2, mainly including subjects with traumatic brain injuries, showed the lowest rate of conversion. Lastly, Cluster 4, including a high load of hearing loss and depression, showed an intermediate risk of conversion. This study underscores the significant impact of specific comorbidity profiles on the progression from MCI to dementia, highlighting the need for targeted interventions and management strategies for individuals with these comorbidity profiles to potentially delay or prevent the onset of dementia.

Alzheimer's disease (AD) causes a significant challenge to global healthcare systems, with limited effective treatments available. This review examines the landscape of novel therapeutic strategies for AD, focusing on the shortcomings of traditional therapies against amyloid-beta (Aβ) and exploring emerging alternatives. Despite decades of research emphasizing the role of Aβ accumulation in AD pathogenesis, clinical trials targeting Aβ have obtained disappointing results, highlighting the complexity of AD pathophysiology and the need for investigating other therapeutic approaches. In this manuscript, we first discuss the challenges associated with anti-Aβ therapies, including limited efficacy and potential adverse effects, underscoring the necessity of exploring alternative mechanisms and targets. Thereafter, we review promising non-Aβ-based strategies, such as tau-targeted therapies, neuroinflammation modulation, and gene and stem cell therapy. These approaches offer new avenues for AD treatment by addressing additional pathological hallmarks and downstream effects beyond Aβ deposition.

Introduction: Amnestic mild cognitive impairment (aMCI) is emerging as a heterogeneous condition., Methods: We looked at a cohort of N = 207 aMCI subjects, with baseline fluorodeoxyglucose positron emission tomography (FDG-PET), T1 magnetic resonance imaging, cerebrospinal fluid (CSF), apolipoprotein E (APOE), and neuropsychological assessment. An algorithm based on FDG-PET hypometabolism classified each subject into subtypes, then compared biomarker measures and clinical progression., Results: Three subtypes emerged: hippocampal sparing-cortical hypometabolism, associated with younger age and the highest level of Alzheimer's disease (AD)-CSF pathology; hippocampal/cortical hypometabolism, associated with a high percentage of APOE ε3/ε4 or ε4/ε4 carriers; medial-temporal hypometabolism, characterized by older age, the lowest AD-CSF pathology, the most severe hippocampal atrophy, and a benign course. Within the whole cohort, the severity of temporo-parietal hypometabolism, correlated with AD-CSF pathology and marked the rate of progression of cognitive decline., Discussion: FDG-PET can distinguish clinically comparable aMCI at single-subject level with different risk of progression to AD dementia or stability. The obtained results can be useful for the optimization of pharmacological trials and automated-classification models., Highlights: Algorithm based on FDG-PET hypometabolism demonstrates distinct subtypes across aMCI; Three different subtypes show heterogeneous biological profiles and risk of progression; The cortical hypometabolism is associated with AD pathology and cognitive decline; MTL hypometabolism is associated with the lowest conversion rate and CSF-AD pathology., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Neurodegenerative diseases are progressive brain disorders characterized by inexorable synaptic dysfunction and neuronal loss. Since the most consistent risk factor for developing neurodegenerative diseases is aging, the prevalence of these disorders is intended to increase with increasing life expectancy. Alzheimer's disease is the most common cause of neurodegenerative dementia, representing a significant medical, social, and economic burden worldwide. Despite growing research to reach an early diagnosis and optimal patient management, no disease-modifying therapies are currently available. Chronic neuroinflammation has been recognized as a crucial player in sustaining neurodegenerative processes, along with pathological deposition of misfolded proteins, including amyloid-β and tau protein. Modulating neuroinflammatory responses may be a promising therapeutic strategy in future clinical trials. Among factors that are able to regulate neuroinflammatory mechanisms, diet, and nutrients represent easily accessible and modifiable lifestyle components. Mediterranean diet and several nutrients, including polyphenols, vitamins, and omega-3 polyunsaturated fatty acids, can exert antioxidant and anti-inflammatory properties, impacting clinical manifestations, cognitive decline, and dementia. This review aims to provide an updated overview of the relationship between neuroinflammation, nutrition, gut microbiota, and neurodegeneration. We summarize the major studies exploring the effects of diet regimes on cognitive decline, primarily focusing on Alzheimer's disease dementia and the impact of these results on the design of ongoing clinical trials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Parkinson's disease (PD) is a neurodegenerative disease characterized by both motor and non-motor symptoms. A progressive neuronal loss and the consequent clinical impairment lead to deleterious effects on daily living and quality of life. Despite effective symptomatic therapeutic approaches, no disease-modifying therapies are currently available. Emerging evidence suggests that adopting a healthy lifestyle can improve the quality of life of PD patients. In addition, modulating lifestyle factors can positively affect the microstructural and macrostructural brain levels, corresponding to clinical improvement. Neuroimaging studies may help to identify the mechanisms through which physical exercise, dietary changes, cognitive enrichment, and exposure to substances modulate neuroprotection. All these factors have been associated with a modified risk of developing PD, with attenuation or exacerbation of motor and non-motor symptomatology, and possibly with structural and molecular changes. In the present work, we review the current knowledge on how lifestyle factors influence PD development and progression and the neuroimaging evidence for the brain structural, functional, and molecular changes induced by the adoption of positive or negative lifestyle behaviours., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FDT) are progressive neurodegenerative disorders that, in several cases, overlap in clinical presentation, and genetic and pathological disease mechanisms. About 10-15% of ALS cases and up to 40% of FTD are familial, usually with dominant traits. ALS and FTD, in several cases, share common gene mutations, such as in C9ORF72 , TARDBP , SQSTM-1 , FUS , VCP , CHCHD10 , and TBK-1 . Also, several mechanisms are involved in ALS and FTD pathogenesis, such as protein misfolding, oxidative stress, and impaired axonal transport. In addition, neuroinflammation and neuroinflammatory cells, such as astrocytes, oligodendrocytes, microglia, and lymphocytes and, overall, the cellular microenvironment, have been proposed as pivotal players in the pathogenesis the ALS-FTD spectrum disorders. This review overviews the current evidence regarding neuroinflammatory markers in the ALS/FTD continuum, focusing on the neuroinflammatory pathways involved in the genetic cases, moving from post-mortem reports to in vivo biofluid and neuroimaging data. We further discuss the potential link between genetic and autoimmune disorders and potential therapeutic implications.

Growing evidence suggests that neuroinflammation plays a critical role in the pathogenesis of neurodegenerative diseases. Peripheral markers of inflammation, including blood cell counts and their ratios, such as the neutrophil-to-lymphocyte ratio (NLR), have been reported as an easily accessible and reliable proxy of central nervous system inflammation. However, the role of peripheral inflammation in dementia and Mild Cognitive Impairment (MCI) still needs to be clarified. In the current study, we aimed to assess the prognostic role of the NLR and other peripheral markers of inflammation in a sample of 130 amnestic MCI, followed up for two to five years. The Mini-Mental state examination (MMSE) score at baseline and follow-up visits was used to assess global cognitive status at each visit and the degree of cognitive decline over time. Baseline peripheral markers of inflammation included blood cell counts and ratios, specifically the NLR, the platelet-to-lymphocyte ratio (PLR), the monocyte-to-lymphocyte ratio (MLR), and the systemic immune inflammation index (SII). After classifying subjects into CONVERTERS and non-CONVERTERS (respectively, patients converting to dementia and subjects showing stability at the last available follow-up), we compared peripheral markers of inflammation among groups ed correlated them with cognitive measures, testing the ability of significant factors to predict conversion to dementia. In our cohort, CONVERTERS showed lower baseline MMSE scores ( p -value = 0.004) than non-CONVERTERS. In addition, CONVERTERS had statistically elevated NLR ( p -value = 0.005), PLR ( p -value = 0.002), and SII levels ( p -value = 0.015), besides a lower number of lymphocytes ( p -value = 0.004) compared with non-CONVERTERS. In a logistic regression analysis, baseline MMSE scores and NLR predicted conversion to dementia. Tertiles analysis showed that MCI with the highest NLR values had a higher conversion risk. Our study supports the hypothesis that a dysregulation of peripheral inflammation involving both lymphocytes and neutrophils may play a role in the pathogenesis of dementia, even at the early stages of neurodegeneration, as in the MCI condition.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are severely debilitating and progressive neurodegenerative disorders. A distinctive pathological feature of several neurodegenerative diseases, including ALS and FTD, is the deposition of aberrant protein inclusions in neuronal cells, which leads to cellular dysfunction and neuronal damage and loss. Despite this, to date, the biological process behind developing these protein inclusions must be better clarified, making the development of disease-modifying treatment impossible until this is done. Proteomics is a powerful tool to characterize the expression, structure, functions, interactions, and modifications of proteins of tissue and biological fluid, including plasma, serum, and cerebrospinal fluid. This protein-profiling characterization aims to identify disease-specific protein alteration or specific pathology-based mechanisms which may be used as markers of these conditions. Our narrative review aims to highlight the need for biomarkers and the potential use of proteomics in clinical practice for ALS-FTD spectrum disorders, considering the emerging rationale in proteomics for new drug development. Certainly, new data will emerge in the near future in this regard and support clinicians in the development of personalized medicine.

Functional network-level alterations in the semantic variant of Primary Progressive Aphasia (sv-PPA) are relevant to understanding the clinical features and the neural spreading of the pathology. We assessed the effect of neurodegeneration on brain systems reorganization in early sv-PPA, using advanced brain metabolic connectivity approaches. Forty-four subjects with sv-PPA and forty-four age-matched healthy controls (HC) were included. We applied two multivariate approaches to [18F]FDG-PET data - i.e., sparse inverse covariance estimation and seed-based interregional correlation analysis - to assess the integrity of (i) the whole-brain metabolic connectivity and (ii) the connectivity of brain regions relevant for cognitive and behavioral functions. Whole-brain analysis revealed a global-scale connectivity reconfiguration in sv-PPA, with widespread changes in metabolic connections of frontal, temporal, and parietal regions. In comparison to HC, the seed-based analysis revealed a) functional isolation of the left anterior temporal lobe (ATL), b) decreases in temporo-occipital connections and contralateral homologous regions, c) connectivity increases to the dorsal parietal cortex from the spared posterior temporal cortex, d) a disruption of the large-scale limbic brain networks. In sv-PPA, the severe functional derangement of the left ATL may lead to an extensive connectivity reconfiguration, encompassing several brain regions, including those not yet affected by neurodegeneration. These findings support the hypothesis that in sv-PPA the focal vulnerability of the core region (i.e., ATL) can potentially drive the widespread cerebral connectivity changes, already present in the early phase., Competing Interests: Declaration of competing interest No competing financial interests exist., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The COVID-19 pandemic has led to unprecedented demand on the global healthcare system. Remarkably, at the end of 2021, COVID-19 vaccines received approvals for human use in several countries worldwide. Since then, a solid base for response in the fight against the virus has been placed. COVID-19 vaccines have been shown to be safe and effective drugs. Nevertheless, all kinds of vaccines may be associated with the possible appearance of neurological complications, and COVID-19 vaccines are not free from neurological side effects. Neurological complications of COVID-19 vaccination are usually mild, short-duration, and self-limiting. However, severe and unexpected post-vaccination complications are rare but possible events. They include the Guillain-Barré syndrome, facial palsy, other neuropathies, encephalitis, meningitis, myelitis, autoimmune disorders, and cerebrovascular events. The fear of severe or fatal neurological complications fed the "vaccine hesitancy" phenomenon, posing a vital communication challenge between the scientific community and public opinion. This review aims to collect and discuss the frequency, management, and outcome of reported neurological complications of COVID-19 vaccines after eighteen months of the World Health Organization's approval of COVID-19 vaccination, providing an overview of safety and concerns related to the most potent weapon against the SARS-CoV-2.

Background and Objectives: The ALS diagnosis requires an integrative approach, combining the clinical examination and supporting tests. Nevertheless, in several cases, the diagnosis proves to be suboptimal, and for this reason, new diagnostic methods and novel biomarkers are catching on. The 18 F-fluorodeoxyglucose ( 18 F-FDG)-PET could be a helpful method, but it still requires additional research for sensitivity and specificity. We performed an 18 F-FDG-PET single-subject analysis in a sample of familial ALS patients carrying different gene mutations, investigating the genotype-phenotype correlations and exploring metabolism correlations with clinical and neuropsychological data., Methods: We included ten ALS patients with pathogenic gene mutation who underwent a complete clinical and neuropsychological evaluation and an 18 F-FDG-PET scan at baseline. Patients were recruited between 2018 and 2022 at the ALS Tertiary Centre in Novara, Italy. Patients were selected based on the presence of ALS gene mutation (C9orf72, SOD1, TBK1, and KIF5A). Following a validated voxel-based Statistical Parametric Mapping (SPM) procedure, we obtained hypometabolism maps at single-subject level. We extracted regional hypometabolism from the SPM maps, grouping significant hypometabolism regions into three meta-ROIs (motor, prefrontal association and limbic). Then, the corresponding 18 F-FDG-PET regional hypometabolism was correlated with clinical and neuropsychological features., Results: Classifying the patients with C9orf72-ALS based on the rate of disease progression from symptoms onset to the time of scan, we observed two different patterns of brain hypometabolism: an extensive motor and prefrontal hypometabolism in patients classified as fast progressors, and a more limited brain hypometabolism in patients grouped as slow progressors. Patients with SOD1-ALS showed a hypometabolic pattern involving the motor cortex and prefrontal association regions, with a minor involvement of the limbic regions. The patient with TBK1-ALS showed an extended hypometabolism, in limbic systems, along with typical motor involvement, while the hypometabolism in the patient with KIF5A-ALS involved almost exclusively the motor regions, supporting the predominantly motor impairment linked to this gene mutation. Additionally, we observed strong correlations between the hypometabolism in the motor, prefrontal association and limbic meta-ROI and the specific neuropsychological performances., Conclusions: To our knowledge, this is the first study investigating brain hypometabolism at the single-subject level in genetic ALS patients carrying different mutations. Our results show high heterogeneity in the hypometabolism maps and some commonalities in groups sharing the same mutation. Specifically, in patients with C9orf72-ALS the brain hypometabolism was larger in patients classified as fast progressors than slow progressors. In addition, in the whole group, the brain metabolism showed specific correlations with clinical and neuropsychological impairment, confirming the ability of 18 F-FDG-PET in revealing pattern of neuronal dysfunction, aiding the diagnostic workup in genetic ALS patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The novel coronavirus disease of 2019 (COVID-19) outbreak provoked a profound healthcare system reorganization. This study aimed to compare the reasons for requesting a non-deferrable neurological evaluation before the COVID-19 pandemic and during the lockdown., Methods: Retrospective observational study including non-deferrable neurological outpatients before the pandemic (pre-COVID-19 group, n = 223) and during the Italian second wave of the COVID-19 pandemic (LOCKDOWN group, n = 318)., Results: The number of patients sent for cerebrovascular disorders, headache, and vertigo significantly dropped between the pre-COVID-19 era and the lockdown period. While in the pre-COVID-19 group, the most frequent diagnosis was cerebrovascular disorder; neuropsychiatric disorders ranked first in the LOCKDOWN group. Moreover, the percentage of appropriate non-deferrable neurological evaluations significantly increased in the LOCKDOWN group compared with the pre-COVID-19 group., Discussion: Our study shows a significant increase of neuropsychiatric disorders in non-deferrable neurologic evaluations during the Italian second wave of the COVID-19. Overall, cases were more severe and required a more complex management during the lockdown compared with the pre-COVID era. These findings confirm that a careful approach to prevent the psychological consequences of the pandemic is needed, and long-term rearrangements of the healthcare system are desirable to guarantee appropriate management.

(1) Background: To limit the COVID-19 outbreak, the Italian government implemented social restrictions that may have had psychological and cognitive repercussions on people with dementia. We aimed to analyze cognitive decline during the pandemic year in people evaluated in a memory clinic in northern Italy, the epicenter of COVID-19 spread. (2) Methods: A single-center retrospective study was carried out, including individuals with annual follow-up evaluated in three different years (2020-GROUP, 2019-GROUP, 2018-GROUP). We performed an intergroup comparison of cognitive decline over a one-year follow-up, and an intragroup comparison in the 2020-GROUP to analyze the five-year cognitive decline trajectory, as measured by the MMSE. (3) Results: The 2020-GROUP showed a significant loss of MMSE points per year in the considered follow-up period compared with the 2019-GROUP and 2018-GROUP ( p = 0.021). Demographics, clinical features, and the other analyzed variables, including rate of diagnosis, therapy, and comorbidities, did not significantly differ between groups. The five-year cognitive decline trajectory confirmed a significant worsening of cognitive decline between 2019 and 2020 ( p < 0.001), while the decrease in MMSE scores was not statistically significant between previous time points. (4) Conclusions: COVID-19 pandemic measures have induced a significant worsening of cognitive decline in people with dementia, needing more careful assistance to minimize the adverse effects of social isolation in case of future lockdowns.

Background: The amnestic presentation of mild cognitive impairment (aMCI) represents the most common prodromal stage of Alzheimer's disease (AD) dementia. There is, however, some evidence of aMCI with typical amnestic syndrome but showing long-term clinical stability. The ability to predict stability or progression to dementia in the aMCI condition is important, particularly for the selection of candidates in clinical trials. We aimed to establish the role of in vivo biomarkers, as assessed by cerebrospinal fluid (CSF) measures and [ 18 F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging, in predicting prognosis in a large aMCI cohort., Methods: We conducted a retrospective study, including 142 aMCI subjects who had a long follow-up (4-19 years), baseline CSF data and [ 18 F]FDG-PET scans individually assessed by validated voxel-based procedures, classifying subjects into either limbic-predominant or AD-like hypometabolism patterns., Results: The two aMCI cohorts were clinically comparable at baseline. At follow-up, the aMCI group with a limbic-predominant [ 18 F]FDG-PET pattern showed clinical stability over a very long follow-up (8.20 ± 3.30 years), no decline in Mini-Mental State Examination score, and only 7% conversion to dementia. Conversely, the aMCI group with an AD-like [ 18 F]FDG-PET pattern had a high rate of dementia progression (86%) over a shorter follow-up (6.47 ± 2.07 years). Individual [ 18 F]FDG-PET hypometabolism patterns predicted stability or conversion with high accuracy (area under the curve = 0.89), sensitivity (0.90) and specificity (0.89). In the limbic-predominant aMCI cohort, CSF biomarkers showed large variability and no prognostic value., Conclusions: In a large series of clinically comparable subjects with aMCI at baseline, the specific [ 18 F]FDG-PET limbic-predominant hypometabolism pattern was associated with clinical stability, making progression to AD very unlikely. The identification of a biomarker-based benign course in aMCI subjects has important implications for prognosis and in planning clinical trials., (© 2020 European Academy of Neurology.)

Positron emission tomography (PET) allows for the in vivo assessment of early brain functional and molecular changes in neurodegenerative conditions, representing a unique tool in the diagnostic workup. The increased use of multivariate PET imaging analysis approaches has provided the chance to investigate regional molecular processes and long-distance brain circuit functional interactions in the last decade. PET metabolic and neurotransmission connectome can reveal brain region interactions. This review is an overview of concepts and methods for PET molecular and metabolic covariance assessment with evidence in neurodegenerative conditions, including Alzheimer's disease and Lewy bodies disease spectrum. We highlight the effects of environmental and biological factors on brain network organization. All of the above might contribute to innovative diagnostic tools and potential disease-modifying interventions.

Background: The COVID-19 pandemic caused drastic changes in healthcare and severe social restrictions. Healthcare workers (HCWs) are on the front line against the virus and have been highly exposed to pandemic-related stressors, but there are limited data on their psychological involvement for a large sample in Italy., Aims: To investigate the prevalence of anxiety, distress and burnout in HCWs of North-West Italy during the COVID-19 pandemic, and to detect potential psychosocial factors associated with their emotional response., Method: This cross-sectional, survey-based study enrolled 797 HCWs. Participants completed the Impact of Event Scale - Revised, the State-Trait Anxiety Inventory - Form Y and the Maslach Burnout Inventory; demographic, family and work characteristics were also collected. Global psychological outcome, differences among professions and independent factors associated with worst psychological outcome were assessed., Results: Almost a third of the sample had severe state anxiety and distress, high emotional exhaustion and depersonalisation, and low personal accomplishment. Distress was higher in women and nurses, whereas depersonalisation was higher in men. Family division, increased workload, job changes and frequent contact with COVID-19 were associated with worst psychological outcome. Trait anxiety was associated with significantly higher risk for developing state anxiety, distress and burnout., Conclusions: An elevated psychological burden related to the COVID-19 pandemic was observed in HCWs of North-West Italy. The identification of family and work characteristics and a psychological pre-existing condition as factors associated with worst psychological outcome may help provide a tailored, preventive, organisational and psychological approach in counteracting the psychological effects of future pandemics.

Background: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. [18F]FDG-PET reveals brain hypometabolism patterns reflecting neuronal/synaptic dysfunction, already in the prodromal MCI phase. Activated microglia is part of the pathogenetic processes leading to neurodegeneration., Objective: Using [11C]-(R)-PK11195 and [18F]FDG-PET, we aimed to in vivo investigate the presence of microglial activation, and the relationship with brain glucose metabolism, in single MCI subjects., Methods: Eight MCI subjects underwent both [18F]FDG-PET and [11C]-(R)-PK11195 PET. We used validated quantification methods to obtain brain hypometabolism maps and microglia activation peaks in single subjects. We investigated both the spatial overlap and the relationship between brain glucose hypometabolism and microglia activation, by means of Dice similarity coefficient and using Pearson's correlation at single subject level., Results: Each MCI showed a specific brain hypometabolism pattern indicative of different possible etiologies, as expected in MCI population (i.e., Alzheimer's disease-like, frontotemporal dementia-like, hippocampal-type, normal aging type). [11C]-(R)-PK11195 PET analysis revealed a spatial concordance with regional hypometabolism in all subjects with several clusters of significant microglia activation showing an inverse correlation with the regional metabolism. This was proportional to the strength of between-signals correlation coefficient (β  =  -0.804; p = 0.016)., Conclusion: Microglia activation is present in the prodromal MCI phase of different underlying etiologies, showing spatial concordance and inverse correlation with brain glucose metabolism at single-subject level. These findings suggest a possible contribution of activated microglia to neurodegeneration, showing important implications for local immune activity in the early neurodegenerative processes.

Objective: Neuroinflammation is considered a key driver for neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 20% of familial ALS, and related pathology might generate microglial activation triggering neurodegeneration. 11 C-PK11195 is the prototypical and most validated PET radiotracer, targeting the 18-kDa translocator protein which is overexpressed in activated microglia. In this study, we investigated microglia activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 mutated carriers, by using 11 C-PK11195 and PET imaging., Methods: We included 20 subjects: 4 ASYM-carriers, neurologically normal, 6 SYM-carriers with probable ALS, and 10 healthy controls. A receptor parametric mapping procedure estimated 11 C-PK11195 binding potentials and voxel-wise statistical comparisons were performed at group and single-subject levels., Results: Both the SYM- and ASYM-carriers showed significant microglia activation in cortical and subcortical structures, with variable patterns at individual level. Clusters of activation were present in occipital and temporal regions, cerebellum, thalamus, and medulla oblongata. Notably, SYM-carriers showed microglia activation also in supplementary and primary motor cortices and in the somatosensory regions., Interpretation: In vivo neuroinflammation occurred in all SOD1 mutated cases since the presymptomatic stages, as shown by a significant cortical and subcortical microglia activation. The involvement of sensorimotor cortex became evident at the symptomatic disease stage. Although our data indicate the role of in vivo PET imaging for assessing resident microglia in the investigation of SOD1-ALS pathophysiology, further studies are needed to clarify the temporal and spatial dynamics of microglia activation and its relationship with neurodegeneration., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Early-onset Alzheimer's disease (EOAD) is characterized by young age of onset (< 65 years), severe neurodegeneration, and rapid disease progression, thus differing significantly from typical late-onset Alzheimer's disease. Growing evidence suggests a primary role of neuroinflammation in AD pathogenesis. However, the role of microglia activation in EOAD remains a poorly explored field. Investigating microglial activation and its influence on the development of synaptic dysfunction and neuronal loss in EOAD may contribute to the understanding of its pathophysiology and to subject selection in clinical trials. In our study, we aimed to assess the amount of neuroinflammation and neurodegeneration and their relationship in EOAD patients, through positron emission tomography (PET) measures of microglia activation and brain metabolic changes., Methods: We prospectively enrolled 12 EOAD patients, classified according to standard criteria, who underwent standard neurological and neuropsychological evaluation, CSF analysis, brain MRI, and both [ 18 F]-FDG PET and [ 11 C]-(R)-PK11195 PET. Healthy controls databases were used for statistical comparison. [ 18 F]-FDG PET brain metabolism in single subjects and as a group was assessed by an optimized SPM voxel-wise single-subject method. [ 11 C]-PK11195 PET binding potentials were obtained using reference regions selected with an optimized clustering procedure followed by a parametric analysis. We performed a topographic interaction analysis and correlation analysis in AD-signature metabolic dysfunctional regions and regions of microglia activation. A network connectivity analysis was performed using the interaction regions of hypometabolism and [ 11 C]-PK11195 PET BP increases., Results: EOAD patients showed a significant and extended microglia activation, as [ 11 C]-PK11195 PET binding potential increases, and hypometabolism in typical AD-signature brain regions, i.e., temporo-parietal cortex, with additional variable frontal and occipital hypometabolism in the EOAD variants. There was a spatial concordance in the interaction areas and significant correlations between the two biological changes. The network analysis showed a disruption of frontal connectivity induced by the metabolic/microglia effects., Conclusion: The severe microglia activation characterizing EOAD and contributing to neurodegeneration may be a marker of rapid disease progression. The coupling between brain glucose hypometabolism and local immune response in AD-signature regions supports their biological interaction.

Background: Ultrasonography of the optic nerve sheath diameter (ONSD) is used for the non-invasive assessment of increased intracranial pressure (ICP). ONSD values are usually obtained by averaging the measurements of the two eyes, but asymmetric ONSD dilation is possible, leading to potentially inaccurate ICP estimation when using binocular averaging. In addition, few data are available about the asymmetry of the ONSD and the use of the maximum ONSD value between eyes for raised ICP detection. The aim of the study was to evaluate the interocular ONSD asymmetry in healthy subjects and patients with intracranial hypertension (IH) by ultrasonography and to investigate whether the maximum ONSD could be as useful as the binocular assessment., Methods: Forty healthy subjects and 40 patients with IH (20 with idiopathic intracranial hypertension and 20 with intracerebral hemorrhage) who underwent transorbital sonography were retrospectively enrolled. The prevalence and degree of ONSD asymmetry were compared among groups; ONSD median binocular and maximum values were compared., Results: Forty-two out of 80 subjects (52.5%) showed significant ONSD asymmetry, without significant differences in prevalence among groups (p = 0.28). The median asymmetry was higher in patients than in healthy subjects (0.45 mm vs 0.23 mm; p = 0.007), without significant differences between the two pathologies (p = 0.58). Both binocular and maximum ONSD measurements were significantly higher in patients with IH than in controls (p < 0.001)., Conclusions: Interocular ONSD asymmetry occurs both in healthy subjects and, more consistently, in patients with IH. Both binocular and maximum ONSD may be useful markers for increased ICP detection.

Increasing evidence suggests that pathogenic mechanisms underlying neurodegeneration are strongly linked with neuroinflammatory responses. Tyro3, Axl, and Mertk (TAM receptors) constitute a subgroup of the receptor tyrosine kinase family, cell surface receptors which transmit signals from the extracellular space to the cytoplasm and nucleus. TAM receptors and the corresponding ligands, Growth Arrest Specific 6 and Protein S, are expressed in different tissues, including the nervous system, playing complex roles in tissue repair, inflammation and cell survival, proliferation, and migration. In the nervous system, TAM receptor signalling modulates neurogenesis and neuronal migration, synaptic plasticity, microglial activation, phagocytosis, myelination, and peripheral nerve repair, resulting in potential interest in neuroinflammatory and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Multiple Sclerosis. In Alzheimer and Parkinson diseases, a role of TAM receptors in neuronal survival and pathological protein aggregate clearance has been suggested, while in Multiple Sclerosis TAM receptors are involved in myelination and demyelination processes. To better clarify roles and pathways involving TAM receptors may have important therapeutic implications, given the fine modulation of multiple molecular processes which could be reached. In this review, we summarise the roles of TAM receptors in the central nervous system, focusing on the regulation of immune responses and microglial activities and analysing in vitro and in vivo studies regarding TAM signalling involvement in neurodegeneration., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Giacomo Tondo et al.)

Even before the success of combined positron emission tomography and computed tomography (PET/CT), the neuroimaging community was conceiving the idea to integrate the positron emission tomography (PET), with very high molecular quantitative data but low spatial resolution, and magnetic resonance imaging (MRI), with high spatial resolution. Several technical limitations have delayed the use of a hybrid scanner in neuroimaging studies, including the full integration of the PET detector ring within the MRI system, the optimization of data acquisition, and the implementation of reliable methods for PET attenuation, motion correction, and joint image reconstruction. To be valid and useful in clinical and research settings, this instrument should be able to simultaneously acquire PET and MRI, and generate quantitative parametric PET images comparable to PET-CT. While post hoc co-registration of combined PET and MRI data acquired separately became the most reliable technique for the generation of "fused" PET-MRI images, only hybrid PET-MRI approach allows merging these measurements naturally and correlating them in a temporal manner. Furthermore, hybrid PET-MRI represents the most accurate tool to investigate in vivo the interplay between molecular and functional aspects of brain pathophysiology. Hybrid PET-MRI technology is still in the early stages in the movement disorders field, due to the limited availability of scanners with integrated optimized methodological models. This technology is ideally suited to investigate interactions between resting-state functional/arterial spin labeling MRI and [ 18 F]FDG PET glucose metabolism in the evaluation of the brain "hubs" particularly vulnerable to neurodegeneration, areas with a high degree of connectivity and associated with an efficient synaptic neurotransmission. In Parkinson's disease, hybrid PET-MRI is also the ideal instrument to deeper explore the relationship between resting-state functional MRI and dopamine release at [ 11 C]raclopride PET challenge, in the identification of early drug-naïve Parkinson's disease patients at higher risk of motor complications and in the evaluation of the efficacy of novel neuroprotective treatment able to restore at the same time the altered resting state and the release of dopamine. In this chapter, we discuss the key methodological aspects of hybrid PET-MRI; the evidence in movement disorders of the key resting-state functional and perfusion MRI; [ 18 F]FDG PET and [ 11 C]raclopride PET challenge studies; the potential advantages of using hybrid PET-MRI to investigate the pathophysiology of movement disorders and neurodegenerative diseases. Future directions of hybrid PET-MRI will be discussed alongside with up-to-date technological innovations on hybrid systems., (© 2019 Elsevier Inc. All rights reserved.)

Background and Aim: Chronic obstructive pulmonary disease (COPD) may be associated with worsening of cognitive performance. We studied patients with Alzheimer's disease (AD) with and without COPD, and we analyzed, in a retrospective way, clinical and neuropsychological variables to verify if COPD plays a pejorative role on cognitive or functional autonomy in patients with dementia., Methods: We enrolled 23 adult patients (AD-COPD) with probable AD and COPD and 23 with AD only (AD-only); they were matched for sex, age, educational level, and Mini Mental State Examination (MMSE) at the disease onset. Global cognitive status was estimated using MMSE at the first assessment and after 24 months. Memory, executive functions, praxia, and language were the other cognitive domains analyzed. The two groups were also compared for the presence of behavioral disorders (anxiety, depression)., Results: AD-COPD had worse results in executive functions screening than AD-only; no significant differences were found comparing other cognitive domains; moreover, there was no significant difference between the two groups considering the decrease in MMSE scores. AD-COPD also showed a higher presence of depression., Discussion: COPD is known to be associated with the development of cognitive deficits, in particular, regarding for executive functions and attention, memory and logical reasoning. In this context, MMSE has a low diagnostic accuracy to underline effective cognitive impairment in AD-COPD. Our study shows a higher frequency of frontal deficits and behavioral disturbances in patients with AD and COPD than patients with AD-only. COPD could complicate the management of AD patients, thus necessitating a closer and multidisciplinary monitoring.

Behavioral variant frontotemporal dementia, the most common form of frontotemporal dementia, is characterized by executive dysfunction and changes in personality and behavior, sometimes with associated psychiatric disorders. We report a man who suddenly developed a gambling disorder when he was 55 years old. A year later he developed personality changes of agitation, euphoria, and disinhibition, along with binge eating and dysthymia. He did not improve on paroxetine 40 mg/day. Two years after the onset of his symptoms, he came to our clinic for evaluation. Neuropsychological testing showed deficits in cognitive control, planning, and attention. Brain magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography scans showed predominant frontal and temporal alterations, worse in the right hemisphere than the left. Cerebrospinal fluid analysis was not compatible with Alzheimer disease. On the basis of current criteria, we gave him a diagnosis of probable behavioral variant frontotemporal dementia presenting with a psychiatric symptom. Our findings in this unusual patient confirm the importance of close clinical monitoring in people who have a psychiatric disorder with atypical features, because the condition may mask an underlying neurodegenerative disease.

Background: Focal epilepsies (FEs) arise from a lateralized network, while in generalized epilepsies (GEs) there is a bilateral involvement from the outset. Intuitively, the corpus callosum is the anatomical substrate for interhemispheric spread., Objective: We used transcranial magnetic stimulation (TMS) to explore whether there are any physiological differences in the corpus callosum of drug-treated patients with FE and those with genetic GE (GGE), compared to healthy subjects (HS)., Methods: TMS was used to measure the interhemispheric inhibition (IHI) from right-to-left primary motor cortex (M1) and viceversa in 16 patients with FE, 17 patients with GGE and 17 HS. A conditioning stimulus (CS) was given to one M1 10 and 50 ms before a test stimulus delivered to the contralateral M1. Motor evoked potentials (MEPs) were analysed both as a function of the side of stimulation and of the epileptic focus (left-right)., Results: In HS, IHI was reproducible with suppression of MEPs at ISIs of 10 and 50 ms. Similar effects occurred in GGE patients. FE patients behaved differently, since IHI was significantly reduced bilaterally. When FE patients were stratified according to the side of their epileptic focus, the long-ISI IHI (=50 ms) appeared to be defective only when the CS was applied over the "focal" hemisphere., Conclusions: FE patients had a defective inhibitory response of contralateral M1 to inputs travelling from the "focal" hemisphere that was residual to the drug action. Whilst IHI changes would not be crucial for the GGE pathophysiology, they may represent one key factor for the contralateral spread of focal discharges, and seizure generalization., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Abnormal cortical plasticity has been hypothesized to play a crucial role in the pathogenesis of juvenile myoclonic epilepsy (JME). To study the motor cortical plasticity we used paired associative stimulation (PAS). When a repetitive electrical stimulus to the median nerve is paired with a transcranial magnetic stimulus (TMS) pulse over the controlateral motor cortex with at an interstimulus interval (ISI) of 21.5-25ms, a long term potentiation (LTP)-like synaptic plasticity is induced in the corticospinal system. Aim of this study was to investigate the motor cortex LTP-like synaptic plasticity by means of PAS in patients with JME., Methods: Twelve adult patients with JME were compared with 13 healthy subjects of similar age and sex. PAS consisted of 180 electrical stimuli of the right median nerve paired with a single TMS over the hotspot of right abductor pollicis brevis (APB) at an ISI of 25ms (PAS25). We measured motor evoked potentials (MEPs) before and after each intervention for up to 30min., Results: In healthy subjects the PAS25 protocol was followed by a significant increase of the MEP amplitude (p<0.001). On the contrary, in patients with JME, the MEP amplitude did not change., Conclusion: Defective motor cortex plasticity is likely involved in the pathogenesis of JME., (Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Some previous studies in brain-damaged patients suggested that neural systems in the left temporal lobe might be crucial in the production and comprehension of nouns, while analogous systems in posterior frontal cortical areas might be involved in the production and comprehension of verbs. We assessed performance on neuropsychological tasks of production and comprehension of nouns and action-verbs in 10 patients with progressive supranuclear palsy (PSP) and in 10 age-matched healthy controls. PSP patients also underwent measurements of regional cerebral blood flow by means of single photon emission computed tomography (SPECT), using 99mTc-Ethyl Cysteinate Dimer. In all PSP patients, SPECT showed a significant hypoperfusion in the inferior frontal gyrus (IFG). PSP patients performed significantly worse than controls on all lexical-semantic tasks, except for the auditory lexical decision task on nouns. Within PSP patients, however, a significantly lower performance was observed on action-verbs as compared to nouns on various lexical-semantic tasks (oral and written confrontation naming, auditory and visual single-word comprehension). Analysis of individual performance revealed heterogeneous patterns of neuropsychological impairment in different PSP patients. Despite some difficulty in drawing clear-cut conclusions about the locus of functional damage, we hypothesise that in most of our PSP patients such selective impairment in the production and in the comprehension of action-verbs could be due to semantic deficits affecting the conceptual category of actions. These findings are consistent with the hypothesis that in PSP a dysfunction of neural systems in posterior frontal cortical areas (mainly involving the IFG) critical for processing the conceptual category of actions might result in a selective impairment of production and comprehension of action-verbs., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We show that the notion of generalized Lenard chains naturally allows formulation of the theory of multiseparable and superintegrable systems in the context of bi-Hamiltonian geometry. We prove that the existence of generalized Lenard chains generated by a Hamiltonian function defined on a four-dimensional ωN manifold guarantees the separation of variables. As an application, we construct such chains for the Hénon-Heiles systems and for the classical Smorodinsky-Winternitz systems. New bi-Hamiltonian structures for the Kepler potential are found.