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12 pages, 1677 KiB

Open AccessArticle

Correlation between Retinal Vascularization and Disease Aggressiveness in Amyotrophic Lateral Sclerosis

by Gilda Cennamo, Daniela Montorio, Francesco Pio Ausiello, Luigifilippo Magno, Rosa Iodice, Alberto Mazzucco, Valentina Virginia Iuzzolino, Gianmaria Senerchia, Vincenzo Brescia Morra, Maria Nolano, Ciro Costagliola and Raffaele Dubbioso

Biomedicines 2022, 10(10), 2390; https://doi.org/10.3390/biomedicines10102390 - 25 Sep 2022

Cited by 8 | Viewed by 1986

Abstract

Abnormalities in retinal vascularization and neural density have been found in many neurodegenerative diseases; however, conflicting results are described in Amyotrophic Lateral Sclerosis (ALS). The aim of the present study was, therefore, to systematically analyze retinal layers and vascularization by means of spectral-domain [...] Read more.

Abnormalities in retinal vascularization and neural density have been found in many neurodegenerative diseases; however, conflicting results are described in Amyotrophic Lateral Sclerosis (ALS). The aim of the present study was, therefore, to systematically analyze retinal layers and vascularization by means of spectral-domain (SD-OCT) and optical coherence tomography angiography (OCT-A) in ALS patients. We enrolled 48 ALS patients and 45 healthy controls. ALS patients were divided into three groups: slow progressors (n = 10), intermediate progressors (n = 24) and fast progressors (n = 14), according to the disease progression rate. For SD-OCT, we evaluated the Subfoveal choroidal thickness (SFCT), ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL). Regarding the OCT-A, we assessed the vessel density (VD) in superficial and deep capillary plexuses, radial peripapillary capillary plexus, choriocapillary and the foveal avascular zone (FAZ) area. SD-OCT exam did not show any significant differences in GCC and RNFL thickness between patients and controls and among the three ALS groups. The SFCT was statistically greater in patients compared with controls (357.95 ± 55.15 µm vs. 301.3 ± 55.80 µm, p < 0.001); interestingly, the SFCT was thicker in patients with slow and intermediate disease progression than in those with fast disease progression (394.45 ± 53.73 µm vs. 393.09 ± 42.17 µm vs. 267.71 ± 56.24 µm, p < 0.001). OCT-A did not reveal any significant results. Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-r) and disease duration did not correlate with any of the OCT parameters, except for SFCT with ALSFRS-r (r = 0.753, p = 0.024). This study demonstrated the possible association between choroidal thickness and disease activity in ALS. OCT could be a useful biomarker in the management of the disease. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Figure 1
Spectral domain optical coherence tomography (SD-OCT) images from a healthy subject’s right eye (male, 58 years) with normal thicknesses of ganglion cell complex (GCC) (A) and retinal nerve fiber layer (RNFL) (B). The OCT B-scan shows normal retinal and choroidal thickness (C). Patient’s right eye (female, 60 years) affected by amyotrophic lateral sclerosis (ALS) with slow disease progression. SD-OCT shows normal GCC and RNFL thickness (A1,B1). The OCT B-scan shows normal retinal thickness and a thicker choroid (C1). Patient’s right eye (female, 61 years) affected by ALS with intermediate disease progression. SD-OCT shows normal GCC and RNFL thickness (A2,B2). The OCT B-scan shows normal retinal thickness and an increased choroidal thickness (C2). The bottom row reveals a patient’s left eye (female, 57 years) affected by ALS with fast disease progression. SD-OCT shows normal GCC and RNFL thickness (A3,B3). The OCT B-scan shows normal retinal and a thinner choroid (C3). Full article ">Figure 2
OCT-A from a healthy subject’s right eye (male, 58 years) shows normal vasculature texture in macular region (retinal superficial, deep capillary plexuses and in coriocapillary) and in papillary region (A–C,E). The foveal avascular zone (FAZ) area shows a normal size (D). The second row shows the patient’s right eye (female, 60 years) affected by amyotrophic lateral sclerosis (ALS) with slow disease progression. OCT-A images reveal absence of abnormalities in retinal and choriocapillary vascular plexuses in macular and papillary regions (A1,B1,C1,E1). The FAZ shows a normal area (D1). The third row shows a patient’s left eye (female, 61 years) affected by ALS with intermediate disease progression. OCT-A reveals absence of abnormalities in retinal and choriocapillary vascular plexuses in macular and papillary regions (A2,B2,C2,E2). The FAZ shows a normal area (D2). The bottom row reveals the patient’s left eye (female, 57 years) affected by ALS with fast disease progression. OCT-A images show normal retinal and choriocapillary vascular plexuses in macular and papillary regions (A3,B3,C3,E3). The FAZ shows a normal area (D3). Full article ">

12 pages, 274 KiB

Open AccessArticle

Freezing of Gait in Parkinson’s Disease Patients Treated with Bilateral Subthalamic Nucleus Deep Brain Stimulation: A Long-Term Overview

by Giulia Di Rauso, Francesco Cavallieri, Isabella Campanini, Annalisa Gessani, Valentina Fioravanti, Alberto Feletti, Benedetta Damiano, Sara Scaltriti, Elisa Bardi, Maria Giulia Corni, Francesca Antonelli, Vittorio Rispoli, Francesca Cavalleri, Maria Angela Molinari, Sara Contardi, Elisa Menozzi, Annette Puzzolante, Jessica Rossi, Stefano Meletti, Giuseppe Biagini, Giacomo Pavesi, Valerie Fraix, Mirco Lusuardi, Alessandro Fraternali, Annibale Versari, Carla Budriesi, Elena Moro, Andrea Merlo and Franco Valzania Show full author list Hide full author list

Biomedicines 2022, 10(9), 2214; https://doi.org/10.3390/biomedicines10092214 - 7 Sep 2022

Cited by 7 | Viewed by 2894

Abstract

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced Parkinson’s Disease (PD). However, the effects of STN-DBS on freezing of gait (FOG) are still debated, particularly in the long-term follow-up (≥5-years). The main aim of the current study is [...] Read more.

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced Parkinson’s Disease (PD). However, the effects of STN-DBS on freezing of gait (FOG) are still debated, particularly in the long-term follow-up (≥5-years). The main aim of the current study is to evaluate the long-term effects of STN-DBS on FOG. Twenty STN-DBS treated PD patients were included. Each patient was assessed before surgery through a detailed neurological evaluation, including FOG score, and revaluated in the long-term (median follow-up: 5-years) in different stimulation and drug conditions. In the long term follow-up, FOG score significantly worsened in the off-stimulation/off-medication condition compared with the pre-operative off-medication assessment (z = −1.930; p = 0.05) but not in the on-stimulation/off-medication (z = −0.357; p = 0.721). There was also a significant improvement of FOG at long-term assessment by comparing on-stimulation/off-medication and off-stimulation/off-medication conditions (z = −2.944; p = 0.003). These results highlight the possible beneficial long-term effects of STN-DBS on FOG. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

15 pages, 1698 KiB

Open AccessArticle

“Mens Sana in Corpore Sano”: The Emerging Link of Motor Reserve with Motor and Cognitive Abilities and Compensatory Brain Networks in SCA2 Patients

by Libera Siciliano, Giusy Olivito, Nicole Urbini, Maria Caterina Silveri and Maria Leggio

Biomedicines 2022, 10(9), 2166; https://doi.org/10.3390/biomedicines10092166 - 2 Sep 2022

Cited by 7 | Viewed by 2272

Abstract

The ability to resiliently cope with neuropathological lesions is a key scientific concern. Accordingly, this study aims to investigate whether motor reserve (MR), likely to be boosted by exercise engagement in a lifetime, affects motor symptom severity, cognitive functioning, and functional brain networks [...] Read more.

The ability to resiliently cope with neuropathological lesions is a key scientific concern. Accordingly, this study aims to investigate whether motor reserve (MR), likely to be boosted by exercise engagement in a lifetime, affects motor symptom severity, cognitive functioning, and functional brain networks in spinocerebellar ataxia type 2 (SCA2)—a cerebellar neurodegenerative disease. The MR of 12 SCA2 patients was assessed using the Motor Reserve Index Questionnaire (MRIq), developed ad hoc for estimating lifespan MR. The International Cooperative Ataxia Rating Scale was used to assess clinical motor features, and neuropsychological tests were used to evaluate cognitive functioning. Patients underwent an MRI examination, and network-based statistics (NBS) analysis was carried out to detect patterns of functional connectivity (FC). Significant correlations were found between MRIq measures and the severity of motor symptoms, educational and intellectual levels, executive function, and processing speed. NBS analysis revealed a higher FC within subnetworks consisting of specific cerebellar and cerebral areas. FC patterns were positively correlated with MRIq measures, likely indicating the identification of an MR network. The identified network might reflect a biomarker likely to underlie MR, influenced by education and cognitive functioning, and impacting the severity of motor symptoms. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Data scatterplots of significant correlations between education and (a) MRIq_DA—domestic activities, (b) MRIq_WA—working activities, and (c) MRIq_Tot—total score. The green dots indicate the values for an individual data point; the fit lines representing the trend of the data are reported in red. Full article ">Figure 2
Data scatterplots of significant correlations between MRIq and cognitive domains: Correlations between MRIq_PE—physical exercise and (a) intellectual level, (b) long-term memory, and (c) processing speed; between MRIq_Tot—total score and (d) processing time; and between MRIq_LA—leisure activities and (e) executive function. The green dots indicate the values for an individual data point; the fit lines representing the trend of the data are reported in red. Full article ">Figure 3
Data scatterplots of significant correlations between MRIq and clinical motor symptoms: Correlations between MRIq_PE—physical exercise and (a) posture and gait disturbances, (b) kinetic functions, and (c) total ICARS scores. The green dots indicate the values for an individual data point; the fit lines representing the trend of the data are reported in red. Full article ">Figure 4
Internodal increased FC patterns: Significantly increased internodal connectivity in SCA2 patients as assessed by NBS analysis (FWE = 0.05) (bigger and smaller nodes). Labels represent bigger nodes that correspond to cerebellar and cortical regions showing significant correlations with MRIq (see <a href="#biomedicines-10-02166-t006" class="html-table">Table 6</a>). The brain network is visualised using the BrainNet Viewer (<a href="https://www.nitrc.org/projects/bnv/" target="_blank">https://www.nitrc.org/projects/bnv/</a>) [<a href="#B42-biomedicines-10-02166" class="html-bibr">42</a>] in axial (z), sagittal (x), and coronal (y) sections. MFC = medial frontal cortex; SMA = supplementary motor area; R = right; L = left. Full article ">Figure 5
Data scatterplots of significant correlations between MRIq and increased internodal FC between (a) the right MFC and the left SMA, (b) the right MFC and the right SMA, and (c) the vermis X and the left cerebellar anterior lobules (IV–V). The green dots indicate the values for an individual data point; the fit lines representing the trend of the data are reported in red. Full article ">

15 pages, 24293 KiB

Open AccessArticle

Metabolic Profile Variations along the Differentiation of Human-Induced Pluripotent Stem Cells to Dopaminergic Neurons

by Emma Veronica Carsana, Matteo Audano, Silvia Breviario, Silvia Pedretti, Massimo Aureli, Giulia Lunghi and Nico Mitro

Biomedicines 2022, 10(9), 2069; https://doi.org/10.3390/biomedicines10092069 - 24 Aug 2022

Cited by 3 | Viewed by 2754

Abstract

In recent years, the availability of induced pluripotent stem cell-based neuronal models has opened new perspectives on the study and therapy of neurological diseases such as Parkinson’s disease. In particular, P. Zhang set up a protocol to efficiently generate dopaminergic neurons from induced [...] Read more.

In recent years, the availability of induced pluripotent stem cell-based neuronal models has opened new perspectives on the study and therapy of neurological diseases such as Parkinson’s disease. In particular, P. Zhang set up a protocol to efficiently generate dopaminergic neurons from induced pluripotent stem cells. Although the differentiation process of these cells has been widely investigated, there is scant information related to the variation in metabolic features during the differentiation process of pluripotent stem cells to mature dopaminergic neurons. For this reason, we analysed the metabolic profile of induced pluripotent stem cells, neuronal precursors and mature neurons by liquid chromatography–tandem mass spectrometry. We found that induced pluripotent stem cells primarily rely on fatty acid beta-oxidation as a fuel source. Upon progression to neuronal progenitors, it was observed that cells began to shut down fatty acid β-oxidation and preferentially catabolised glucose, which is the principal source of energy in fully differentiated neurons. Interestingly, in neuronal precursors, we observed an increase in amino acids that are likely the result of increased uptake or synthesis, while in mature dopaminergic neurons, we also observed an augmented content of those amino acids needed for dopamine synthesis. In summary, our study highlights a metabolic rewiring occurring during the differentiation stages of dopaminergic neurons. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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12 pages, 3313 KiB

Open AccessArticle

Fluorescent In Situ Staining and Flow Cytometric Procedures as New Pre-Diagnostic Tests for Sialidosis, GM1 Gangliosidosis and Niemann–Pick Type C

by Claudia Capitini, Federica Feo, Anna Caciotti, Rodolfo Tonin, Matteo Lulli, Domenico Coviello, Renzo Guerrini, Martino Calamai and Amelia Morrone

Biomedicines 2022, 10(8), 1962; https://doi.org/10.3390/biomedicines10081962 - 12 Aug 2022

Cited by 4 | Viewed by 2295

Abstract

Background: Early diagnosis is essential in the field of lysosomal storage disorders for the proper management of patients and for starting therapies before irreversible damage occurs, particularly in neurodegenerative conditions. Currently, specific biomarkers for the diagnosis of lysosomal storage disorders are lacking in [...] Read more.

Background: Early diagnosis is essential in the field of lysosomal storage disorders for the proper management of patients and for starting therapies before irreversible damage occurs, particularly in neurodegenerative conditions. Currently, specific biomarkers for the diagnosis of lysosomal storage disorders are lacking in routine laboratory practice, except for enzymatic tests, which are available only in specialized metabolic centers. Recently, we established a method for measuring and verifying changes in GM1 ganglioside levels in peripheral blood lymphocytes in patients with GM1 gangliosidosis. However, fresh blood is not always available, and using frozen/thawed lymphocytes can lead to inaccurate results. Methods: We used frozen/thawed fibroblasts obtained from stored biopsies to explore the feasibility of fluorescent imaging and flow-cytometric methods to track changes in storage materials in fibroblasts from patients with three lysosomal neurodegenerative conditions: GM1 gangliosidosis, Sialidosis, and Niemann–Pick type C. We used specific markers for each pathology. Results and Conclusions: We demonstrated that with our methods, it is possible to clearly distinguish the levels of accumulated metabolites in fibroblasts from affected and unaffected patients for all the three pathologies considered. Our methods proved to be rapid, sensitive, unbiased, and potentially applicable to other LSDs. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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GM1 gangliosidosis. Thawed primary cultures of fibroblasts isolated from control and GM1 gangliosidosis patients were cultured, fixed, permeabilized, labeled with CTXb-FITC, and imaged with CLSM (A) or analyzed with flow cytometry (B,C). (A) The juvenile patient (Pt1) shows higher values of CTXb-FITC fluorescence intensity compared to WT, indicating an increase in GM1 content. Scale bar 30 µm. >20 cells were analyzed for each condition. Error bar S.D. (B) Schematic representation of the workflow to analyze the cells of affected and unaffected cells with flow cytometry. The FSC-A vs. SSC-A plot is gated (blue line) to exclude cellular debris, the corresponding CTXb-FITC fluorescence intensity distributions of affected (red line) and unaffected (black line) are analyzed, and median fluorescence values (MFI) are extrapolated. (C) MFI/MFIWTmean values are obtained by dividing the MFI of a distribution by the mean MFI obtained from the controls. MFI/MFIWTmean values increase proportionally to the severity of the pathology in juvenile (Pt1 and Pt2) and infantile patients (Pt3). >5000 cells were analyzed for each MFI. Student’s t-test ** p ≤ 0.01, *** p ≤ 0.001. Full article ">Figure 2
Sialidosis. Thawed primary cultures of fibroblasts isolated from control and Sialidosis patients (Pt4 and Pt5) were cultured, fixed, permeabilized, labeled with WGA-594, and imaged with CLSM (A) or analyzed with flow cytometry (B). (A) The Pt4 patient shows higher values of WGA-594 fluorescence intensity compared to WT control, indicating a rise in content of molecules containing sialic acid groups. Scale bar 30 µm. >20 cells were analyzed for each condition. Error bar S.D. (B) MFI/MFIWTmean values increased in the fibroblast populations of both patients (Pt4 and Pt5) analyzed with respect to control. >5000 cells were analyzed for each MFI. Student’s t-test ** p ≤ 0.01, *** p ≤ 0.001. Full article ">Figure 3
Type C Niemann–Pick disease. Thawed primary cultures of fibroblasts isolated from control and NPC patients (Pt6 and Pt7) were cultured, fixed, permeabilized, labeled with Filipin III (A,B) or CTXb-FITC (C,D), and imaged with wide field epifluorescence microscopy and CLSM, respectively (A,C), or analyzed with flow cytometry (B,D). Significantly higher values of Filipin III (A) and CTXb-FITC (C) fluorescence intensities were found analyzing Pt6 images compared to control, indicating a rise in cellular cholesterol and GM1 content, respectively. Scale bar 30 µm. >20 cells were analyzed for each condition. Error bar S.D. Flow cytometry MFI/MFIWTmean values related to cholesterol (B) and GM1 (D) levels were found to increase in the fibroblast populations of Pt6 and Pt7 with respect to control. >5000 cells were analyzed for each MFI. Student’s t-test * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001. (E) A significant linear correlation (R = 0.79, ** p ≤ 0.01) is found between the MFI/MFIWTmean values relative to cholesterol and GM1 content. Full article ">

20 pages, 4820 KiB

Open AccessArticle

Differential Neuropathology, Genetics, and Transcriptomics in Two Kindred Cases with Alzheimer’s Disease and Lewy Body Dementia

by Ilaria Palmieri, Tino Emanuele Poloni, Valentina Medici, Susanna Zucca, Annalisa Davin, Orietta Pansarasa, Mauro Ceroni, Livio Tronconi, Antonio Guaita, Stella Gagliardi and Cristina Cereda

Biomedicines 2022, 10(7), 1687; https://doi.org/10.3390/biomedicines10071687 - 13 Jul 2022

Cited by 2 | Viewed by 2699

Abstract

Alzheimer’s disease (AD) and Lewy body dementia (LBD) are two different forms of dementia, but their pathology may involve the same cortical areas with overlapping cognitive manifestations. Nonetheless, the clinical phenotype is different due to the topography of the lesions driven by the [...] Read more.

Alzheimer’s disease (AD) and Lewy body dementia (LBD) are two different forms of dementia, but their pathology may involve the same cortical areas with overlapping cognitive manifestations. Nonetheless, the clinical phenotype is different due to the topography of the lesions driven by the different underlying molecular processes that arise apart from genetics, causing diverse neurodegeneration. Here, we define the commonalities and differences in the pathological processes of dementia in two kindred cases, a mother and a son, who developed classical AD and an aggressive form of AD/LBD, respectively, through a neuropathological, genetic (next-generation sequencing), and transcriptomic (RNA-seq) comparison of four different brain areas. A genetic analysis did not reveal any pathogenic variants in the principal AD/LBD-causative genes. RNA sequencing highlighted high transcriptional dysregulation within the substantia nigra in the AD/LBD case, while the AD case showed lower transcriptional dysregulation, with the parietal lobe being the most involved brain area. The hippocampus (the most degenerated area) and basal ganglia (lacking specific lesions) expressed the lowest level of dysregulation. Our data suggest that there is a link between transcriptional dysregulation and the amount of tissue damage accumulated across time, assessed through neuropathology. Moreover, we highlight that the molecular bases of AD and LBD follow very different pathways, which underlie their neuropathological signatures. Indeed, the transcriptome profiling through RNA sequencing may be an important tool in flanking the neuropathological analysis for a deeper understanding of AD and LBD pathogenesis. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
Comparison of the neuropathological picture among mother, son, and the control case. (A,B) the BG of mother and son show widespread diffuse and dense Aβ plaques (asterisks) and physiological intracellular amyloid in some neurons (arrows) (4G8 antibody; magnification 10×); (C) absence of Aβ in the BG of the control case (4G8 antibody; magnification 10×). (D–F) the SN of mother, son, and control, respectively (α-SYN-KM51 antibody; magnification 20×); only the son presents severe LTS with many LBs ((E); arrowheads); LBs are also easily detectable by using Hematoxylin &Eosin staining only (image (E’); magnification 20×). (G–I) the PL (cortex) of mother, son, and control, respectively; image G shows mother’s picture, characterized by the presence of strong pTau deposits with NFT (arrows) and NP (asterisks), according to her Braak stage VI (AT8 antibody; magnification 4×); image H demonstrates son’s picture, characterized by LTS with many LBs (arrowhead), according to his Beach’s stage IV (α-SYN-KM51 antibody; magnification 10×); image I shows the parietal cortex of the control case without any pathology (AT8 and α-SYN-KM51 antibodies; magnification 10×). (J–M) the HiC of the three cases; image (J) demonstrates mother’s picture with NFT (arrows) and NP (asterisks) due to severe pTAU pathology (AT8 antibody; magnification 4×); image (K) shows son’s neuropathology in the HiC, characterized by both LBs (arrowhead) and LNs (circles) (α-SYN-KM51 antibody; magnification 40×); image (L) proves the contemporary presence of pTAU lesions in the HiC of the son with NFT (arrows) and NP (asterisks) (AT8 antibody; magnification 10×); image (M) proves the absence of pathology in the HiC of the control case (AT8 and α-SYN-KM51 antibodies; magnification 4×). The 1 cm calibration bar in the lower right corner of the figure applies to all images corresponding to 85 µm in (A–C,H,I); 47 µm in (D,E,E’,F); 194 µm in (G,J,M); 35 µm in (K); and 107 µm in (L). Full article ">Figure 2
PCA of the RNA-seq libraries of each brain area in the two principal component spaces. (A) PCA of all the RNA-seq libraries together; (B) PCA of the substantia nigra; (C) PCA of the parietal lobe; (D) PCA of the hippocampus; (E) PCA of the basal ganglia. BB105: mother (AD); BB181: son (LBD); and BB118: nondemented control. Full article ">Figure 3
KEGG pathways and GO chord analysis relative to the DEGs of the substantia nigra of the son (BB181). (A) top ten KEGG pathways and top three GO-enriched terms in terms of biological processes, cellular components, and molecular functions related to the ALL UP DEGs; (B) top ten KEGG pathways and top three GO-enriched terms in terms of biological processes, cellular components, and molecular functions related to the ALL DOWN DEGs. The genes of the GOchords related to the SN_All Up_DEGs_Son have been listed in <a href="#app1-biomedicines-10-01687" class="html-app">Supplementary Data</a>. Full article ">Figure 4
KEGG pathway related to the synaptic vesicle cycle. In green, the molecules associated with the downregulated DEGs, while in red the molecules associated with the upregulated DEGs found in the son [<a href="#B43-biomedicines-10-01687" class="html-bibr">43</a>]. Full article ">Figure 5
KEGG pathways and GO chord analysis relative to the DEGs of the parietal lobe of the mother (BB105). (A) top ten KEGG pathways and top three GO-enriched terms in terms of biological processes, cellular components, and molecular functions related to the ALL UP DEGs; (B) top ten KEGG pathways and top three GO-enriched terms in terms of biological processes, cellular components, and molecular functions related to the ALL DOWN DEGs. Full article ">Figure 6
KEGG pathways and biological processes GO chords. (A) Top ten KEGG pathways and top three GO-enriched terms in terms of biological processes related to the ALL DOWN DEGs; (B) Top ten KEGG pathways related to the ALL UP DEGs. Full article ">

12 pages, 708 KiB

Open AccessArticle

CT-Detected MTA Score Related to Disability and Behavior in Older People with Cognitive Impairment

by Michele Lauriola, Grazia D’Onofrio, Annamaria la Torre, Filomena Ciccone, Carmela Germano, Leandro Cascavilla and Antonio Greco

Biomedicines 2022, 10(6), 1381; https://doi.org/10.3390/biomedicines10061381 - 10 Jun 2022

Cited by 2 | Viewed by 2689

Abstract

Our study aims to investigate the relationship between medial temporal lobe atrophy (MTA) score, assessed by computed tomography (CT) scans, and functional impairment, cognitive deficit, and psycho-behavioral disorder severity. Overall, 239 (M = 92, F = 147; mean age of 79.3 ± 6.8 [...] Read more.

Our study aims to investigate the relationship between medial temporal lobe atrophy (MTA) score, assessed by computed tomography (CT) scans, and functional impairment, cognitive deficit, and psycho-behavioral disorder severity. Overall, 239 (M = 92, F = 147; mean age of 79.3 ± 6.8 years) patients were evaluated with cognitive, neuropsychiatric, affective, and functional assessment scales. MTA was evaluated from 0 (no atrophy) to 4 (severe atrophy). The homocysteine serum was set to two levels: between 0 and 10 µmol/L, and >10 µmol/L. The cholesterol and glycemia blood concentrations were measured. Hypertension and atrial fibrillation presence/absence were collected. A total of 14 patients were MTA 0, 44 patients were MTA 1, 63 patients were MTA 2, 79 patients were MTA 3, and 39 patients were MTA 4. Cognitive (p < 0.0001) and functional (p < 0.0001) parameters decreased according to the MTA severity. According to the diagnosis distribution, AD patient percentages increased by MTA severity (p < 0.0001). In addition, the homocysteine levels increased according to MTA severity (p < 0.0001). Depression (p < 0.0001) and anxiety (p = 0.001) increased according to MTA severity. This study encourages and supports the potential role of MTA score and CT scan in the field of neurodegenerative disorder research and diagnosis. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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15 pages, 5079 KiB

Open AccessArticle

Intranasal Administration of a TRAIL Neutralizing Monoclonal Antibody Adsorbed in PLGA Nanoparticles and NLC Nanosystems: An In Vivo Study on a Mouse Model of Alzheimer’s Disease

by Teresa Musumeci, Giulia Di Benedetto, Claudia Carbone, Angela Bonaccorso, Giovanni Amato, Maria Josè Lo Faro, Chiara Burgaletto, Giovanni Puglisi, Renato Bernardini and Giuseppina Cantarella

Biomedicines 2022, 10(5), 985; https://doi.org/10.3390/biomedicines10050985 - 23 Apr 2022

Cited by 21 | Viewed by 3574 | Correction

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder that progressively compromises cognitive functions. Tumor necrosis factor (TNF)-Related Apoptosis Inducing Ligand (TRAIL), a proinflammatory cytokine belonging to the TNF superfamily, appears to be a key player in the inflammatory/immune orchestra of the AD brain. Despite [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder that progressively compromises cognitive functions. Tumor necrosis factor (TNF)-Related Apoptosis Inducing Ligand (TRAIL), a proinflammatory cytokine belonging to the TNF superfamily, appears to be a key player in the inflammatory/immune orchestra of the AD brain. Despite the ability of an anti-TRAIL monoclonal antibody to reach the brain producing beneficial effects in AD mice, we attempted to develop such a TRAIL-neutralizing monoclonal antibody adsorbed on lipid and polymeric nanocarriers, for intranasal administration, in a valid approach to overcome issues related to both high dose and drug transport across the blood–brain barrier. The two types of nanomedicines produced showed physico-chemical characteristics appropriate for intranasal administration. As confirmed by enzyme-linked immunosorbent assay (ELISA), both nanomedicines were able to form a complex with the antibody with an encapsulation efficiency of ≈99%. After testing in vitro the immunoneutralizing properties of the nanomedicines, the latter were intranasally administered in AD mice. The antibody–nanocarrier complexes were detectable in the brain in substantial amounts at concentrations significantly higher compared to the free form of the anti-TRAIL antibody. These data support the use of nanomedicine as an optimal method for the delivery of the TRAIL neutralizing antibody to the brain through the nose-to-brain route, aiming to improve the biological attributes of anti-TRAIL-based therapy for AD treatment. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Scanning electron microscopy (SEM) micrographies of (a) NANO-B (Scale bar = 400 nm); (b) NANO-B complex (Scale bar = 400 nm); (c) NANO-A (Scale bar = 400 nm); (d) NANO-A complex (Scale bar = 400 nm). Full article ">Figure 2
Cell viability percentage after 72 h of treatment with TRAIL (100 ng/mL), anti-TRAIL (1 μg/mL) or the combination of the compounds. Data are expressed as mean ± SD. One-way ANOVA followed by the Fisher’s LSD test were used for statistical analysis. * p < 0.05. Full article ">Figure 3
RAW 264.7 cell viability (%) after 72 h of treatment with empty nanoparticles (NANO-A and NANO-B) (A). In (B) is depicted the cell viability percentage after treatment with TRAIL (100 ng/mL) alone or in combination with either nanoparticles complexed with the anti-TRAIL antibody (NANO-A or NANO-B complexes). Data are expressed as mean ± SD. One-way ANOVA followed by the Fisher’s LSD test were used for statistical analysis. * p < 0.05 or ** p < 0.01. Full article ">Figure 4
Experimental design for the nanoparticles administration. Twelve-month-old wild-type (WT) and 3xTg-AD mice were intranasally administered with both empty and anti-TRAIL loaded nanoparticles (PLGA or NANO-A and NLC or NANO-B NPs). After 24 h, brains were collected for immunofluorescence analysis. Created with <a href="http://www.BioRender.com" target="_blank">www.BioRender.com</a> (accessed on 10 February 2022). Full article ">Figure 5
Comparison of polymeric or lipidic nanoparticles complexed with anti-TRAIL in the hippocampus of 3xTg-AD mice after intranasal administration. Representative immunofluorescence microscopy images showing the localization of the anti-TRAIL monoclonal antibody in the hippocampal sections from WT (A) or 3×Tg-AD (B) mice intranasally administered for 24 h with the anti-TRAIL monoclonal antibody, empty, or anti-TRAIL-loaded NANO-A, NANO-B nanoparticles. The fluorescence signal was detected by using a fluorescent secondary anti-rat IgG. The insets represent the respective areas magnified. (C) The densitometric count of fluorescence was performed with the aid of ImageJ software (available online: <a href="https://imagej.nih.gov/ij/" target="_blank">https://imagej.nih.gov/ij/</a> (accessed on 12 January 2022)) and represented as integrated density (% of control). Data are expressed as the mean ± SD. One-way ANOVA followed by Fisher’s LSD test was used for statistical analysis. * p < 0.05. (a–o scale bar = 50 µm; c’, f’, i’, l’, o’ scale bar = 10 µm). Full article ">

16 pages, 2623 KiB

Open AccessArticle

Multimodal Characterization of Seizures in Zebrafish Larvae

by Lapo Turrini, Michele Sorelli, Giuseppe de Vito, Caterina Credi, Natascia Tiso, Francesco Vanzi and Francesco Saverio Pavone

Biomedicines 2022, 10(5), 951; https://doi.org/10.3390/biomedicines10050951 - 20 Apr 2022

Cited by 15 | Viewed by 3838

Abstract

Epilepsy accounts for a significant proportion of the world’s disease burden. Indeed, many research efforts are produced both to investigate the basic mechanism ruling its genesis and to find more effective therapies. In this framework, the use of zebrafish larvae, owing to their [...] Read more.

Epilepsy accounts for a significant proportion of the world’s disease burden. Indeed, many research efforts are produced both to investigate the basic mechanism ruling its genesis and to find more effective therapies. In this framework, the use of zebrafish larvae, owing to their peculiar features, offers a great opportunity. Here, we employ transgenic zebrafish larvae expressing GCaMP6s in all neurons to characterize functional alterations occurring during seizures induced by pentylenetetrazole. Using a custom two-photon light-sheet microscope, we perform fast volumetric functional imaging of the entire larval brain, investigating how different brain regions contribute to seizure onset and propagation. Moreover, employing a custom behavioral tracking system, we outline the progressive alteration of larval swim kinematics, resulting from different grades of seizures. Collectively, our results show that the epileptic larval brain undergoes transitions between diverse neuronal activity regimes. Moreover, we observe that different brain regions are progressively recruited into the generation of seizures of diverse severity. We demonstrate that midbrain regions exhibit highest susceptibility to the convulsant effects and that, during periods preceding abrupt hypersynchronous paroxysmal activity, they show a consistent increase in functional connectivity. These aspects, coupled with the hub-like role that these regions exert, represent important cues in their identification as epileptogenic hubs. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Figure 1
Zebrafish brain regions present different susceptibility to convulsant effects. (a) Dorsal (upper) and lateral (lower) schemes representing in different colors the ten brain districts into which volumetric calcium imaging data were segmented for further analysis. Dotted lines show the outer larval boundaries. A: anterior; P: posterior; R: right; L: left; D: dorsal; V: ventral. (b) Scheme representing the brain functional imaging protocol adopted. After PTZ treatment, larvae were imaged for 5 min every 10, along 60 min. (c) Map showing in color-code the neuronal activity (ΔF/F0) of one larva over time of each of the ten brain regions (colored as in panel (a)) along 60 min of seizure mapping. Warmer colors indicate higher activity. Below the map, the different brain activity regimes, discussed in <a href="#biomedicines-10-00951-f002" class="html-fig">Figure 2</a>, are reported. (d) Plot showing for each of the ten brain regions (abbreviations and colors as in panel (c)) the frequency of activity peaks at different PTZ concentrations (1.0, 2.5, 7.5 and 15 mM, see legend for colors) over 60 min of activity monitoring. Values represent mean ± s.e.m. of n = 3 larvae per concentration. * indicates p-value < 0.05 for intra-group comparison with respect to control (−5 min) values, one-way repeated measures ANOVA and post hoc Tukey’s test (see <a href="#app1-biomedicines-10-00951" class="html-app">Table S1</a> for p-values). Diamond symbol indicates p-value < 0.05 for inter-group comparison at the same time point, two-way repeated measures ANOVA and post hoc Tukey’s test (<a href="#app1-biomedicines-10-00951" class="html-app">Table S2</a>). Color couples in each symbol denote compared groups. Full article ">Figure 2
Zebrafish brain undergoes transition between different activity regimes during seizures. (a) ΔF/F0 traces of the ten larval brain regions (colored as in <a href="#biomedicines-10-00951-f001" class="html-fig">Figure 1</a>a) during four diverse activity regimes observed at maximal PTZ concentration (15 mM). CTRL (pre-exposure), PRE (preictal), ICTAL and POST (postictal). (b) Average frequency of activity peaks in the different regimes presented in panel (a). * indicates p-value < 0.05 for inter-regime comparison, one-way repeated measures ANOVA and post hoc Tukey’s test (for p-values see <a href="#app1-biomedicines-10-00951" class="html-app">Table S3</a>). Values represent mean ± s.e.m of n = 3 larvae per concentration. (c) Scatter plot showing peak duration as a function of peak prominence for each of the four regimes. (d) Normalized distributions of calcium transients’ kinetic features (peak duration, rise time, decay time and prominence) in each of the four activity regimes. For each parameter, all four distributions appear significantly different (two-samples K-S test with Bonferroni correction, α = 0.00833), except for peak prominence of CTRL vs. PRE and POST. For p-values, see <a href="#app1-biomedicines-10-00951" class="html-app">Table S4</a>. (e) Peak prominence during ictal regime for each of the ten brain regions. * indicates p-value < 0.00111 for inter-region comparison with telencephalon, two-samples K-S test with Bonferroni correction, α = 0.00111 (for p-values see <a href="#app1-biomedicines-10-00951" class="html-app">Table S5</a>). Box: IQR; error bar: 1.5 IQR; black line: median; white square: mean; black diamond: outlier. (f) Correlation matrices reporting average pairwise Pearson’s correlation coefficients of neuronal activity during the four regimes across the ten brain regions. Full article ">Figure 3
Zebrafish larvae undergo alteration of their swimming kinematic during seizures. (a) Scheme representing the behavioral tracking protocol adopted. The larvae were tracked along 5 min before the exposure to PTZ and 30–60 min after. (b) Swimming trajectories over 5 min of behavioral recording of one larva for each of the following conditions: pre-exposure (CTRL) and 60 min after the exposure to the different PTZ concentrations. (c,d) Average total distance traveled (c) and percentage of time spent in movement (d) in 5 min recording in the 3 different tracking windows (CTRL, 30 and 60 min), in larvae exposed to one of the four PTZ concentrations tested (see legend for colors). (e) Representative swimming bout shapes observed in each of the conditions reported, presented as larval displacement over time. Traces are color-mapped according to swimming velocity (warmer colors higher speed). (f–j) Average kinematic features of swimming bouts -maximum speed (f), maximum acceleration (g), duration (h), displacement (i) and frequency (j)—during 5-min recording epochs before PTZ exposure and 30–60 min after. * indicates p-value < 0.05 for intra-group comparison with respect to control (CTRL) values, one-way repeated measures ANOVA and post hoc Tukey’s test (for p-values see <a href="#app1-biomedicines-10-00951" class="html-app">Table S6</a>). Diamond symbol indicates p-value < 0.05 for inter-group comparison at 60 min exposure, two-way repeated measures ANOVA and post hoc Tukey’s test (for p-values see <a href="#app1-biomedicines-10-00951" class="html-app">Table S7</a>). Color couples in each symbol indicate groups compared. Values represent mean ± s.e.m. of n = 4 larvae per concentration. Full article ">

13 pages, 555 KiB

Open AccessArticle

Epidemiological, Clinical and Genetic Features of ALS in the Last Decade: A Prospective Population-Based Study in the Emilia Romagna Region of Italy

by Giulia Gianferrari, Ilaria Martinelli, Elisabetta Zucchi, Cecilia Simonini, Nicola Fini, Marco Vinceti, Salvatore Ferro, Annalisa Gessani, Elena Canali, Franco Valzania, Elisabetta Sette, Maura Pugliatti, Valeria Tugnoli, Lucia Zinno, Salvatore Stano, Mario Santangelo, Silvia De Pasqua, Emilio Terlizzi, Donata Guidetti, Doriana Medici, Fabrizio Salvi, Rocco Liguori, Veria Vacchiano, Mario Casmiro, Pietro Querzani, Marco Currò Dossi, Alberto Patuelli, Simonetta Morresi, Marco Longoni, Patrizia De Massis, Rita Rinaldi, Annamaria Borghi, ERRALS GROUP, Amedeo Amedei and Jessica Mandrioli Show full author list Hide full author list

Biomedicines 2022, 10(4), 819; https://doi.org/10.3390/biomedicines10040819 - 31 Mar 2022

Cited by 16 | Viewed by 4128

Abstract

Increased incidence rates of amyotrophic lateral sclerosis (ALS) have been recently reported across various Western countries, although geographic and temporal variations in terms of incidence, clinical features and genetics are not fully elucidated. This study aimed to describe demographic, clinical feature and genotype–phenotype [...] Read more.

Increased incidence rates of amyotrophic lateral sclerosis (ALS) have been recently reported across various Western countries, although geographic and temporal variations in terms of incidence, clinical features and genetics are not fully elucidated. This study aimed to describe demographic, clinical feature and genotype–phenotype correlations of ALS cases over the last decade in the Emilia Romagna Region (ERR). From 2009 to 2019, our prospective population-based registry of ALS in the ERR of Northern Italy recorded 1613 patients receiving a diagnosis of ALS. The age- and sex-adjusted incidence rate was 3.13/100,000 population (M/F ratio: 1.21). The mean age at onset was 67.01 years; women, bulbar and respiratory phenotypes were associated with an older age, while C9orf72-mutated patients were generally younger. After peaking at 70–75 years, incidence rates, among women only, showed a bimodal distribution with a second slight increase after reaching 90 years of age. Familial cases comprised 12%, of which one quarter could be attributed to an ALS-related mutation. More than 70% of C9orf72-expanded patients had a family history of ALS/fronto-temporal dementia (FTD); 22.58% of patients with FTD at diagnosis had C9orf72 expansion (OR 6.34, p = 0.004). In addition to a high ALS incidence suggesting exhaustiveness of case ascertainment, this study highlights interesting phenotype–genotype correlations in the ALS population of ERR. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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14 pages, 1238 KiB

Open AccessArticle

The Potential Role of Peripheral Oxidative Stress on the Neurovascular Unit in Amyotrophic Lateral Sclerosis Pathogenesis: A Preliminary Report from Human and In Vitro Evaluations

by Elena Grossini, Divya Garhwal, Sakthipriyan Venkatesan, Daniela Ferrante, Angelica Mele, Massimo Saraceno, Ada Scognamiglio, Jessica Mandrioli, Amedeo Amedei, Fabiola De Marchi and Letizia Mazzini

Biomedicines 2022, 10(3), 691; https://doi.org/10.3390/biomedicines10030691 - 17 Mar 2022

Cited by 12 | Viewed by 2213

Abstract

Oxidative stress, the alteration of mitochondrial function, and changes in the neurovascular unit (NVU) could play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. Our aim was to analyze the plasma redox system and nitric oxide (NO) in 25 ALS new-diagnosed patients and [...] Read more.

Oxidative stress, the alteration of mitochondrial function, and changes in the neurovascular unit (NVU) could play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. Our aim was to analyze the plasma redox system and nitric oxide (NO) in 25 ALS new-diagnosed patients and five healthy controls and the effects of plasma on the peroxidation/mitochondrial function in human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes. In plasma, thiobarbituric acid reactive substances (TBARS), glutathione (GSH), and nitric oxide (NO) were analyzed by using specific assays. In HUVEC/astrocytes, the effects of plasma on the release of mitochondrial reactive oxygen species (mitoROS) and NO, viability, and mitochondrial membrane potential were investigated. In the plasma of ALS patients, an increase in TBARS and a reduction in GSH and NO were found. In HUVEC/astrocytes treated with a plasma of ALS patients, mitoROS increased, whereas cell viability and mitochondrial membrane potential decreased. Our results show that oxidative stress and NVU play a central role in ALS and suggest that unknown plasma factors could be involved in the disease pathogenesis. Quantifiable changes in ALS plasma related to redox state alterations can possibly be used for early diagnosis. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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13 pages, 13611 KiB

Open AccessArticle

Predicting Outcome of Traumatic Brain Injury: Is Machine Learning the Best Way?

by Roberta Bruschetta, Gennaro Tartarisco, Lucia Francesca Lucca, Elio Leto, Maria Ursino, Paolo Tonin, Giovanni Pioggia and Antonio Cerasa

Biomedicines 2022, 10(3), 686; https://doi.org/10.3390/biomedicines10030686 - 16 Mar 2022

Cited by 20 | Viewed by 4009

Abstract

One of the main challenges in traumatic brain injury (TBI) patients is to achieve an early and definite prognosis. Despite the recent development of algorithms based on artificial intelligence for the identification of these prognostic factors relevant for clinical practice, the literature lacks [...] Read more.

One of the main challenges in traumatic brain injury (TBI) patients is to achieve an early and definite prognosis. Despite the recent development of algorithms based on artificial intelligence for the identification of these prognostic factors relevant for clinical practice, the literature lacks a rigorous comparison among classical regression and machine learning (ML) models. This study aims at providing this comparison on a sample of TBI patients evaluated at baseline (T0), after 3 months from the event (T1), and at discharge (T2). A Classical Linear Regression Model (LM) was compared with independent performances of Support Vector Machine (SVM), k-Nearest Neighbors (k-NN), Naïve Bayes (NB) and Decision Tree (DT) algorithms, together with an ensemble ML approach. The accuracy was similar among LM and ML algorithms on the analyzed sample when two classes of outcome (Positive vs. Negative) approach was used, whereas the NB algorithm showed the worst performance. This study highlights the utility of comparing traditional regression modeling to ML, particularly when using a small number of reliable predictor variables after TBI. The dataset of clinical data used to train ML algorithms will be publicly available to other researchers for future comparisons. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Most significant features selected using 2 classes of outcome, respectively, using MRMR and Chi-Square selection methods. Full article ">Figure 2
Most significant features selected using 4 classes of outcome, respectively, using MRMR and Chi-Square selection methods. Full article ">Figure 3
Correlation matrix with paired correlations between each pair of clinical predictors. On the diagonal: distribution of each variable, on the bottom of the diagonal: bivariate scatterplots with a fitted line, on the top of the diagonal: correlation value with significance level. Symbols “***”, “**”, “*”, “.”, indicates respectively p-values <0.001, <0.01, <0.05, <0.1. Full article ">Figure 4
Comparison of accuracies between LM and ML models (2 classes of outcome). Legend: Linear Regression Model (LM), Support Vector Machine (SVM), k-Nearest Neighbors (k-NN), Naïve Bayes (NB), Decision Tree (DT) and Ensemble of Machine Learning models (Ensemble ML). Symbols ***, p-values <0.001. Full article ">Figure 5
Comparison of accuracies between LM and ML models (4 classes of outcome). Legend: Linear Regression Model (LM), Support Vector Machine (SVM), k-Nearest Neighbors (k-NN), Naïve Bayes (NB), Decision Tree (DT) and Ensemble of Machine Learning models (Ensemble ML). Full article ">

13 pages, 883 KiB

Open AccessArticle

Neutrophils-to-Lymphocyte Ratio Is Associated with Progression and Overall Survival in Amyotrophic Lateral Sclerosis

by Maurizio A. Leone, Jessica Mandrioli, Sergio Russo, Aliona Cucovici, Giulia Gianferrari, Vitalie Lisnic, Dafin Fior Muresanu, Francesco Giuliani, Massimiliano Copetti, The Pooled Resource Open-Access ALS Clinical Trials Consortium and Andrea Fontana

Biomedicines 2022, 10(2), 354; https://doi.org/10.3390/biomedicines10020354 - 1 Feb 2022

Cited by 18 | Viewed by 3200

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease, with a 3–5-year survival from diagnosis. Possible prognostic serum biomarkers include albumin, C-reactive protein, ferritin, creatinine, uric acid, hemoglobin, potassium, sodium, calcium, glucose, and the neutrophil-to-lymphocyte ratio (NLR), a marker [...] Read more.

Background: Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease, with a 3–5-year survival from diagnosis. Possible prognostic serum biomarkers include albumin, C-reactive protein, ferritin, creatinine, uric acid, hemoglobin, potassium, sodium, calcium, glucose, and the neutrophil-to-lymphocyte ratio (NLR), a marker of subclinical inflammation. Objective: To ascertain the influence of NLR on ALS progression rate and survival. Methods: Cross-sectional multicenter study including 146 consecutive incident and prevalent patients (88 males), aged >18 years, diagnosed according to the El Escorial criteria. The exclusion criteria were: (1) patients with tracheostomy or receiving mechanical ventilation; (2) patients with percutaneous endoscopic gastrostomy; and (3) patients who did not sign the informed consent. The rate of disease progression (ΔFS score) represents the monthly decline of the ALSFRS-R score, and was computed as (48 − total ALSFRS-R at recruitment)/symptom duration in months. Patients were followed up to tracheotomy, death, or the end of the follow-up, whichever occurred first. To validate our findings, we used data retrieved from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database. Results: The median disease duration was 15 (range = 2–30) months. The mean ALSFRS-R score at recruitment was 35.8 ± 8.0 (range: 10–48), and the median ΔFS was 0.66 (range: 0–5.33). Age at onset, at diagnosis, and at recruitment were significantly lower in the lowest NLR tertile. NLR values positively correlated with ΔFS values (r = 0.28): the regression slope of NLR (log-values) was 0.60 (p < 0.001) before and 0.49 (p = 0.006) after adjustment for age at recruitment. The ΔFS score progressively increased from the lowest to the highest NLR tertile: 0.35 (IQR: 0.18–0.93), 0.62 (IQR: 0.25–1.09), and 0.86 (IQR: 0.53–1.92). Patients were followed for a median of 2 years. The mortality rate passed from 15.9 events per 100 person-years in patients belonging to the lowest NLR tertile to 52.8 in those in the highest tertile. The optimal cut-off value which best classified patients with the lowest and the highest mortality rate was set at the NLR value of 2.315. Indeed, the mortality rate of patients with an NLR value above such cut-off was twice the mortality rate of patients with a value below the cut-off (age adjusted hazard ratio (HR): 2.16, 95% confidence interval (CI): 1.32–3.53). In the PRO-ACT validation sample, patients with an NLR value above the cut-off consistently had a higher mortality rate than those with a value below the cut-off (age adjusted HR: 1.17, 95%CI: 1.01–1.35). Conclusions: NLR could be a candidate easy, fast, and low-cost marker of disease progression and survival in ALS. It may be associated with low-grade inflammation either as a direct mirror of the pathological process of disease progression, or as a consequence of neuronal death (reverse causation). However, prospective studies are needed to understand whether NLR changes during the course of the disease, before using it to monitor disease progression in ALS. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Patients’ disposition flow diagram. Full article ">Figure 2
Relationship between neutrophil-to-lymphocyte ratio (NLR) values evaluated at recruitment and progression rate (ΔFS) and overall survival of ALS patients. (A) Log-transformed NLR and ΔFS values were shown by a scatterplot with fitted regression line, along with estimated Pearson correlation coefficient (R) and p-value; (B) variable dependence plot of patients’ survival at 4 years on NLR values estimated by the random survival forest algorithm with 10,000 trees. Individual cases are marked with blue (alive or censored) and red circles (dead). Loess smooth curve with shaded 95% confidence band indicates decreasing survival with increasing NLR values; (C) conditional inference tree (CTree) on NLR to predict the overall survival of ALS patients; (D,E) Kaplan–Meier (KM) survival curves according to NLR tertiles (D) or CTree groups (E). Censored observations are evidenced on the KM curves as tick marks (“+”). CTree identifies patient subgroups at different NLR mortality rate. The tree-growing algorithm recursively splits the data into subgroups, choosing the best binary split for NLR, to identify the most homogeneous sets within each node and the most heterogeneous ones between the nodes (i.e., NLR at 2.315 represents the optimal cut-off). Condition sending patients to left or right sibling is on relative branch. Grey squares (i.e., nodes 2 and 3) represent the final CTree classes. Numbers inside CTree classes represent the median survival time (in years, top) and the number of subjects (bottom), respectively. p-value from test of the global null hypothesis of independence between NLR groups and the response (i.e., patients’ overall survival) is reported in the root note (p = 0.001). Full article ">

10 pages, 870 KiB

Open AccessArticle

Amyloid Precursor Protein A713T Mutation in Calabrian Patients with Alzheimer’s Disease: A Population Genomics Approach to Estimate Inheritance from a Common Ancestor

by Paolo Abondio, Stefania Sarno, Cristina Giuliani, Valentina Laganà, Raffaele Maletta, Livia Bernardi, Francesco Bruno, Rosanna Colao, Gianfranco Puccio, Francesca Frangipane, Barbara Borroni, Christine Van Broeckhoven, Donata Luiselli and Amalia Bruni

Biomedicines 2022, 10(1), 20; https://doi.org/10.3390/biomedicines10010020 - 23 Dec 2021

Cited by 15 | Viewed by 3160

Abstract

Mutation A713T in the amyloid precursor protein (APP) has been linked to cases of Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA) and cerebrovascular disease. Despite its rarity, it has been observed in several families from the same geographical area, in the Calabria region [...] Read more.

Mutation A713T in the amyloid precursor protein (APP) has been linked to cases of Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA) and cerebrovascular disease. Despite its rarity, it has been observed in several families from the same geographical area, in the Calabria region in Southern Italy. Genotyping of 720,000 genome-wide SNPs with the HumanOmniExpress BeadChip was performed for six patients that were representative of apparently unrelated Calabrian families, as well as a Belgian subject of Italian descent (all with the same A713T mutation and disease). Their genomic structure and genetic relationships were analyzed. Demographic reconstruction and coalescent theory were applied to estimate the time of the most recent common ancestor (tMRCA) among patients. Results show that all A713T carriers fell into the genetic variability of Southern Italy and were not more closely related to each other than to any other healthy Calabrian individual. However, five out of seven patients shared a 1.7 Mbp-long DNA segment centered on the A713T mutation, making it possible to estimate a tMRCA for its common origin in the Calabrian region dating back over 1000 years. The analysis of affected individuals with methodologies based on human population genomics thus provides informative insights in support of clinical observations and biomedical research. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Review

Jump to: Research, Other

9 pages, 256 KiB

Open AccessReview

Amyotrophic Lateral Sclerosis—The Complex Phenotype—From an Epidemiological Perspective: A Focus on Extrapyramidal and Non-Motor Features

by Daniele Urso, Stefano Zoccolella, Valentina Gnoni and Giancarlo Logroscino

Biomedicines 2022, 10(10), 2537; https://doi.org/10.3390/biomedicines10102537 - 11 Oct 2022

Cited by 8 | Viewed by 2165

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND) and has emerged, among the disorders, with the largest increase in incidence in Western countries. Although the typical clinical phenotype of ALS involves simultaneous upper and lower motor neurons, there is [...] Read more.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND) and has emerged, among the disorders, with the largest increase in incidence in Western countries. Although the typical clinical phenotype of ALS involves simultaneous upper and lower motor neurons, there is growing evidence that the neurodegeneration during the course of the disease can also involve other motor and non-motor regions. In this review, we analyzed and discussed available data from epidemiological population-based studies on extrapyramidal and non-motor features during the course of ALS. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

21 pages, 1761 KiB

Open AccessReview

Current Insights on Neurodegeneration by the Italian Proteomics Community

by Tiziana Alberio, Martina Brughera and Marta Lualdi

Biomedicines 2022, 10(9), 2297; https://doi.org/10.3390/biomedicines10092297 - 15 Sep 2022

Cited by 4 | Viewed by 2351

Abstract

The growing number of patients affected by neurodegenerative disorders represents a huge problem for healthcare systems, human society, and economics. In this context, omics strategies are crucial for the identification of molecular factors involved in disease pathobiology, and for the discovery of biomarkers [...] Read more.

The growing number of patients affected by neurodegenerative disorders represents a huge problem for healthcare systems, human society, and economics. In this context, omics strategies are crucial for the identification of molecular factors involved in disease pathobiology, and for the discovery of biomarkers that allow early diagnosis, patients’ stratification, and treatment response prediction. The integration of different omics data is a required step towards the goal of personalized medicine. The Italian proteomics community is actively developing and applying proteomics approaches to the study of neurodegenerative disorders; moreover, it is leading the mitochondria-focused initiative of the Human Proteome Project, which is particularly important given the central role of mitochondrial impairment in neurodegeneration. Here, we describe how Italian research groups in proteomics have contributed to the knowledge of many neurodegenerative diseases, through the elucidation of the pathobiology of these disorders, and through the discovery of disease biomarkers. In particular, we focus on the central role of post-translational modifications analysis, the implementation of network-based approaches in functional proteomics, the integration of different omics in a systems biology view, and the development of novel platforms for biomarker discovery for the high-throughput quantification of thousands of proteins at a time. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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22 pages, 797 KiB

Open AccessReview

Calabria as a Genetic Isolate: A Model for the Study of Neurodegenerative Diseases

by Francesco Bruno, Valentina Laganà, Raffaele Di Lorenzo, Amalia C. Bruni and Raffaele Maletta

Biomedicines 2022, 10(9), 2288; https://doi.org/10.3390/biomedicines10092288 - 15 Sep 2022

Cited by 9 | Viewed by 3132

Abstract

Although originally multi-ethnic in its structure, nowadays the Calabria region of southern Italy represents an area with low genetic heterogeneity and a high level of consanguinity that allows rare mutations to be maintained due to the founder effect. A complex research methodology—ranging from [...] Read more.

Although originally multi-ethnic in its structure, nowadays the Calabria region of southern Italy represents an area with low genetic heterogeneity and a high level of consanguinity that allows rare mutations to be maintained due to the founder effect. A complex research methodology—ranging from clinical activity to the genealogical reconstruction of families/populations across the centuries, the creation of databases, and molecular/genetic research—was modelled on the characteristics of the Calabrian population for more than three decades. This methodology allowed the identification of several novel genetic mutations or variants associated with neurodegenerative diseases. In addition, a higher prevalence of several hereditary neurodegenerative diseases has been reported in this population, such as Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, Niemann–Pick type C disease, spinocerebellar ataxia, Creutzfeldt–Jakob disease, and Gerstmann–Straussler–Scheinker disease. Here, we summarize and discuss the results of research data supporting the view that Calabria could be considered as a genetic isolate and could represent a model, a sort of outdoor laboratory—similar to very few places in the world—useful for the advancement of knowledge on neurodegenerative diseases. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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15 pages, 704 KiB

Open AccessReview

Predicting Outcome in Patients with Brain Injury: Differences between Machine Learning versus Conventional Statistics

by Antonio Cerasa, Gennaro Tartarisco, Roberta Bruschetta, Irene Ciancarelli, Giovanni Morone, Rocco Salvatore Calabrò, Giovanni Pioggia, Paolo Tonin and Marco Iosa

Biomedicines 2022, 10(9), 2267; https://doi.org/10.3390/biomedicines10092267 - 13 Sep 2022

Cited by 24 | Viewed by 3338

Abstract

Defining reliable tools for early prediction of outcome is the main target for physicians to guide care decisions in patients with brain injury. The application of machine learning (ML) is rapidly increasing in this field of study, but with a poor translation to [...] Read more.

Defining reliable tools for early prediction of outcome is the main target for physicians to guide care decisions in patients with brain injury. The application of machine learning (ML) is rapidly increasing in this field of study, but with a poor translation to clinical practice. This is basically dependent on the uncertainty about the advantages of this novel technique with respect to traditional approaches. In this review we address the main differences between ML techniques and traditional statistics (such as logistic regression, LR) applied for predicting outcome in patients with stroke and traumatic brain injury (TBI). Thirteen papers directly addressing the different performance among ML and LR methods were included in this review. Basically, ML algorithms do not outperform traditional regression approaches for outcome prediction in brain injury. Better performance of specific ML algorithms (such as Artificial neural networks) was mainly described in the stroke domain, but the high heterogeneity in features extracted from low-dimensional clinical data reduces the enthusiasm for applying this powerful method in clinical practice. To better capture and predict the dynamic changes in patients with brain injury during intensive care courses ML algorithms should be extended to high-dimensional data extracted from neuroimaging (structural and fMRI), EEG and genetics. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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20 pages, 1927 KiB

Open AccessReview

The Involvement of Polyamines Catabolism in the Crosstalk between Neurons and Astrocytes in Neurodegeneration

by Manuela Cervelli, Monica Averna, Laura Vergani, Marco Pedrazzi, Sarah Amato, Cristian Fiorucci, Marianna Nicoletta Rossi, Guido Maura, Paolo Mariottini, Chiara Cervetto and Manuela Marcoli

Biomedicines 2022, 10(7), 1756; https://doi.org/10.3390/biomedicines10071756 - 21 Jul 2022

Cited by 19 | Viewed by 3986

Abstract

In mammalian cells, the content of polyamines is tightly regulated. Polyamines, including spermine, spermidine and putrescine, are involved in many cellular processes. Spermine oxidase specifically oxidizes spermine, and its deregulated activity has been reported to be linked to brain pathologies involving neuron damage. [...] Read more.

In mammalian cells, the content of polyamines is tightly regulated. Polyamines, including spermine, spermidine and putrescine, are involved in many cellular processes. Spermine oxidase specifically oxidizes spermine, and its deregulated activity has been reported to be linked to brain pathologies involving neuron damage. Spermine is a neuromodulator of a number of ionotropic glutamate receptors and types of ion channels. In this respect, the Dach-SMOX mouse model overexpressing spermine oxidase in the neocortex neurons was revealed to be a model of chronic oxidative stress, excitotoxicity and neuronal damage. Reactive astrocytosis, chronic oxidative and excitotoxic stress, neuron loss and the susceptibility to seizure in the Dach-SMOX are discussed here. This genetic model would help researchers understand the linkage between polyamine dysregulation and neurodegeneration and unveil the roles of polyamines in the crosstalk between astrocytes and neurons in neuroprotection or neurodegeneration. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Enzymes involved in PA biosynthesis (encircled) and catabolism (boxed). ODC, ornithine decarboxylase enzyme; PAOX, N1-acetylpolyamine oxidase; SAT1, spermidine/spermine N1-acetyltransferase; SMS, spermine synthase; SRM, spermidine synthase. The enzyme spermine oxidase (SMOX), which is overexpressed in the Dach-SMOX mice model, is highlighted in red. Full article ">Figure 2
Spermine oxidase chemical reaction. Spermine (Spm) is oxidized to produce spermidine (Spd), 3-aminopropanal (3-AP) and hydrogen peroxide (H2O2). Full article ">Figure 3
Schematic representation of the major mechanisms involved in neuronal damage resulting from polyamine dyshomeostasis in the central nervous system. Polyamine dyshomeostasis-dependent mechanisms that have been suggested to play pivotal roles in representative relevant diseases are also highlighted. AD, Alzheimer’s disease; DR, diabetic retinopathy; HIV D, HIV-associated dementia; PD, Parkinson’s disease. Full article ">Figure 4
SMOX overexpression in neurons resulted in chronic oxidative and excitotoxic stress and in neuron loss. Schematic representation of the main mechanisms taking place at cerebrocortical glutamatergic synapses in the SMOX-overexpressing mouse model. NeuN positive cells were reduced [<a href="#B37-biomedicines-10-01756" class="html-bibr">37</a>,<a href="#B121-biomedicines-10-01756" class="html-bibr">121</a>], and a relative increase in the abundance of astrocyte processes and a decrease in nerve terminals (an increase in GFAP, ezrin and vimentin-positive cells vs. a reduction in synaptophysin and NeuN-positive cells) were found. SMOX overexpression in neurons leads to oxidative stress in neurons, increased by an ROS response in astrocytes and leading to the depletion of catalase (a reduction in the antioxidant defence in nerve terminals). A defective control of the AMPA-evoked intracellular Ca2+ response in the nerve terminals can exacerbate the reactive astrocytes-dependent excitotoxic mechanism activation. For further details, see the text. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; Glu, glutamate; SMOX, spermine oxidase; Spm, spermine. Full article ">

19 pages, 1660 KiB

Open AccessReview

Neurosensory Alterations in Retinopathy of Prematurity: A Window to Neurological Impairments Associated to Preterm Birth

by Martina Lucchesi, Silvia Marracci, Rosario Amato, Luca Filippi, Maurizio Cammalleri and Massimo Dal Monte

Biomedicines 2022, 10(7), 1603; https://doi.org/10.3390/biomedicines10071603 - 6 Jul 2022

Cited by 10 | Viewed by 4395

Abstract

Retinopathy of prematurity (ROP) is one of the main blinding diseases affecting preterm newborns and is classically considered a vascular disorder. The premature exposure to the extrauterine environment, which is hyperoxic in respect to the intrauterine environment, triggers a cascade of events leading [...] Read more.

Retinopathy of prematurity (ROP) is one of the main blinding diseases affecting preterm newborns and is classically considered a vascular disorder. The premature exposure to the extrauterine environment, which is hyperoxic in respect to the intrauterine environment, triggers a cascade of events leading to retinal ischemia which, in turn, makes the retina hypoxic thus setting off angiogenic processes. However, many children with a history of ROP show persistent vision impairment, and there is evidence of an association between ROP and neurosensory disabilities. This is not surprising given the strict relationship between neuronal function and an adequate blood supply. In the present work, we revised literature data evidencing to what extent ROP can be considered a neurodegenerative disease, also taking advantage from data obtained in preclinical models of ROP. The involvement of different retinal cell populations in triggering the neuronal damage in ROP was described along with the neurological outcomes associated to ROP. The situation of ROP in Italy was assessed as well. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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17 pages, 767 KiB

Open AccessReview

The Gut Microbiome–Brain Crosstalk in Neurodegenerative Diseases

by Laura Ghezzi, Claudia Cantoni, Emanuela Rotondo and Daniela Galimberti

Biomedicines 2022, 10(7), 1486; https://doi.org/10.3390/biomedicines10071486 - 23 Jun 2022

Cited by 33 | Viewed by 6541

Abstract

The gut–brain axis (GBA) is a complex interactive network linking the gut to the brain. It involves the bidirectional communication between the gastrointestinal and the central nervous system, mediated by endocrinological, immunological, and neural signals. Perturbations of the GBA have been reported in [...] Read more.

The gut–brain axis (GBA) is a complex interactive network linking the gut to the brain. It involves the bidirectional communication between the gastrointestinal and the central nervous system, mediated by endocrinological, immunological, and neural signals. Perturbations of the GBA have been reported in many neurodegenerative diseases, suggesting a possible role in disease pathogenesis, making it a potential therapeutic target. The gut microbiome is a pivotal component of the GBA, and alterations in its composition have been linked to GBA dysfunction and CNS inflammation and degeneration. The gut microbiome might influence the homeostasis of the central nervous system homeostasis through the modulation of the immune system and, more directly, the production of molecules and metabolites. Small clinical and preclinical trials, in which microbial composition was manipulated using dietary changes, fecal microbiome transplantation, and probiotic supplements, have provided promising outcomes. However, results are not always consistent, and large-scale randomized control trials are lacking. Here, we give an overview of how the gut microbiome influences the GBA and could contribute to disease pathogenesis in neurodegenerative diseases. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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13 pages, 577 KiB

Open AccessReview

Experimental Models for Testing the Efficacy of Pharmacological Treatments for Neonatal Hypoxic-Ischemic Encephalopathy

by Elisa Landucci, Domenico E. Pellegrini-Giampietro and Fabrizio Facchinetti

Biomedicines 2022, 10(5), 937; https://doi.org/10.3390/biomedicines10050937 - 19 Apr 2022

Cited by 14 | Viewed by 3500

Abstract

Representing an important cause of long–term disability, term neonatal hypoxic-ischemic encephalopathy (HIE) urgently needs further research aimed at repurposing existing drug as well as developing new therapeutics. Since various experimental in vitro and in vivo models of HIE have been developed with distinct [...] Read more.

Representing an important cause of long–term disability, term neonatal hypoxic-ischemic encephalopathy (HIE) urgently needs further research aimed at repurposing existing drug as well as developing new therapeutics. Since various experimental in vitro and in vivo models of HIE have been developed with distinct characteristics, it becomes important to select the appropriate preclinical screening cascade for testing the efficacy of novel pharmacological treatments. As therapeutic hypothermia is already a routine therapy for neonatal encephalopathy, it is essential that hypothermia be administered to the experimental model selected to allow translational testing of novel or repurposed drugs on top of the standard of care. Moreover, a translational approach requires that therapeutic interventions must be initiated after the induction of the insult, and the time window for intervention should be evaluated to translate to real world clinical practice. Hippocampal organotypic slice cultures, in particular, are an invaluable intermediate between simpler cell lines and in vivo models, as they largely maintain structural complexity of the original tissue and can be subjected to transient oxygen–glucose deprivation (OGD) and subsequent reoxygenation to simulate ischemic neuronal injury and reperfusion. Progressing to in vivo models, generally, rodent (mouse and rat) models could offer more flexibility and be more cost-effective for testing the efficacy of pharmacological agents with a dose–response approach. Large animal models, including piglets, sheep, and non-human primates, may be utilized as a third step for more focused and accurate translational studies, including also pharmacokinetic and safety pharmacology assessments. Thus, a preclinical proof of concept of efficacy of an emerging pharmacological treatment should be obtained firstly in vitro, including organotypic models, and, subsequently, in at least two different animal models, also in combination with hypothermia, before initiating clinical trials. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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24 pages, 1240 KiB

Open AccessReview

The Role of Tau beyond Alzheimer’s Disease: A Narrative Review

by Eleonora Virgilio, Fabiola De Marchi, Elena Contaldi, Umberto Dianzani, Roberto Cantello, Letizia Mazzini and Cristoforo Comi

Biomedicines 2022, 10(4), 760; https://doi.org/10.3390/biomedicines10040760 - 24 Mar 2022

Cited by 21 | Viewed by 5459

Abstract

Nowadays, there is a need for reliable fluid biomarkers to improve differential diagnosis, prognosis, and the prediction of treatment response, particularly in the management of neurogenerative diseases that display an extreme variability in clinical phenotypes. In recent years, Tau protein has been progressively [...] Read more.

Nowadays, there is a need for reliable fluid biomarkers to improve differential diagnosis, prognosis, and the prediction of treatment response, particularly in the management of neurogenerative diseases that display an extreme variability in clinical phenotypes. In recent years, Tau protein has been progressively recognized as a valuable neuronal biomarker in several neurological conditions, not only Alzheimer’s disease (AD). Cerebrospinal fluid and serum Tau have been extensively investigated in several neurodegenerative disorders, from classically defined proteinopathy, e.g., amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD), but also in inflammatory conditions such as multiple sclerosis (MS), as a marker of axonal damage. In MS, total Tau (t-Tau) may represent, along with other proteins, a marker with diagnostic and prognostic value. In ALS, t-Tau and, mainly, the phosphorylated-Tau/t-Tau ratio alone or integrated with transactive DNA binding protein of ~43 kDa (TDP-43), may represent a tool for both diagnosis and differential diagnosis of other motoneuron diseases or tauopathies. Evidence indicated the crucial role of the Tau protein in the pathogenesis of PD and other parkinsonian disorders. This narrative review summarizes current knowledge regarding non-AD neurodegenerative diseases and the Tau protein. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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10 pages, 512 KiB

Open AccessReview

Stathmins and Motor Neuron Diseases: Pathophysiology and Therapeutic Targets

by Delia Gagliardi, Elisa Pagliari, Megi Meneri, Valentina Melzi, Federica Rizzo, Giacomo Pietro Comi, Stefania Corti, Michela Taiana and Monica Nizzardo

Biomedicines 2022, 10(3), 711; https://doi.org/10.3390/biomedicines10030711 - 19 Mar 2022

Cited by 17 | Viewed by 4999

Abstract

Motor neuron diseases (MNDs) are a group of fatal, neurodegenerative disorders with different etiology, clinical course and presentation, caused by the loss of upper and lower motor neurons (MNs). MNs are highly specialized cells equipped with long, axonal processes; axonal defects are some [...] Read more.

Motor neuron diseases (MNDs) are a group of fatal, neurodegenerative disorders with different etiology, clinical course and presentation, caused by the loss of upper and lower motor neurons (MNs). MNs are highly specialized cells equipped with long, axonal processes; axonal defects are some of the main players underlying the pathogenesis of these disorders. Microtubules are key components of the neuronal cytoskeleton characterized by dynamic instability, switching between rapid polymerization and shrinkage. Proteins of the stathmin family affect microtubule dynamics regulating the assembly and the dismantling of tubulin. Stathmin-2 (STMN2) is one of the most abundantly expressed genes in MNs. Following axonal injury, STMN2 expression is upregulated, and the protein is transported toward the growth cones of regenerating axons. STMN2 has a critical role in axonal maintenance, and its dysregulation plays an important role in neurodegenerative processes. Stathmin-1 (STMN1) is a ubiquitous protein that is highly expressed during the development of the nervous system, and its phosphorylation controls microtubule dynamics. In the present review, we summarize what is currently known about the involvement of stathmin alterations in MNDs and the potential therapeutic effect of their modulation, with a specific focus on the most common forms of MND, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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13 pages, 1356 KiB

Open AccessReview

Gangliosides and the Treatment of Neurodegenerative Diseases: A Long Italian Tradition

by Maria Fazzari, Giulia Lunghi, Elena Chiricozzi, Laura Mauri and Sandro Sonnino

Biomedicines 2022, 10(2), 363; https://doi.org/10.3390/biomedicines10020363 - 2 Feb 2022

Cited by 19 | Viewed by 3958

Abstract

Gangliosides are glycosphingolipids which are particularly abundant in the plasma membrane of mammalian neurons. The knowledge of their presence in the human brain dates back to the end of 19th century, but their structure was determined much later, in the middle of the [...] Read more.

Gangliosides are glycosphingolipids which are particularly abundant in the plasma membrane of mammalian neurons. The knowledge of their presence in the human brain dates back to the end of 19th century, but their structure was determined much later, in the middle of the 1950s. From this time, neurochemical studies suggested that gangliosides, and particularly GM1 ganglioside, display neurotrophic and neuroprotective properties. The involvement of GM1 in modulating neuronal processes has been studied in detail by in vitro experiments, and the results indicated its direct role in modulating the activity of neurotrophin-dependent receptor signaling, the flux of calcium through the plasma membrane, and stabilizing the correct conformation of proteins, such as α-synuclein. Following, in vivo experiments supported the use of ganglioside drugs for the therapy of peripheral neuropathies, obtaining very positive results. However, the clinical use of gangliosides for the treatment of central neurodegeneration has not been followed due to the poor penetrability of these lipids at the central level. This, together with an ambiguous association (later denied) between ganglioside administration and Guillain-Barrè syndrome, led to the suspension of ganglioside drugs. In this critical review, we report on the evolution of research on gangliosides, on the current knowledge on the role played by gangliosides in regulating the biology of neurons, on the past and present use of ganglioside-based drugs used for therapy of peripheral neuropathies or used in human trials for central neurodegenerations, and on the therapeutic potential represented by the oligosaccharide chain of GM1 ganglioside for the treatment of neurodegenerative diseases. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Figure 1
Chemical structure of (a) GM1 ganglioside, (b) the GM1 permeable analogue LIGA 20, and (c) the GMI oligosaccharide chain, the OligoGM1. Full article ">Figure 2
Chemical structure of (a) the tritium-labeled, photoactivable compounds. OligoGM1 containing tritium at C6 of the external galactose and the nitrophenyl azide at C1 of glucose; (b) GM1 ganglioside containing the nitrophenyl azide at C6 of galactose and tritium at C3 of sphingosine; (c) GM1 ganglioside containing tritium at C6 of external galactose and nitrophenyl azide at the end of the acyl chain. Full article ">Figure 3
Steps of the biosynthesis of the main brain gangliosides: (a) in the absence of B4galnt1, the biosynthesis of GM2 cannot proceed and (b) the process stops with GM3 and GD3. Full article ">Figure 4
Neuronal processes modulated by plasma membrane GM1. GM1 is a component of the outer layer of the plasma membrane and when available in physiological amounts it interacts with the NGF receptor TrkA. This interaction is necessary for TrkA dimerization and activation when NGF is released by the cell. From here, the process activates the down-streaming pathway, finally leading to the differentiation, protection, and survival of neurons. Gangliosides around the calcium channel concentrate calcium ions to realize a strong gradient and accelerate calcium’s entrance into the cell. The GM1 associated with the synapsis stabilizes the α-synuclein, avoiding its aggregation, and allowing it to transfer to the post-synapsis as an unfolded protein. Full article ">

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2 pages, 3127 KiB

Open AccessCorrection

Correction: Musumeci et al. Intranasal Administration of a TRAIL Neutralizing Monoclonal Antibody Adsorbed in PLGA Nanoparticles and NLC Nanosystems: An In Vivo Study on a Mouse Model of Alzheimer’s Disease. Biomedicines 2022, 10, 985

by Teresa Musumeci, Giulia Di Benedetto, Claudia Carbone, Angela Bonaccorso, Giovanni Amato, Maria Josè Lo Faro, Chiara Burgaletto, Giovanni Puglisi, Renato Bernardini and Giuseppina Cantarella

Biomedicines 2024, 12(11), 2447; https://doi.org/10.3390/biomedicines12112447 - 25 Oct 2024

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Abstract

Figure 5 in the original publication [...] Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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15 pages, 814 KiB

Open AccessViewpoint

Reward System Dysfunction and the Motoric-Cognitive Risk Syndrome in Older Persons

by Fulvio Lauretani, Crescenzo Testa, Marco Salvi, Irene Zucchini, Beatrice Lorenzi, Sara Tagliaferri, Chiara Cattabiani and Marcello Maggio

Biomedicines 2022, 10(4), 808; https://doi.org/10.3390/biomedicines10040808 - 30 Mar 2022

Cited by 7 | Viewed by 6255

Abstract

During aging, many physiological systems spontaneously change independent of the presence of chronic diseases. The reward system is not an exception and its dysfunction generally includes a reduction in dopamine and glutamate activities and the loss of neurons of the ventral tegmental area [...] Read more.

During aging, many physiological systems spontaneously change independent of the presence of chronic diseases. The reward system is not an exception and its dysfunction generally includes a reduction in dopamine and glutamate activities and the loss of neurons of the ventral tegmental area (VTA). These impairments are even more pronounced in older persons who have neurodegenerative diseases and/or are affected by cognitive and motoric frailty. All these changes may result in the occurrence of cognitive and motoric frailty and accelerated progression of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. In particular, the loss of neurons in VTA may determine an acceleration of depressive symptoms and cognitive and motor frailty trajectory, producing an increased risk of disability and mortality. Thus, we hypothesize the existence of a loop between reward system dysfunction, depression, and neurodegenerative diseases in older persons. Longitudinal studies are needed to evaluate the determinant role of the reward system in the onset of motoric-cognitive risk syndrome. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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