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1.
Mult Scler ; 28(13): 2027-2037, 2022 11.
Article in English | MEDLINE | ID: covidwho-2138773

ABSTRACT

BACKGROUND: The use of advanced magnetic resonance imaging (MRI) techniques in MS research has led to new insights in lesion evolution and disease outcomes. It has not yet been determined if, or how, pre-lesional abnormalities in normal-appearing white matter (NAWM) relate to the long-term evolution of new lesions. OBJECTIVE: To investigate the relationship between abnormalities in MRI measures of axonal and myelin volume fractions (AVF and MVF) in NAWM preceding development of black-hole (BH) and non-BH lesions in people with MS. METHODS: We obtained magnetization transfer and diffusion MRI at 6-month intervals in patients with MS to estimate MVF and AVF during lesion evolution. Lesions were classified as either BH or non-BH on the final imaging visit using T1 maps. RESULTS: Longitudinal data from 97 new T2 lesions from 9 participants were analyzed; 25 lesions in 8 participants were classified as BH 6-12 months after initial appearance. Pre-lesion MVF, AVF, and MVF/AVF were significantly lower, and T1 was significantly higher, in the lesions that later became BHs (p < 0.001) compared to those that did not. No significant pre-lesion abnormalities were found in non-BH lesions (p > 0.05). CONCLUSION: The present work demonstrated that pre-lesion abnormalities are associated with worse long-term lesion-level outcome.


Subject(s)
Multiple Sclerosis , White Matter , Axons/pathology , Brain/pathology , Humans , Magnetic Resonance Imaging/methods , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/pathology , Myelin Sheath/pathology , White Matter/diagnostic imaging , White Matter/pathology
2.
Phys Rev E ; 104(2-1): 024417, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1393562

ABSTRACT

In several pathological conditions, such as coronavirus infections, multiple sclerosis, Alzheimer's and Parkinson's diseases, the physiological shape of axons is altered and a periodic sequence of bulges appears. Experimental evidences suggest that such morphological changes are caused by the disruption of the microtubules composing the cytoskeleton of the axon. In this paper, we develop a mathematical model of damaged axons based on the theory of continuum mechanics and nonlinear elasticity. The axon is described as a cylinder composed of an inner passive part, called axoplasm, and an outer active cortex, composed mainly of F-actin and able to contract thanks to myosin-II motors. Through a linear stability analysis we show that, as the shear modulus of the axoplasm diminishes due to the disruption of the cytoskeleton, the active contraction of the cortex makes the cylindrical configuration unstable to axisymmetric perturbations, leading to a beading pattern. Finally, the nonlinear evolution of the bifurcated branches is investigated through finite element simulations.


Subject(s)
Axons/pathology , Elasticity , Models, Neurological , Actins/metabolism , Axons/metabolism , Biomechanical Phenomena
3.
Immunol Res ; 69(6): 553-557, 2021 12.
Article in English | MEDLINE | ID: covidwho-1345196

ABSTRACT

The persistence of neurological symptoms after SARS-CoV-2 infection, as well as the presence of late axonal damage, is still unknown. We performed extensive systemic and neurological follow-up evaluations in 107 out of 193 consecutive patients admitted to the COVID-19 medical unit, University Hospital of Verona, Italy between March and June 2020. We analysed serum neurofilament light chain (NfL) levels in all cases including a subgroup (n = 29) of patients with available onset samples. Comparisons between clinical and biomarker data were then performed. Neurological symptoms were still present in a significant number (n = 49) of patients over the follow-up. The most common reported symptoms were hyposmia (n = 11), fatigue (n = 28), myalgia (n = 14), and impaired memory (n = 11) and were more common in cases with severe acute COVID-19. Follow-up serum NfL values (15.2 pg/mL, range 2.4-62.4) were within normal range in all except 5 patients and did not differentiate patients with vs without persistent neurological symptoms. In patients with available onset and follow-up samples, a significant (p < 0.001) decrease of NfL levels was observed and was more evident in patients with a severe acute disease. Despite the common persistence of neurological symptoms, COVID-19 survivors do not show active axonal damage, which seems a peculiar feature of acute SARS-CoV-2 infection.


Subject(s)
Axons/pathology , COVID-19/pathology , Nervous System Diseases/pathology , Adult , Aged , Aged, 80 and over , Ageusia/pathology , Ageusia/virology , Anosmia/pathology , Anosmia/virology , Axons/virology , Disease Progression , Fatigue/pathology , Fatigue/virology , Female , Humans , Italy , Male , Memory Disorders/pathology , Memory Disorders/virology , Middle Aged , Myalgia/pathology , Myalgia/virology , Nervous System Diseases/virology , Neurofilament Proteins/blood , SARS-CoV-2
4.
J Virol ; 94(14)2020 07 01.
Article in English | MEDLINE | ID: covidwho-823496

ABSTRACT

Mouse hepatitis virus (MHV) is a murine betacoronavirus (m-CoV) that causes a wide range of diseases in mice and rats, including hepatitis, enteritis, respiratory diseases, and encephalomyelitis in the central nervous system (CNS). MHV infection in mice provides an efficient cause-effect experimental model to understand the mechanisms of direct virus-induced neural-cell damage leading to demyelination and axonal loss, which are pathological features of multiple sclerosis (MS), the most common disabling neurological disease in young adults. Infiltration of T lymphocytes, activation of microglia, and their interplay are the primary pathophysiological events leading to disruption of the myelin sheath in MS. However, there is emerging evidence supporting gray matter involvement and degeneration in MS. The investigation of T cell function in the pathogenesis of deep gray matter damage is necessary. Here, we employed RSA59 (an isogenic recombinant strain of MHV-A59)-induced experimental neuroinflammation model to compare the disease in CD4-/- mice with that in CD4+/+ mice at days 5, 10, 15, and 30 postinfection (p.i.). Viral titer estimation, nucleocapsid gene amplification, and viral antinucleocapsid staining confirmed enhanced replication of the virions in the absence of functional CD4+ T cells in the brain. Histopathological analyses showed elevated susceptibility of CD4-/- mice to axonal degeneration in the CNS, with augmented progression of acute poliomyelitis and dorsal root ganglionic inflammation rarely observed in CD4+/+ mice. Depletion of CD4+ T cells showed unique pathological bulbar vacuolation in the brain parenchyma of infected mice with persistent CD11b+ microglia/macrophages in the inflamed regions on day 30 p.i. In summary, the current study suggests that CD4+ T cells are critical for controlling acute-stage poliomyelitis (gray matter inflammation), chronic axonal degeneration, and inflammatory demyelination due to loss of protective antiviral host immunity.IMPORTANCE The current trend in CNS disease biology is to attempt to understand the neural-cell-immune interaction to investigate the underlying mechanism of neuroinflammation, rather than focusing on peripheral immune activation. Most studies in MS are targeted toward understanding the involvement of CNS white matter. However, the importance of gray matter damage has become critical in understanding the long-term progressive neurological disorder. Our study highlights the importance of CD4+ T cells in safeguarding neurons against axonal blebbing and poliomyelitis from murine betacoronavirus-induced neuroinflammation. Current knowledge of the mechanisms that lead to gray matter damage in MS is limited, because the most widely used animal model, experimental autoimmune encephalomyelitis (EAE), does not present this aspect of the disease. Our results, therefore, add to the existing limited knowledge in the field. We also show that the microglia, though important for the initiation of neuroinflammation, cannot establish a protective host immune response without the help of CD4+ T cells.


Subject(s)
Axons/immunology , Axons/metabolism , CD4 Antigens/deficiency , Coronavirus Infections/immunology , Coronavirus Infections/virology , Murine hepatitis virus/physiology , Poliomyelitis/etiology , Animals , Axons/pathology , Brain/immunology , Brain/metabolism , Brain/pathology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Coronavirus Infections/pathology , Cytokines/metabolism , Disease Models, Animal , Disease Susceptibility/immunology , Ganglia, Spinal/immunology , Ganglia, Spinal/metabolism , Ganglia, Spinal/pathology , Immunohistochemistry , Inflammation Mediators/metabolism , Mice
5.
Am J Hum Genet ; 107(4): 763-777, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-758482

ABSTRACT

Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.


Subject(s)
Axons/metabolism , Charcot-Marie-Tooth Disease/genetics , Guanine Nucleotide Exchange Factors/genetics , Muscle Weakness/genetics , Muscular Atrophy, Spinal/genetics , Musculoskeletal Abnormalities/genetics , Adult , Aged , Aged, 80 and over , Amino Acid Sequence , Animals , Axons/pathology , COP-Coated Vesicles/metabolism , COP-Coated Vesicles/pathology , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/metabolism , Charcot-Marie-Tooth Disease/pathology , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Gene Expression , Golgi Apparatus/metabolism , Golgi Apparatus/pathology , Guanine Nucleotide Exchange Factors/metabolism , Heterozygote , Humans , Male , Mice , Middle Aged , Mitochondria/metabolism , Mitochondria/pathology , Motor Neurons/metabolism , Motor Neurons/pathology , Muscle Weakness/diagnosis , Muscle Weakness/metabolism , Muscle Weakness/pathology , Muscular Atrophy, Spinal/diagnosis , Muscular Atrophy, Spinal/metabolism , Muscular Atrophy, Spinal/pathology , Musculoskeletal Abnormalities/diagnosis , Musculoskeletal Abnormalities/metabolism , Musculoskeletal Abnormalities/pathology , Mutation , Pedigree , Primary Cell Culture , Spinal Cord/abnormalities , Spinal Cord/metabolism
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