Mechanisms and Treatments of Neurodegenerative Diseases

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Life life	3.2	2.7	2011	17.5 Days	CHF 2600
Diseases diseases	3.7	-	2013	18.8 Days	CHF 1800
Physiologia physiologia	-	-	2021	17.5 Days	CHF 1000
Brain Sciences brainsci	3.3	3.9	2011	15.6 Days	CHF 2200
Medicina medicina	2.6	3.6	1920	19.6 Days	CHF 1800

3 pages, 210 KiB

Open AccessComment

Can Immersive Sound Therapy Counteract Neurodegeneration by Enhancing Glymphatic Clearance? Comment on Sachdeva et al. Effects of Sound Interventions on the Permeability of the Blood–Brain Barrier and Meningeal Lymphatic Clearance. Brain Sci. 2022, 12, 742

by Peter Wostyn and Piet Goddaer

Brain Sci. 2023, 13(1), 98; https://doi.org/10.3390/brainsci13010098 - 04 Jan 2023

Cited by 2 | Viewed by 1558

Abstract

We would like to congratulate Sachdeva and colleagues for establishing an informative review regarding the effects of music/sound exposure on blood–brain barrier permeability and meningeal lymphatic/glymphatic clearance, and would appreciate the opportunity to make a comment. The review by Sachdeva and colleagues documents [...] Read more.

We would like to congratulate Sachdeva and colleagues for establishing an informative review regarding the effects of music/sound exposure on blood–brain barrier permeability and meningeal lymphatic/glymphatic clearance, and would appreciate the opportunity to make a comment. The review by Sachdeva and colleagues documents the beneficial effects of sound interventions on blood–brain barrier permeability and the activity of the meningeal lymphatic/glymphatic system. The authors further note that sound interventions may have the potential to reduce the accumulation of amyloid-β within the brain in Alzheimer’s disease through improved meningeal lymphatic/glymphatic clearance. The authors also nicely discuss evidence that music influences sleep quality, which may facilitate glymphatic solute clearance as a result of an increase in the interstitial space, which results in reduced resistance to fluid transport. We fully agree with this notion, since we recently hypothesized that immersive sound therapy may be an innovative approach to reduce the individual risk of developing neurodegenerative diseases, such as Alzheimer’s disease, by inducing EEG slow-wave delta oscillations (which characterize deep sleep), thereby promoting glymphatic clearance. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

8 pages, 1653 KiB

Open AccessCase Report

Oral Health Status and Multiple Sclerosis: Classic and Non-Classic Manifestations—Case Report

by Céu Costa, Hugo Santiago, Sofia Pereira, Ana Rita Castro and Sandra Clara Soares

Diseases 2022, 10(3), 62; https://doi.org/10.3390/diseases10030062 - 09 Sep 2022

Cited by 2 | Viewed by 7883

Abstract

Background: Multiple sclerosis is an autoimmune disease of the central nervous system with neurological and motor symptoms that affect the orofacial region. The aim of this work is to present a patient that lacks the three classic orofacial manifestations but has other less [...] Read more.

Background: Multiple sclerosis is an autoimmune disease of the central nervous system with neurological and motor symptoms that affect the orofacial region. The aim of this work is to present a patient that lacks the three classic orofacial manifestations but has other less common clinical alterations. Case presentation: A 49-year-old female patient diagnosed with long-term relapsing–remitting multiple sclerosis visited the dentist complaining of mild but persistent orofacial pain including the temporomandibular joint and pain not specific to any tooth. She presented mucosal irritation, xerostomia, halitosis, and localized gingivitis. There was excessive wear of the upper and lower incisal edges and the occlusal faces of the upper canines and loss of six teeth due to caries. After a clinical oral examination, the diagnosis was temporomandibular joint disorder, gingivitis, dental hypersensitivity, bruxism, hyposalivation, xerostomia, and halitosis. Conclusions: Patients with multiple sclerosis present classic orofacial manifestations. Although these were not observed in this patient, she had others, such as gingivitis, tooth hypersensitivity, and bruxism. In addition, despite few studies associating a higher prevalence of caries with these patients, the number of carious and missing teeth in this patient highlight the evidence that multiple sclerosis has had a significant impact on the patient’s dental status over the years. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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10 pages, 4376 KiB

Open AccessCase Report

Spinal Cord Injury and Postdural Puncture Headache following Cervical Interlaminar Epidural Steroid Injection: A Case Report

by Hyung Joon Park, Heezoo Kim, Sung Jin Jeong, Jae Hak Lee, Sang Sik Choi and Chung Hun Lee

Medicina 2022, 58(9), 1237; https://doi.org/10.3390/medicina58091237 - 07 Sep 2022

Cited by 2 | Viewed by 2040

Abstract

Background: Cervical interlaminar epidural steroid injection (CIESI) is increasingly used as an interventional treatment for pain originating from the cervical spine. However, serious neurological complications may occur during CIESI because of direct nerve damage following inappropriate needle placement. Case report: A [...] Read more.

Background: Cervical interlaminar epidural steroid injection (CIESI) is increasingly used as an interventional treatment for pain originating from the cervical spine. However, serious neurological complications may occur during CIESI because of direct nerve damage following inappropriate needle placement. Case report: A 35-year-old woman presented with posterior neck pain radiating to the left upper arm. Cervical magnetic resonance imaging (MRI) revealed left C6 nerve impingement. CIESI under fluoroscopic guidance was performed at another hospital using the left C5/6 interlaminar approach. Immediately after the procedure, the patient experienced dizziness, decreased blood pressure, motor weakness in the left upper arm, and sensory loss. She visited our emergency department with postdural puncture headache (PDPH) that worsened after the procedure. Post-admission cervical MRI revealed intramedullary T2 high signal intensity and cord swelling from the C4/5 to C6/7 levels; thus, a diagnosis of spinal cord injury was made. The patient’s PDPH spontaneously improved after 48 h. However, despite conservative treatment with steroids, the decrease in abduction of the left fifth finger and loss of sensation in the dorsum of the left hand persisted for up to 6 months after the procedure. As noticed in the follow-up MRI performed 6 months post-procedure, the T2 high signal intensity in the left intramedullary region had decreased compared to that observed previously; however, cord swelling persisted. Furthermore, left C7/8 radiculopathy with acute denervation was confirmed by electromyography performed 6 months after the procedure. Conclusions: Fluoroscopy does not guarantee the prevention of spinal cord penetration during CIESI. Moreover, persistent neurological deficits may occur, particularly due to intrathecal perforation or drug administration during CIESI. Therefore, in accordance with the recommendations of the Multisociety Pain Workgroup, we recommend performing CIESI at the C6/7 or C7/T1 levels, where the epidural space is relatively large, rather than at the C5/6 level or higher. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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14 pages, 441 KiB

Open AccessArticle

Challenges in the Detection of Clinically Useful Biomarkers for the Diagnosis of Delirium in Older People in the Emergency Department—A Case–Control Study

by Angela Soler-Sanchis, Francisco Miguel Martínez-Arnau, José Sánchez-Frutos and Pilar Pérez-Ros

Life 2022, 12(8), 1127; https://doi.org/10.3390/life12081127 - 27 Jul 2022

Cited by 1 | Viewed by 1392

Abstract

Background: The identification of biomarkers associated with delirium in the emergency department could contribute to the understanding, prediction and diagnosis of this disorder. The present study was carried out to identify biomarkers included in easily and quickly obtained standard blood examinations in older [...] Read more.

Background: The identification of biomarkers associated with delirium in the emergency department could contribute to the understanding, prediction and diagnosis of this disorder. The present study was carried out to identify biomarkers included in easily and quickly obtained standard blood examinations in older patients with delirium in the emergency department. Methods: A case–control study was carried out in the emergency department of Francesc de Borja Hospital (Gandía, Valencia, Spain). Older adults (≥65 years of age) diagnosed with delirium (n = 128) were included. Cases due to alcohol or substance abuse were excluded. Controls were selected on a randomized basis from the remaining patients (n = 128). All laboratory test parameters included in the routine blood and urine tests of the emergency department were collected. Results: The mean age of the patients was 81.24 ± 7.51 years, and 56.2% were males, while the mean age of the controls was 78.97 ± 7.99 years, and 45.3% were males. Significant differences were found between the cases and controls in relation to the following parameters: urea 43 (32–58) mg/dL versus 50 (37–66) mg/dL, respectively; neutrophils 69.6 (62.05–78.75)% versus 75.5 (65.1–83.2)%; monocytes 8.7 (7–10.4)% versus 7.6 (5.5–9.2)%; platelets 213 (159–266) × 10⁹/L versus 224 (182–289) × 10⁹/L; neutrophil–lymphocyte ratio 3.88 (2.45–7.07) versus 5 (2.75–8.83); platelet–lymphocyte ratio 281.4 (210–360) versus 357.1 (257.8–457.1); and mean platelet volume 10.6 (10–11.5) fl versus 10.4 (9.67–10.9) fl. Although the mean values were above desirable levels in both groups, they were higher for most parameters in the control group. No significant differences were observed in C-reactive protein concentration (9.99 (1.69–51) mg/L versus 12.3 (3.09–65.97) mg/L). Conclusions: The identification of delirium biomarkers poses difficulties due to the urgent nature of the disorders found in older people admitted to the emergency department. Research in this field is needed, since it would allow early identification and treatment of delirium. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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9 pages, 1977 KiB

Open AccessEditor’s ChoiceArticle

The Prophylactic and Multimodal Activity of Two Isatin Thiosemicarbazones against Alzheimer’s Disease In Vitro

by Barbara Mavroidi, Archontia Kaminari, Dimitris Matiadis, Dimitra Hadjipavlou-Litina, Maria Pelecanou, Athina Tzinia and Marina Sagnou

Brain Sci. 2022, 12(6), 806; https://doi.org/10.3390/brainsci12060806 - 19 Jun 2022

Cited by 15 | Viewed by 1836

Abstract

Alzheimer’s disease (AD) is a multifactorial disorder strongly involving the formation of amyloid-β (Aβ) oligomers, which subsequently aggregate into the disease characteristic insoluble amyloid plaques, in addition to oxidative stress, inflammation and increased acetylcholinesterase activity. Moreover, Aβ oligomers interfere with the expression and [...] Read more.

Alzheimer’s disease (AD) is a multifactorial disorder strongly involving the formation of amyloid-β (Aβ) oligomers, which subsequently aggregate into the disease characteristic insoluble amyloid plaques, in addition to oxidative stress, inflammation and increased acetylcholinesterase activity. Moreover, Aβ oligomers interfere with the expression and activity of Glycogen synthase kinase-3 (GSK3) and Protein kinase B (PKB), also known as AKT. In the present study, the potential multimodal effect of two synthetic isatin thiosemicarbazones (ITSCs), which have been previously shown to prevent Aβ aggregation was evaluated. Both compounds resulted in fully reversing the Aβ-mediated toxicity in SK-NS-H cells treated with exogenous Aβ peptides at various pre-incubation time points and at 1 μM. Cell survival was not recovered when compounds were applied after Aβ cell treatment. The ITSCs were non-toxic against wild type and 5xFAD primary hippocampal cells. They reversed the inhibition of Akt and GSK-3β phosphorylation in 5xFAD cells. Finally, they exhibited good antioxidant potential and moderate lipoxygenase and acetylcholinesterase inhibition activity. Overall, these results suggest that isatin thiosemicarbazone is a suitable scaffold for the development of multimodal anti-AD agents. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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3 pages, 247 KiB

Open AccessReply

Reply to Aljabali et al. Comment on “Abbas et al. The Safety and Efficacy of Nusinersen in the Treatment of Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Medicina 2022, 58, 213”

by Basel Abdelazeem, Kirellos Said Abbas and James Robert Brašić

Medicina 2022, 58(6), 793; https://doi.org/10.3390/medicina58060793 - 13 Jun 2022

Viewed by 1650

Abstract

We appreciate Ahmed Sami Aljabali and his colleagues for their interest and comments [...] Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

3 pages, 259 KiB

Open AccessComment

Comment on Abbas et al. The Safety and Efficacy of Nusinersen in the Treatment of Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Medicina 2022, 58, 213

by Ahmed Aljabali, Maha Abdo and Ahmed Negida

Medicina 2022, 58(6), 766; https://doi.org/10.3390/medicina58060766 - 06 Jun 2022

Cited by 1 | Viewed by 2010

Abstract

We read with interest the article by Abbas et al. [...] Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

6 pages, 812 KiB

Open AccessCase Report

Can Disruption of Basal Ganglia-Thalamocortical Circuit in Wilson Disease Be Associated with Juvenile Myoclonic Epilepsy Phenotype?

by Jessica Rossi, Francesco Cavallieri, Giada Giovannini, Francesca Benuzzi, Daniela Ballotta, Anna Elisabetta Vaudano, Francesca Ferrara, Sara Contardi, Antonello Pietrangelo, Elena Corradini, Fausta Lui and Stefano Meletti

Brain Sci. 2022, 12(5), 553; https://doi.org/10.3390/brainsci12050553 - 26 Apr 2022

Cited by 2 | Viewed by 1715

Abstract

In this paper, we describe the multimodal MRI findings in a patient with Wilson disease and a seizure disorder, characterized by an electroclinical picture resembling juvenile myoclonic epilepsy. The brain structural MRI showed a deposition of ferromagnetic materials in the basal ganglia, with [...] Read more.

In this paper, we describe the multimodal MRI findings in a patient with Wilson disease and a seizure disorder, characterized by an electroclinical picture resembling juvenile myoclonic epilepsy. The brain structural MRI showed a deposition of ferromagnetic materials in the basal ganglia, with marked hypointensities in T2-weighted images of globus pallidus internus bilaterally. A resting-state fMRI study revealed increased functional connectivity in the patient, compared to control subjects, in the following networks: (1) between the primary motor cortex and several cortical regions, including the secondary somatosensory cortex and (2) between the globus pallidus and the thalamo-frontal network. These findings suggest that globus pallidus alterations, due to metal accumulation, can lead to a reduction in the normal globus pallidus inhibitory tone on the thalamo-(motor)-cortical pathway. This, in turn, can result in hyperconnectivity in the motor cortex circuitry, leading to myoclonus and tonic-clonic seizures. We suppose that, in this patient, Wilson disease generated a ‘lesion model’ of myoclonic epilepsy. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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19 pages, 3965 KiB

Open AccessArticle

Nimodipine Exerts Beneficial Effects on the Rat Oligodendrocyte Cell Line OLN-93

by Felix Boltz, Michael Enders, Andreas Feigenspan, Philipp Kirchner, Arif Ekici and Stefanie Kuerten

Brain Sci. 2022, 12(4), 476; https://doi.org/10.3390/brainsci12040476 - 04 Apr 2022

Cited by 2 | Viewed by 2670

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). Therapy is currently limited to drugs that interfere with the immune system; treatment options that primarily mediate neuroprotection and prevent neurodegeneration are not available. Here, we studied the effects [...] Read more.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). Therapy is currently limited to drugs that interfere with the immune system; treatment options that primarily mediate neuroprotection and prevent neurodegeneration are not available. Here, we studied the effects of nimodipine on the rat cell line OLN-93, which resembles young mature oligodendrocytes. Nimodipine is a dihydropyridine that blocks the voltage-gated L-type calcium channel family members Ca_v1.2 and Ca_v1.3. Our data show that the treatment of OLN-93 cells with nimodipine induced the upregulation of myelin genes, in particular of proteolipid protein 1 (Plp1), which was confirmed by a significantly greater expression of PLP1 in immunofluorescence analysis and the presence of myelin structures in the cytoplasm at the ultrastructural level. Whole-genome RNA sequencing additionally revealed the upregulation of genes that are involved in neuroprotection, remyelination, and antioxidation pathways. Interestingly, the observed effects were independent of Ca_v1.2 and Ca_v1.3 because OLN-93 cells do not express these channels, and there was no measurable response pattern in patch-clamp analysis. Taking into consideration previous studies that demonstrated a beneficial effect of nimodipine on microglia, our data support the notion that nimodipine is an interesting drug candidate for the treatment of MS and other demyelinating diseases. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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13 pages, 1094 KiB

Open AccessEditor’s ChoiceArticle

Changes in the Serum Levels of Cytokines: IL-1β, IL-4, IL-8 and IL-10 in Depression with and without Posttraumatic Stress Disorder

by Ewa Ogłodek

Brain Sci. 2022, 12(3), 387; https://doi.org/10.3390/brainsci12030387 - 14 Mar 2022

Cited by 14 | Viewed by 2411

Abstract

Background: Both depressive disorders (DD) and post-traumatic stress disorders (PTSD) are caused by immune system dysfunction. Affected individuals show increased proinflammatory cytokine concentration levels. Also, it has been hypothesized that DD and PTSD might be associated with a generalized proinflammatory cytokine signature. The [...] Read more.

Background: Both depressive disorders (DD) and post-traumatic stress disorders (PTSD) are caused by immune system dysfunction. Affected individuals show increased proinflammatory cytokine concentration levels. Also, it has been hypothesized that DD and PTSD might be associated with a generalized proinflammatory cytokine signature. The study assessed the concentration of IL-1β, IL-4, IL-8 and IL-10 in depression alone and with PTSD. Methods: The study involved 460 participants. Out of them, 420 subjects comprised a study group and 40 subjects comprised a control group. Each study group consisted of 60 patients with mild depression (MD), moderate depression (MOD), severe depression (SeD), MD and PTSD (MD + PTSD), MOD and PTSD (MOD + PTSD), SeD and PTSD (SeD + PTSD), and with PTSD alone. All patients had serum concentration of IL-1β, IL-4, IL-8 and IL-10 measured with ELISA. Results: DD and PTSD are reflected in IL-1β, IL-4, IL-8 and IL-10 concentration levels. It was reported that mean levels of IL-1β, IL-4, IL-8 increase as depression became more severe. A regular decrease in IL-10 concentration levels was noted with the onset and exacerbation of depressive symptoms. Conclusion: The findings might be useful when considering chronic inflammation as a potential target or biomarker in depression and PTSD treatment. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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15 pages, 864 KiB

Open AccessArticle

Effect of Two Different Rehabilitation Approaches on Pulmonary Functional Tests, Neuromuscular Functions and Quality of Life in Juvenile Myasthenia Gravis: A Randomized Controlled Trial Study

by Rasha A. Mohamed, El Sayed H. Mohamed, Mohamed A. Basiouny, Ibrahim M. Hamoda, El Sayed M. Hanoura, Elbadawy I. Elhenedi and Abd El Aziz A. Sherief

Medicina 2022, 58(3), 374; https://doi.org/10.3390/medicina58030374 - 02 Mar 2022

Cited by 2 | Viewed by 3719

Abstract

Background and Objectives: Children with juvenile myasthenia gravis have a variety of symptoms, ranging from isolated intermittent ocular complaints to overall muscle weakness with or without respiratory insufficiency. This study aimed to investigate the efficacy of a specialized physical therapy with or [...] Read more.

Background and Objectives: Children with juvenile myasthenia gravis have a variety of symptoms, ranging from isolated intermittent ocular complaints to overall muscle weakness with or without respiratory insufficiency. This study aimed to investigate the efficacy of a specialized physical therapy with or without partial body weight supported treadmill training on pulmonary functional tests, neuromuscular functions, and quality of life. Materials and Methods: Thirty children, ranging in age from 13 to 16 years, were distributed randomly into two study groups (A or B). Both groups underwent a designed physical therapy program. In addition, group A underwent the partial body weight supported treadmill training. The treatment was conducted three times a week for 12 weeks successively. Pulmonary functional tests (FVC, FEV1, PEFR, and MVV), neuromuscular function tests (compound motor action potential, isometric muscle force of biceps brachii and rectus femoris, balance, walking endurance, and fatigue), and quality of life were measured before and after 12 successive weeks. Results: A significant improvement in all investigated variables were recorded in both groups in favor of group A. Conclusions: Both a specialized physical therapy and partial body weight supported treadmill training are effective in terms of enhancing pulmonary functional tests, neuromuscular functions, and quality of life. Partial body weight supported treadmill training is an excellent adjunctive to the physical therapy program. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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6 pages, 517 KiB

Open AccessCase Report

Acute Demyelinating Encephalomyelitis Post-COVID-19 Vaccination: A Case Report and Literature Review

by Khalid Al-Quliti, Ahmad Qureshi, Mohammed Quadri, Babar Abdulhameed, Alhanouf Alanazi and Rakan Alhujeily

Diseases 2022, 10(1), 13; https://doi.org/10.3390/diseases10010013 - 20 Feb 2022

Cited by 11 | Viewed by 4172

Abstract

New advancements in the medical community have rapidly occurred with the development of medical information across the globe during the COVID-19 pandemic. Several vaccine manufacturers were able to obtain clearance to administer vaccines in selected age groups and for those at high risk [...] Read more.

New advancements in the medical community have rapidly occurred with the development of medical information across the globe during the COVID-19 pandemic. Several vaccine manufacturers were able to obtain clearance to administer vaccines in selected age groups and for those at high risk for COVID-19 complications. As vaccines became more readily available, there was a significant effort supported by scientific information to get people vaccinated to boost herd immunity. Acute demyelinating encephalomyelitis (ADEM) is a rare autoimmune disease, causing demyelination in the brain and spinal cord, presenting as monophasic, acute-onset, and rapidly progressive multifocal neurological deficits. A wide variety of precipitating factors can trigger ADEM, and it has long been known to be a rare adverse event following some types of vaccinations including rabies, diphtheria–tetanus–polio, smallpox, measles, mumps, rubella, pertussis, influenza, and hepatitis B vaccines. Recently, ADEM has also been associated with COVID-19 infection and (very rarely) with COVID-19 vaccination. We have a 56-year-old female who was not known to have any medical issues. She voluntarily received her first COVID-19 vaccination (AstraZeneca) ten days after immunization; she developed weakness of the lower limbs and slurred speech. She tested negative for COVID-19, and a brain MRI showed T2-weighted white-matter hyperintense lesions suggesting acute demyelinating encephalomyelitis. She was managed with pulse-dose steroids, which resulted in a marked improvement in her symptoms, and discharged in a stable condition. Physicians should be aware of this neurological disorder and the management options for better patient care and outcomes. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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12 pages, 890 KiB

Open AccessArticle

Safety of Fingolimod in Patients with Multiple Sclerosis Switched from Natalizumab: Results from TRANSITION―A 2-Year, Multicenter, Observational, Cohort Study

by Helmut Butzkueven, Paul S. Giacomini, Stanley Cohan, Tjalf Ziemssen, Daniel Sienkiewicz, Ying Zhang, Yvonne Geissbühler, Diego Silva, Davorka Tomic, Harald Kropshofer and Maria Trojano

Brain Sci. 2022, 12(2), 215; https://doi.org/10.3390/brainsci12020215 - 04 Feb 2022

Cited by 2 | Viewed by 2526

Abstract

Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to [...] Read more.

Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to evaluate the safety of fingolimod over two years in patients with MS after switching from natalizumab in a real-world setting. The safety and effectiveness were assessed by monitoring serious and other adverse events (SAEs, AEs). We assessed effectiveness by recording relapses, Expanded Disability Status Scale (EDSS) scores, and MRI activity. Of 637 patients enrolled, 505 completed the study (mean age, 42 years). Overall, 72.8% and 12.7% experienced AEs and SAEs respectively. The most common AEs were fatigue, headache, and urinary tract infection; no cases of PML were observed. Fingolimod treatment resulted in low disease activity. Patients with ≤8 weeks washout period had a markedly lower risk of relapses (4.5%) than those with >8 weeks (51.4%). In patients switching from natalizumab to fingolimod, no new safety signals with overall low relapse activity were observed in patients with washout latencies of ≤8 weeks before fingolimod initiation. Fingolimod was found to be safe and effective in patients transitioning from natalizumab. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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12 pages, 2141 KiB

Open AccessSystematic Review

The Safety and Efficacy of Nusinersen in the Treatment of Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

by Kirellos Said Abbas, Mennatullah Mohamed Eltaras, Nahla Ahmed El-Shahat, Basel Abdelazeem, Mahmoud Shaqfeh and James Robert Brašić

Medicina 2022, 58(2), 213; https://doi.org/10.3390/medicina58020213 - 01 Feb 2022

Cited by 9 | Viewed by 4821

Abstract

Background and objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disease that leads to progressive proximal muscle weakness and muscle atrophy. To assess the beneficial and adverse effects of nusinersen, a promising intervention for SMA, we conducted a systematic search and meta-analysis [...] Read more.

Background and objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disease that leads to progressive proximal muscle weakness and muscle atrophy. To assess the beneficial and adverse effects of nusinersen, a promising intervention for SMA, we conducted a systematic search and meta-analysis of the published randomized control trials (RCTs) of nusinersen for SMA. Materials and methods: Utilizing the Preferred Reporting for Systematic Review and Meta-Analysis (PRISMA), we searched PubMed, Scopus, Web of Science, Cochrane Central, and Clinicaltrials.gov from inception to 22 July 2021. Results: Three RCTs satisfying the inclusion and exclusion criteria covered 274 patients: 178 patients in the nusinersen group. Our results show a significant risk difference (RD) in the motor milestone response (RD: 0.51; 95% CI: 0.39, 0.62; p < 0.00001) and improvement in the HINE-2 score (RD: 0.26; 95% CI: 0.12, 0.40; p < 0.0003) in the nusinersen group compared to the control group. Moreover, a significant decrease in the risk ratio (RR) for severe adverse events (RR: 0.72; 95% CI: 0.57, 0.92; p = 0.007) and any adverse event leading to treatment discontinuation (RR: 0.40; 95% CI: 0.22, 0.74; p = 0.004) was observed. An insignificant result was found for any adverse effects (RR: 0.93; 95% CI: 0.97, 1.01; p = 0.14) and for serious adverse effects (RR: 0.81; 95% CI: 0.60, 1.07; p = 0.14). Conclusions: This review provides evidence that nusinersen treatment was effective in treatment for infants with SMA and was associated with fewer severe adverse events; however, more RCTs are needed to establish evidence. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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13 pages, 1221 KiB

Open AccessArticle

Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome

by Bruna L. Zampieri and Alberto C. S. Costa

Brain Sci. 2022, 12(1), 83; https://doi.org/10.3390/brainsci12010083 - 06 Jan 2022

Cited by 5 | Viewed by 2205

Abstract

For many decades, neurons have been the central focus of studies on the mechanisms underlying the neurodevelopmental and neurodegenerative aspects of Down syndrome (DS). Astrocytes, which were once thought to have only a passive role, are now recognized as active participants of a [...] Read more.

For many decades, neurons have been the central focus of studies on the mechanisms underlying the neurodevelopmental and neurodegenerative aspects of Down syndrome (DS). Astrocytes, which were once thought to have only a passive role, are now recognized as active participants of a variety of essential physiological processes in the brain. Alterations in their physiological function have, thus, been increasingly acknowledged as likely initiators of or contributors to the pathogenesis of many nervous system disorders and diseases. In this study, we carried out a series of real-time measurements of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in hippocampal astrocytes derived from neonatal Ts65Dn and euploid control mice using a Seahorse XFp Flux Analyzer. Our results revealed a significant basal OCR increase in neonatal Ts65Dn astrocytes compared with those from control mice, indicating increased oxidative phosphorylation. ECAR did not differ between the groups. Given the importance of astrocytes in brain metabolic function and the linkage between astrocytic and neuronal energy metabolism, these data provide evidence against a pure “neurocentric” vision of DS pathophysiology and support further investigations on the potential contribution of disturbances in astrocytic energy metabolism to cognitive deficits and neurodegeneration associated with DS. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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22 pages, 761 KiB

Open AccessEditor’s ChoiceReview

Citicoline and COVID-19-Related Cognitive and Other Neurologic Complications

by Yuda Turana, Michael Nathaniel, Robert Shen, Soegianto Ali and Rajender R. Aparasu

Brain Sci. 2022, 12(1), 59; https://doi.org/10.3390/brainsci12010059 - 31 Dec 2021

Cited by 13 | Viewed by 7536

Abstract

With growing concerns about COVID-19’s hyperinflammatory condition and its potentially damaging impact on the neurovascular system, there is a need to consider potential treatment options for managing short- and long-term effects on neurological complications, especially cognitive function. While maintaining adequate structure and function [...] Read more.

With growing concerns about COVID-19’s hyperinflammatory condition and its potentially damaging impact on the neurovascular system, there is a need to consider potential treatment options for managing short- and long-term effects on neurological complications, especially cognitive function. While maintaining adequate structure and function of phospholipid in brain cells, citicoline, identical to the natural metabolite phospholipid phosphatidylcholine precursor, can contribute to a variety of neurological diseases and hypothetically toward post-COVID-19 cognitive effects. In this review, we comprehensively describe in detail the potential citicoline mechanisms as adjunctive therapy and prevention of COVID-19-related cognitive decline and other neurologic complications through citicoline properties of anti-inflammation, anti-viral, neuroprotection, neurorestorative, and acetylcholine neurotransmitter synthesis, and provide a recommendation for future clinical trials. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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14 pages, 291 KiB

Open AccessFeature PaperReview

Cognitive Rehabilitation in Multiple Sclerosis in the Period from 2013 and 2021: A Narrative Review

by Bruno Brochet

Brain Sci. 2022, 12(1), 55; https://doi.org/10.3390/brainsci12010055 - 30 Dec 2021

Cited by 11 | Viewed by 2444

Abstract

Background: In recent years, several blinded randomized controlled trials (RCT) have been conducted on cognitive rehabilitation (CR) in adults with multiple sclerosis (MS). Objective: To review all blinded RCTs on CR in MS published since 2013. Methods: The National Library of Medicine database [...] Read more.

Background: In recent years, several blinded randomized controlled trials (RCT) have been conducted on cognitive rehabilitation (CR) in adults with multiple sclerosis (MS). Objective: To review all blinded RCTs on CR in MS published since 2013. Methods: The National Library of Medicine database (Medline) and PSYCINFO were searched using the keywords MS and CR or cognitive training or NP rehabilitation or memory rehabilitation or attention rehabilitation. Results: After the exclusion of some papers not specifically focused on CR, a final list of 26 studies was established. The papers belong to three main categories: individual specific rehabilitation (8studies), group rehabilitation (4 studies), and computerized training (CT) (14 studies), while one study combined group rehabilitation and CT. Among the individual rehabilitation studies, 5 were devoted to memory, and most of the 19 other selected studies were about several cognitive domains. Most of the studies mainly concerned RRMS patients, except for 2 studies that were carried out exclusively in progressive forms. Despite the methodological limitations of some studies and the great heterogeneity of the protocols, the results are generally in favor of the efficacy of CR in neuropsychological tests. Conclusion: Recent blinded RCTs about CR in MS show promising results. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

14 pages, 4338 KiB

Open AccessArticle

Mahanimbine Improved Aging-Related Memory Deficits in Mice through Enhanced Cholinergic Transmission and Suppressed Oxidative Stress, Amyloid Levels, and Neuroinflammation

by Vasudevan Mani, Nur Syamimi Mohd Azahan, Kalavathy Ramasamy, Siong Meng Lim and Abu Bakar Abdul Majeed

Brain Sci. 2022, 12(1), 12; https://doi.org/10.3390/brainsci12010012 - 23 Dec 2021

Cited by 5 | Viewed by 2805

Abstract

Murraya koenigii leaves contain mahanimbine, a carbazole alkaloid, reported with improving cholinergic neuronal transmission and reducing neuroinflammation in the CNS. The current research investigated the effects of mahanimbine on age-related memory deficits, oxidative stress, cholinergic dysfunction, amyloid formation, and neuroinflammation in aged mice [...] Read more.

Murraya koenigii leaves contain mahanimbine, a carbazole alkaloid, reported with improving cholinergic neuronal transmission and reducing neuroinflammation in the CNS. The current research investigated the effects of mahanimbine on age-related memory deficits, oxidative stress, cholinergic dysfunction, amyloid formation, and neuroinflammation in aged mice (16 months old). Mahanimbine was administered (1 and 2 mg/kg, p.o.) daily to groups of aged mice for 30 days. The Morris water maze (MWM) task was performed to study spatial learning (escape latency (EL) and swimming distance (SD)) and memory (probe test). The levels of malondialdehyde (MDA), glutathione (GSH), acetylcholine (ACh), acetylcholinesterase (AChE), β-amyloid (Aβ_1-40 and Aβ_1-42), β-secretase (BACE-1), as well as neuroinflammation markers (total cyclooxygenase (COX) and COX-2 expression), were measured from the isolated brain. Mahanimbine reduced the EL time and SD in the MWM test. From the probe trial, the mahanimbine-treated group spent more time in the targeted quadrant related to the age-matched control, which indicated the enhancement of memory retention. From the biochemical tests, the treatment decreased MDA, AChE, Aβ_1-40, and Aβ_1-42, BACE-1, total COX activity, and COX-2 expression. It also raised the brain GSH and ACh levels in aged mice compared to age-matched control. These results have supported the reversal of memory dysfunctions by mahanimbine in aged mice and hypothesized that it could be a potential target to treat age-related neurodegenerative disease. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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12 pages, 1779 KiB

Open AccessArticle

Intake of Vitamin D in Patients with Multiple Sclerosis in the Valencian Region and Its Possible Relationship with the Pathogenesis of the Disease

by Jose Enrique de la Rubia Ortí, María Faus García, Eraci Drehmer, Esther Navarro-Illana, Julia Casani-Cubel, Belén Proaño, Claudia Emmanuela Sanchis-Sanchis and Juan Doménech Escrivá

Life 2021, 11(12), 1380; https://doi.org/10.3390/life11121380 - 10 Dec 2021

Cited by 1 | Viewed by 2052

Abstract

(1) Background: Multiple sclerosis (MS) is a neurodegenerative disease characterized by pronounced inflammation. Interleukin 6 (IL-6) is an accurate marker for the state of inflammation, due to the high levels of this cytokine linked to the pathogenesis of the disease. These IL-6 levels [...] Read more.

(1) Background: Multiple sclerosis (MS) is a neurodegenerative disease characterized by pronounced inflammation. Interleukin 6 (IL-6) is an accurate marker for the state of inflammation, due to the high levels of this cytokine linked to the pathogenesis of the disease. These IL-6 levels could be lowered with an adequate dietary intake of vitamin D. The objective of the study was to determine the level of vitamin D ingested in a sample of patients with MS in the Valencian region (Spain), to establish the vitamin sources, and the possible link between the intake of vitamin D and the pathogenesis of the disease through a relationship with the level of IL-6. (2) Materials and Methods: A descriptive pilot study was carried out with 39 patients with MS in the Valencian region. The dietary-nutritional anamnesis was gained through the food frequency questionnaire (FFQ) and a food diary. Diet and eating habits were analyzed through the Easy Diet (version: 2.0.1)—Consultation Management Program^® software, and IL-6 levels in blood by ELISA technique. (3) Results: The results show a low intake of vitamin D, which is significantly and negatively related to the intake of proteins of vegetable origin, which are consumed in less quantity than proteins of animal origin, and significantly and negatively related with the high blood levels of IL-6, possibly as a consequence of the high intake of fats, mainly unsaturated. (4) Conclusions: MS patients in the Valencian region ingest little vitamin D related to low intake of vegetable protein, which would explain the high levels of IL-6 linked to the high intake of mainly saturated fats. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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13 pages, 2040 KiB

Open AccessArticle

Neuroprotective Effect of Clobenpropit against Lipopolysaccharide-Induced Cognitive Deficits via Attenuating Neuroinflammation and Enhancing Mitochondrial Functions in Mice

by Vasudevan Mani, Minhajul Arfeen, Hussein M. Ali, Abdel-Moneim Hafez Abdel-Moneim, Maha Aldubayan and Ahmad Alhowail

Brain Sci. 2021, 11(12), 1617; https://doi.org/10.3390/brainsci11121617 - 08 Dec 2021

Cited by 7 | Viewed by 2376

Abstract

Clobenpropit (CLO), an antagonist on histamine H₃ receptors (HH3R), has been shown to protect NMDA-induced neuronal necrosis in cortical neuronal cell culture from rats. In this work, we explored its potential on lipopolysaccharide (LPS)-induced memory deficits, neuroinflammation, and mitochondrial dysfunction in mice. [...] Read more.

Clobenpropit (CLO), an antagonist on histamine H₃ receptors (HH3R), has been shown to protect NMDA-induced neuronal necrosis in cortical neuronal cell culture from rats. In this work, we explored its potential on lipopolysaccharide (LPS)-induced memory deficits, neuroinflammation, and mitochondrial dysfunction in mice. CLO (1 and 3 mg/kg, p.o.) was treated continually for 30 days, and neurotoxicity was induced by four doses of LPS (250 µg/kg, i.p.). The radial arm maze (RAM) was used to access memory behaviors. After the REM test, brain tissue was collected from each mouse to estimate pro-inflammatory cytokines (TNFα and IL6), anti-inflammatory cytokines (TGF-β1 and IL-10), cyclooxygenase-2 (COX 2), and mitochondrial respiratory chain complex (MRCC- I, II and IV) enzymes. CLO treatment reversed the LPS-induced behavioral deficits by a significant reduction in time taken to consume all five bites (TTB), working memory error (WME), and reference memory error (REM) in the REM test. Regarding neuroinflammation, it attenuated the release of COX, TNF-α, and IL-6, and augmented TGF-β1 and IL-10 levels in the brain. Reversal of LPS-induced brain MRCC (I, II, and IV) levels also resulted with CLO treatment. From these findings, CLO promises neuroprotection against LPS-induced cognitive deficits by ameliorating neuroinflammation and restoring the MRCC enzymes in mice. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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10 pages, 320 KiB

Open AccessArticle

MOBP rs616147 Polymorphism and Risk of Amyotrophic Lateral Sclerosis in a Greek Population: A Case-Control Study

by Ioannis Liampas, Vasileios Siokas, Athina-Maria Aloizou, Christos Bakirtzis, Zisis Tsouris, Anastasia Nousia, Grigorios Nasios, Dimitra Papadimitriou, Panagiotis Liakos, Dimitrios P. Bogdanos, Georgios M. Hadjigeorgiou and Efthimios Dardiotis

Medicina 2021, 57(12), 1337; https://doi.org/10.3390/medicina57121337 - 07 Dec 2021

Cited by 3 | Viewed by 2267

Abstract

Background and Objectives: To date, only one study has investigated the association between the rs616147 polymorphism of the Myelin-associated Oligodendrocyte Basic Protein (MOBP) locus and Amyotrophic Lateral Sclerosis (ALS). Materials and Methods: A case-control study was performed. Patients with definite sporadic [...] Read more.

Background and Objectives: To date, only one study has investigated the association between the rs616147 polymorphism of the Myelin-associated Oligodendrocyte Basic Protein (MOBP) locus and Amyotrophic Lateral Sclerosis (ALS). Materials and Methods: A case-control study was performed. Patients with definite sporadic ALS were prospectively and consecutively recruited from the inpatient and outpatient clinics of the Neurology Department of the General University Hospital of Larissa, Central Greece. Community based, age and sex matched healthy individuals with a free personal and family history constituted the control group. Results: A total of 155 patients with definite sporadic ALS and an equal number of healthy controls were genotyped. The power of our sample size was slightly above 80% and MOBP rs616147 was determined to be in Hardy-Weinberg Equilibrium among healthy participants (p = 1.00). According to the univariate analysis, there was no significant relationship between rs616147 and ALS [log-additive OR = 0.85 (0.61, 1.19), over-dominant OR = 0.73 (0.46, 1.15), recessive OR = 1.02 (0.50, 2.09), dominant OR = 0.74 (0.47, 1.16), co-dominant OR₁ = 0.71 (0.44, 1.14) and co-dominant OR₂ = 0.88 (0.42, 1.84). Additionally, the effect of rs616147 on the age of ALS onset was determined insignificant using both unadjusted and adjusted (sex, site of onset) cox-proportional models. Finally, rs616147 was not related to the site of ALS onset. Conclusions: Our study is the first to report the absence of an association between MOBP rs616147 and ALS among individuals of Greek ancestry. Additional, larger nationwide and multi-ethnic studies are warranted to shed light on the connection between rs616147 and ALS. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

25 pages, 2314 KiB

Open AccessSystematic Review

The Neuroprotective Effects of Cannabis-Derived Phytocannabinoids and Resveratrol in Parkinson’s Disease: A Systematic Literature Review of Pre-Clinical Studies

by Samay Prakash and Wayne G. Carter

Brain Sci. 2021, 11(12), 1573; https://doi.org/10.3390/brainsci11121573 - 28 Nov 2021

Cited by 11 | Viewed by 4130

Abstract

Currently, there are no pharmacological treatments able to reverse nigral degeneration in Parkinson’s disease (PD), hence the unmet need for the provision of neuroprotective agents. Cannabis-derived phytocannabinoids (CDCs) and resveratrol (RSV) may be useful neuroprotective agents for PD due to their anti-oxidative and [...] Read more.

Currently, there are no pharmacological treatments able to reverse nigral degeneration in Parkinson’s disease (PD), hence the unmet need for the provision of neuroprotective agents. Cannabis-derived phytocannabinoids (CDCs) and resveratrol (RSV) may be useful neuroprotective agents for PD due to their anti-oxidative and anti-inflammatory properties. To evaluate this, we undertook a systematic review of the scientific literature to assess the neuroprotective effects of CDCs and RSV treatments in pre-clinical in vivo animal models of PD. The literature databases MEDLINE, EMBASE, PsychINFO, PubMed, and Web of Science core collection were systematically searched to cover relevant studies. A total of 1034 publications were analyzed, of which 18 met the eligibility criteria for this review. Collectively, the majority of PD rodent studies demonstrated that treatment with CDCs or RSV produced a significant improvement in motor function and mitigated the loss of dopaminergic neurons. Biochemical analysis of rodent brain tissue suggested that neuroprotection was mediated by anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms. This review highlights the neuroprotective potential of CDCs and RSV for in vivo models of PD and therefore suggests their potential translation to human clinical trials to either ameliorate PD progression and/or be implemented as a prophylactic means to reduce the risk of development of PD. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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17 pages, 1573 KiB

Open AccessArticle

Advanced Parkinson’s Disease Treatment Simplification and Long-Term Outcomes with Levodopa Carbidopa Intestinal Gel: COSMOS Romanian Subanalysis

by Mihaela Adriana Simu, Dragoș Cătălin Jianu, Adriana Octaviana Dulamea, Viorelia Adelina Constantin, Diana Popescu, Juan Carlos Parra and József Attila Szász

Brain Sci. 2021, 11(12), 1566; https://doi.org/10.3390/brainsci11121566 - 27 Nov 2021

Cited by 6 | Viewed by 1857

Abstract

The aim of the COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS) was to assess the use of levodopa/carbidopa intestinal gel (LCIG) as monotherapy in patients with advanced Parkinson’s disease (APD) in routine clinical practice. COSMOS was an international [...] Read more.

The aim of the COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS) was to assess the use of levodopa/carbidopa intestinal gel (LCIG) as monotherapy in patients with advanced Parkinson’s disease (APD) in routine clinical practice. COSMOS was an international observational study with one cross-sectional visit and retrospective data collection. In Romania, 95 adult patients with APD on LCIG treatment for at least 12 months were enrolled and stratified according to their LCIG therapy after 12 months: monotherapy (without any add-on PD medication), monotherapy with night PD medication and LCIG + add-on medication. Compared to the moment of LCIG initiation, the percentage of patients on monotherapy increased at three months after LCIG initiation and remained constant up to 12 months, when 30.5% of the patients were on LCIG monotherapy and 11.6% were on monotherapy with night medication. “Off” time and “On” time with dyskinesia decreased from LCIG initiation to patient visit in all groups. LCIG monotherapy with or without night medication may provide a simplified treatment option for selected APD patients, with long-term efficacy similar to that of LCIG plus add-on medication. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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11 pages, 13709 KiB

Open AccessArticle

Relationship between Amyloid-β Deposition and the Coupling between Structural and Functional Brain Networks in Patients with Mild Cognitive Impairment and Alzheimer’s Disease

by Hui Zhang, Edward S. Hui, Peng Cao and Henry K. F. Mak

Brain Sci. 2021, 11(11), 1535; https://doi.org/10.3390/brainsci11111535 - 19 Nov 2021

Cited by 6 | Viewed by 2100

Abstract

Previous studies have demonstrated that the accumulation of amyloid-β (Aβ) pathologies has distinctive stage-specific effects on the structural and functional brain networks along the Alzheimer’s disease (AD) continuum. A more comprehensive account of both types of brain network may provide a better characterization [...] Read more.

Previous studies have demonstrated that the accumulation of amyloid-β (Aβ) pathologies has distinctive stage-specific effects on the structural and functional brain networks along the Alzheimer’s disease (AD) continuum. A more comprehensive account of both types of brain network may provide a better characterization of the stage-specific effects of Aβ pathologies. A potential candidate for this joint characterization is the coupling between the structural and functional brain networks (SC-FC coupling). We therefore investigated the effect of Aβ accumulation on global SC-FC coupling in patients with mild cognitive impairment (MCI), AD, and healthy controls. Patients with MCI were dichotomized according to their level of Aβ pathology seen in ¹⁸F-flutemetamol PET-CT scans—namely, Aβ-negative and Aβ-positive. Our results show that there was no difference in global SC-FC coupling between different cohorts. During the prodromal AD stage, there was a significant negative correlation between the level of Aβ pathology and the global SC-FC coupling of MCI patients with positive Aβ, but no significant correlation for MCI patients with negative Aβ. During the AD dementia stage, the correlation between Aβ pathology and global SC-FC coupling in patients with AD was positive. Our results suggest that Aβ pathology has distinctive stage-specific effects on global coupling between the structural and functional brain networks along the AD continuum. Full article

(This article belongs to the Topic Mechanisms and Treatments of Neurodegenerative Diseases)

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