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Background and Objective: Exercise and physical activity are the most impressive factors in consumption of cellular energy sources which may bring about some changes in key peptides that are effective in adjusting and balancing energy. The purpose of this study was to investigate the probable changes of plasma Neuropeptide Y (NPY) and Ghrelin concentrations after 8 weeks of exercise with different intensities on fat male rats. Materials and Methods: This experimental study was conducted on 75 adult male rats about 2 months old selected randomly from a laboratory. The rats fattened via stimulating their appetite with lettuce and other vegetables for a month. Their average weight changed from 240±15 gr to 320±20 gr. Then, they were divided into three groups of control (n=25), exercise group with moderate intensity ((n=25) and exercise group with high intensity (n=25). The training program of the study consisted of running three times in a week on Rodents' treadmill for 8 weeks. Results: The results showed that after 8 weeks of high intensity exercises, NPY and Ghrelin levels increased significantly (p<0.05), but moderate intensity exercises did not have meaningful effect on NPY and Ghrelin levels. Conclusion: The results of this research shows that exercise causes negative balance of energy in rats, increase their weight and fatten them. To compensate for this negative balance of energy, NPY hormone and Ghrelin levels are increased. [ABSTRACT FROM AUTHOR]

Neurodegeneration in Alzheimer's disease (AD) is known to be mostly driven by tau neurofibrillary tangles. However, both tau and neurodegeneration exhibit variability in their distribution across the brain and among individuals, and the relationship between tau and neurodegeneration might be influenced by several factors. I aimed to map local molecular and connectivity characteristics that affect the association between tau pathology and neurodegeneration. The current study was conducted on the cross-sectional tau-PET and longitudinal T1-weighted MRI scan data of 186 participants from the ADNI dataset including 71 cognitively unimpaired (CU) and 115 mild cognitive impairment (MCI) individuals. Furthermore, the normative molecular profile of a region was defined using neurotransmitter receptor densities, gene expression, T1w/T2w ratio (myelination), FDG-PET (glycolytic index, glucose metabolism, and oxygen metabolism), and synaptic density. I found that the excitatory-inhibitory (E:I) ratio, myelination, synaptic density, glycolytic index, and functional connectivity are linked with deviation in the relationship between tau and neurodegeneration. Furthermore, there was spatial similarity between tau pathology and glycolytic index, synaptic density, and functional connectivity across brain regions. The current study demonstrates that the regional susceptibility to tau-related neurodegeneration is associated with specific molecular and connectomic characteristics of the affected neural systems. I found that the molecular and connectivity architecture of the human brain is linked to the different effects of tau pathology on downstream neurodegeneration., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta plaques initiated approximately 2 decades before the symptom onset followed by build-up and spreading of neurofibrillary tau aggregates. Although it has been suggested that the amyloid-beta amplifies tau spreading the observed spatial disparity called it into question. Yet, it is unclear how neocortical amyloid-beta remotely affects early pathological tau, triggering it to leave the early formation area, and how amyloid-beta facilitates tau aggregate spreading throughout cortical regions. I aimed to investigate how amyloid-beta can facilitate tau spreading through neuronal connections in the Alzheimer's disease pathological process by combining functional magnetic resonance imaging normative connectomes and longitudinal in vivo molecular imaging data. In total, the imaging data of 317 participants, including 173 amyloid-beta-negative non-demented and 144 amyloid-beta -positive non-demented participants, have entered the study from Alzheimer's Disease Neuroimaging Initiative. Furthermore, normative resting-state functional magnetic resonance imaging connectomes were used to model tau spreading through functional connections. It was observed that the amyloid-beta in regions with the highest deposition (amyloid-beta epicenter) is remotely associated with connectivity-based spreading of tau pathology. Moreover, amyloid-beta in regions that exhibit the highest tau pathology (tau epicenter) is associated with increased connectivity-based tau spreading to non-epicenter regions. The findings provide a further explanation for a long-standing question of how amyloid-beta can affect tau aggregate spreading through neuronal connections despite spatial incongruity. The results suggest that amyloid-beta pathology can remotely and locally facilitate connectivity-based spreading of tau aggregates., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Several studies have shown the different relationships between cognitive functions and structural magnetic resonance imaging (MRI) measurements in people with multiple sclerosis (pwMS). However, there is an ongoing debate regarding the magnitude of correlation between MRI measurements and specific cognitive function tests. This systematic review and meta-analysis aimed to synthesize the most consistent correlations between MRI measurements and cognitive function in pwMS., Methods: PubMed/MEDLINE, Embase, Scopus, and Web of Science databases were systematically searched up to February 2023, to find relevant data. The search utilized syntax and medical subject headings (MeSH) relevant to cognitive performance tests and MRI measurements in pwMS. The R software version 4.3.3 with random effect models was used to estimate the pooled effect sizes., Results: 13,559 studies were reviewed, of which 136 were included. The meta-analyses showed that thalamic volume had the most significant correlations with Symbol Digit Modalities Test (SDMT) r = 0.47 (95 % CI: 0.39 to 0.56, p < 0.001, I 2 = 88 %), Brief Visual Memory Test-Revised-Total Recall (BVMT-TR) r = 0.51 (95 % CI: 0.36 to 0.66, p < 0.001, I 2 = 81 %), California Verbal Learning Test-II-Total Recall (CVLT-TR) r = 0.47 (95 % CI: 0.34 to 0.59, p < 0.001, I 2 = 69 %,), and Delis-Kaplan Executive Function System (DKEFS) r = 0.48 (95 % CI: 0.34 to 0.63, p < 0.001, I 2 = 22 %,)., Conclusion: We conclude that thalamic volume exhibits highest relationships with information processing speed (IPS), visuospatial learning-memory, verbal learning-memory, and executive function in pwMS. A comprehensive understanding of the intricacies of the mechanisms underpinning this association requires additional research., Competing Interests: Declaration of competing interest Omid Mirmosayyeb, Fardin Nabizadeh, Elham Moases Ghaffary, Mohammad Yazdan Panah, and Dejan Jakimovski have nothing to disclose. Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Protembis, Janssen, 415 Capital, and Novartis for speaking and consultant fees. He received financial support for research activities from Sanofi, Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, CorEvitas, Protembis and V-WAVE Medical. Bianca Weinstock-Guttman received honoraria as a speaker and/or as a consultant for Biogen Idec, Teva Pharmaceuticals, EMD Serono, Genzyme, Sanofi, Genentech, Novartis, Celgene/BMS, Janssen and Horizon Dr Weinstock-Guttman received research funds from Biogen Idec, EMD Serono, Genzyme, Genentech, Sanofi, Novartis. Ralph HB. Benedict has received consultation or speaking fees from Bristol Myer Squibb, Biogen, Merck, EMD Serono, Roche, Verasci, Immune Therapeutics, Novartis, and Sanofi- Genzyme., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Understanding the exact pathophysiological mechanisms underlying the involvement of triggering receptor expressed on myeloid cells 2 (TREM2) related microglia activation is crucial for the development of clinical trials targeting microglia activation at different stages of Alzheimer's disease (AD). Given the contradictory findings in the literature, it is imperative to investigate the longitudinal alterations in cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) levels as a marker for microglia activation, and its potential association with AD biomarkers, in order to address the current knowledge gap. In this study, we aimed to assess the longitudinal changes in CSF sTREM2 levels within the framework of the A/T/N classification system for AD biomarkers and to explore potential associations with AD pathological features, including the presence of amyloid-beta (Aβ) plaques and tau aggregates. The baseline and longitudinal (any available follow-up visit) CSF sTREM2 levels and processed tau-PET and Aβ-PET data of 1001 subjects were recruited from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A+ /TN+ , A+ /TN- , A- /TN+ , and A- /TN- . Linear regression analyses were conducted to assess the relationship between CSF sTREM2 with cognitive performance, tau and Aβ-PET adjusting for age, gender, education, and APOE ε4 status. Based on our analysis there was a significant difference in baseline and rate of change of CSF sTREM2 between ATN groups. While there was no association between baseline CSF sTREM2 and cognitive performance (ADNI-mem), we found that the rate of change of CSF sTREM2 is significantly associated with cognitive performance in the entire cohort but not the ATN groups. We found that the baseline CSF sTREM2 is significantly associated with baseline tau-PET and Aβ-PET rate of change only in the A+ /TN+ group. A significant association was found between the rate of change of CSF sTREM2 and the tau- and Aβ-PET rate of change only in the A+ /TN- group. Our study suggests that the TREM2-related microglia activation and their relations with AD markers and cognitive performance vary the in presence or absence of Aβ and tau pathology. Furthermore, our findings revealed that a faster increase in the level of CSF sTREM2 might attenuate future Aβ plaque formation and tau aggregate accumulation only in the presence of Aβ pathology., (© 2024. The Author(s).)

Background: There is a lack of enough evidence regarding the epidemiology of Young-onset Parkinson's disease (YOPD) which is needed by clinicians and healthcare policymakers., Aim: Herein, in this systematic review and meta-analysis, we aimed to estimate the global prevalence and incidence rates of YOPD., Methods: We searched the literature in PubMed, Scopus, and Web of Science in May 2022. We included retrospective, prospective, cross-sectional observational population-based studies that reported the prevalence or incidence of PD in individuals younger than 40 years with known diagnostic criteria., Results: After two-step screening, 50 studies were eligible to be included in our study. The age-standardized prevalence of YOPD was 10.2 per 100,000 persons globally while it was 14.7 per 100,000 population in European countries. Age-standardized prevalence estimates for 5-year age bands showed that the YOPD prevalence estimates varied from 6.1 per 100,000 population in the group aged 20-24 to 16.1 per 100,000 population in the group aged 35-39. Also, the age-standardized incidence of YOPD was 1.3 per 100,000 person-years population worldwide and 1.2 per 100,000 person-years in the European population., Conclusion: Based on this systematic review and meta-analysis, the overall prevalence of YOPD is 10.2 per 100,000 population, although estimates of the prevalence and incidence in low-income countries remain scarce. To improve monitoring and certain diagnoses of YOPD, healthcare providers and policymakers should be aware that much more effective tools are required., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Alzheimer's disease may be conceptualized as a 'disconnection syndrome', characterized by the breakdown of neural connectivity within the brain as a result of amyloid-beta plaques, tau neurofibrillary tangles and other factors leading to progressive degeneration and shrinkage of neurons, along with synaptic dysfunction. It has been suggested that misfolded tau proteins spread through functional connections (known as 'prion-like' properties of tau). However, the local effect of tau spreading on the synaptic function and communication between regions is not well understood. I aimed to investigate how the spreading of tau aggregates through connections can locally influence functional connectivity. In total, the imaging data of 211 participants including 117 amyloid-beta-negative non-demented and 94 amyloid-beta-positive non-demented participants were recruited from the Alzheimer's Disease Neuroimaging Initiative. Furthermore, normative resting-state functional MRI connectomes were used to model tau spreading through functional connections, and functional MRI of the included participants was used to determine the effect of tau spreading on functional connectivity. I found that lower functional connectivity to tau epicentres is associated with tau spreading through functional connections in both amyloid-beta-negative and amyloid-beta-positive participants. Also, amyloid-beta-PET in tau epicentres mediated the association of tau spreading and functional connectivity to epicentres suggesting a partial mediating effect of amyloid-beta deposition in tau epicentres on the local effect of tau spreading on functional connectivity. My findings provide strong support for the notion that tau spreading through connection is locally associated with disrupted functional connectivity between tau epicentre and non-epicentre regions independent of amyloid-beta pathology. Also, I defined several groups based on the relationship between tau spreading and functional disconnection, which provides quantitative assessment to investigate susceptibility or resilience to functional disconnection related to tau spreading. I showed that amyloid-beta, other copathologies and the apolipoprotein E epsilon 4 allele can be a leading factor towards vulnerability to tau relative functional disconnection., Competing Interests: The author reports no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Frontal variant Alzheimer's disease (AD) manifests with either behavioral or dysexecutive syndromes. Recent efforts to gain a deeper understanding of this phenotype have led to a re-conceptualization of frontal AD. Behavioral (bAD) and dysexecutive (dAD) phenotypes could be considered subtypes, as suggested by both clinical and neuroimaging studies. In this review, we focused on imaging studies to highlight specific brain patterns in these two uncommon clinical AD phenotypes. Although studies did not compare directly these two variants, a common epicenter located in the frontal cortex could be inferred. On the contrary, 18 F -FDG-PET findings suggested differing metabolic patterns, with bAD showing specific involvement of frontal regions and dAD exhibiting widespread alterations. Structural MRI findings confirmed this pattern, suggesting that degeneration might involve neural circuits associated with behavioral control in bAD and attentional networks in dAD. Furthermore, molecular imaging has identified different neocortical tau distribution in bAD and dAD patients compared to typical AD patients, although the distribution is remarkably heterogeneous. In contrast, Aβ deposition patterns are less differentiated between these atypical variants and typical AD. Although preliminary, these findings underscore the complexity of AD frontal phenotypes and suggest that they represent distinct entities. Further research is essential to refine our understanding of the pathophysiological mechanisms in frontal AD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: Recent studies have shown that gut microbiota can affect the development of Alzheimer's disease (AD) through various mechanisms. Bile acids (BAs), which are the final byproducts of cholesterol metabolism created through both the human body and gut microbiome, appear to be influenced by gut microbiota and may impact AD pathological characteristics such as the accumulation of tau and amyloid-β. We aimed to investigate the associations between various serum BAs and CSF biomarkers (including Aβ, total tau, and p-tau). Additionally, we sought to examine the longitudinal changes in brain Aβ and tau through PET imaging in relation to BAs profile., Methods: The data of 828 subjects including 491 diagnosed with mild cognitive impairment (MCI), 119 patients diagnosed with AD, and 267 cognitively normal (CN) participants were obtained from ADNI. The baseline and longitudinal [ 18 F] florbetapir and [ 18 F] flortaucipir PET standard uptake value ratios (SUVR) measures were obtained to assess the accumulation of tau and Aβ. Moreover, baseline levels of serum BAs and CSF Aβ1-42, tau, and p-tau were used., Results: After FDR correction we observed that five BAs level and relevant calculated ratios were associated with CSF p-tau and tau, three with CSF Aβ1-42. Furthermore, three BAs level and relevant calculated ratios were associated with the tau-PET rate of change, and two with the Aβ rate of change., Conclusion: The findings from our study suggest a correlation between altered profiles of BAs and CSF and imaging biomarkers associated with AD. These results provide supporting evidence for the link between the gut microbiome and the pathological features of AD., (© 2024. The Author(s).)

Background: Progranulin is an anti-inflammatory protein that plays an essential role in the synapse function and the maintenance of neurons in the central nervous system (CNS). It has been shown that the CSF level of progranulin increases in Alzheimer's disease (AD) patients and is associated with the deposition of amyloid-beta (Aβ) and tau in the brain tissue. In this study, we aimed to assess the longitudinal changes in cerebrospinal fluid (CSF) progranulin levels during different pathophysiological stages of AD and investigate associated AD pathologic features., Methods: We obtained the CSF and neuroimaging data of 1001 subjects from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A + /TN + , A + /TN-, A-/TN + , and A-/TN-., Results: Based on our analysis there was a significant difference in CSF progranulin (P = 0.001) between ATN groups. Further ANOVA analysis revealed that there was no significant difference in the rate of change of CSF-progranulin ATN groups. We found that the rate of change of CSF progranulin was associated with baseline Aβ-PET only in the A-/TN + group. A significant association was found between the rate of change of CSF progranulin and the Aβ-PET rate of change only in A-/TN +  CONCLUSION: Our findings revealed that an increase in CSF progranulin over time is associated with faster formation of Aβ plaques in patients with only tau pathology based on the A/T/N classification (suspected non-Alzheimer's pathology). Together, our findings showed that the role of progranulin-related microglial activity on AD pathology can be stage-dependent, complicated, and more prominent in non-AD pathologic changes. Thus, there is a need for further studies to consider progranulin-based therapies for AD treatment., (© 2024. The Author(s).)

Background: In this systematic review and meta-analysis, we aimed to investigate the correlation between disability in patients with Multiple sclerosis (MS) measured by the Expanded Disability Status Scale (EDSS) and brain Magnetic Resonance Imaging (MRI) features to provide reliable results on which characteristics in the MRI can predict disability and prognosis of the disease., Methods: A systematic literature search was performed using three databases including PubMed, Scopus, and Web of Science. The selected peer-reviewed studies must report a correlation between EDSS scores and MRI features. The correlation coefficients of included studies were converted to the Fisher's z scale, and the results were pooled., Results: Overall, 105 studies A total of 16,613 patients with MS entered our study. We found no significant correlation between total brain volume and EDSS assessment (95 % CI: -0.37 to 0.08; z-score: -0.15). We examined the potential correlation between the volume of T1 and T2 lesions and the level of disability. A positive significant correlation was found (95 % CI: 0.19 to 0.43; z-score: 0.31), (95 % CI: 0.17 to 0.33; z-score: 0.25). We observed a significant correlation between white matter volume and EDSS score in patients with MS (95 % CI: -0.37 to -0.03; z-score: -0.21). Moreover, there was a significant negative correlation between gray matter volume and disability (95 % CI: -0.025 to -0.07; z-score: -0.16)., Conclusion: In conclusion, this systematic review and meta-analysis revealed that disability in patients with MS is linked to extensive changes in different brain regions, encompassing gray and white matter, as well as T1 and T2 weighted MRI lesions., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest regarding the publication of this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Considering the different results regarding the correlation between Magnetic Resonance Imaging (MRI) structural measures and cognitive dysfunction in patients with MS, we aimed to perform a systematic review and meta-analysis study to investigate the correlation between T1 and T2 weighted lesions and cognitive scores to find the most robust MRI markers for cognitive function in MS population., Methods: The literature of this paper was identified through a comprehensive search of electronic datasets including PubMed, Scopus, Web of Science, and Embase in February 2022. Studies that reported the correlation between cognitive status and T1 and T2 weighted lesions in MS patients were selected., Results: 21 studies with a total of 3771 MS patients with mean ages ranging from 30 to 57 years were entered into our study. Our analysis revealed that the volume of T1 lesions was significantly correlated with Symbol Digit Modality test (SDMT) (r: -0.30, 95 %CI: -0.59, -0.01) and Paced Auditory Serial-Addition Task (PASAT) scores (r: -0.23, 95 %CI: -0.36, -0.10). We investigated the correlation between T2 lesions and cognitive scores. The pooled estimates of z scores were significant for SDMT (r: -0.27, 95 %CI: -0.51, -0.03) and PASAT (r: -0.27, 95 %CI: -0.41, -0.13)., Conclusion: In conclusion, our systematic review and meta-analysis study provides strong evidence of the correlation between T1 and T2 lesions and cognitive function in MS patients. Further research is needed to explore the potential mechanisms underlying this relationship and to develop targeted interventions to improve cognitive outcomes in MS patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: We aimed to synthesize all available observational studies and clinical trials of rituximab to estimate the safety and efficacy of this monoclonal antibody in people with multiple sclerosis (MS)., Methods: The four databases including PubMed, Scopus, Embase, and Web of Science were comprehensively searched in April 2022. We defined PICO as follows. Problem or study population (P): patients with MS; intervention (I): Rituximab; comparison (C): none; outcome (O): efficacy and safety., Results: After two-step screening, a total of 27 studies entered into our qualitative and quantitative synthesis. Our analysis showed a significant decrease in EDSS score in all patients with MS after treatment (SMD: - 0.44, 95% CI - 0.85, - 0.03). In addition, the ARR was reduced after using rituximab compared to the pre-treatment period (SMD: - 0.65, 95% CI - 1.55, 0.24) but it was not significant. The most common side effect after rituximab with a pooled prevalence of 28.63% (95% CI 16.61%, 42.33%). Furthermore, the pooled prevalence of infection was 24% in patients with MS (95% CI 13%, 36%). In the end, the pooled prevalence of malignancies after rituximab treatment was 0.39% (95% CI 0.02%, 1.03%)., Conclusion: Our findings illustrated an acceptable safety for this treatment. However, further studies with randomized design, long follow-up, and large sample sizes are needed to confirm the safety and efficacy of rituximab in patients with MS., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

Triggering Receptor Expressed on Myeloid Cell 2 (TREM2) plays a crucial role in the transition of microglia from a state of homeostasis to a state associated with the disease. Mutations in TREM2 are strongly linked with a higher risk of developing neurodegenerative diseases, including Alzheimer's disease. There have been contradictory findings regarding the potential detrimental or protective effects of microglial activation and TREM2-related microglial responses in Alzheimer's disease. Although previous studies reported increased CSF soluble TREM2 (sTREM2) in different clinical stages of Alzheimer's disease, the exact association between Alzheimer's disease hallmarks such as amyloid-beta and tau pathology remains unclear. In the present study, I aimed to investigate the association between TREM2-related microglial responses and tau accumulation in the presence and absence of amyloid-beta pathology in order to give a better view of the role of microglial activation in Alzheimer's disease development. Imaging data of 178 non-demented participants including 107 amyloid-beta-negative participants, 71 amyloid-beta-positive were recruited from Alzheimer's disease Neuroimaging Initiative. The CSF sTREM2 was used as an in vivo indicator of microglial responses associated with TREM2. Furthermore, I used longitudinal tau-PET and resting-state functional MRI connectomes in order to investigate the association of TREM2-related microglial activation and tau spreading through functional connections. A higher level of sTREM2 was associated with slower tau aggregate accumulation in non-demented amyloid-beta-positive. Furthermore, measuring the tau spreading through inter-connected regions using functional MRI connectomes confirms that the TREM2-related microglial activity might be a protective factor against tau pathology in brain tissue. These findings demonstrate that in individuals with initial amyloid-beta abnormalities, TREM2-related microglial activation is linked to reduced regional accumulation of tau aggregates and also, spreading across inter-connected brain regions, as evaluated through functional MRI connectomes during the early stages of Alzheimer's disease., Competing Interests: The author reports no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: A small proportion of patients with clinical parkinsonism have normal transporter-single photon emission computed tomography (DaTSPECT) which is commonly defined as scans without evidence of dopaminergic deficits (SWEDD). A better understanding of SWEDD can improve the current therapeutic options and appropriate disease monitoring., Aim: We aimed to assess CSF biomarkers levels including α-synuclein (α-syn), amyloid βeta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in SWEDD and investigate the longitudinal alteration in the CSF profile., Methods: In total, 406 early-stage PD, 58 SWEDD, and 187 healthy controls (HCs) were entered into our study from PPMI. We compared the level of CSF biomarkers at baseline, six months, one year, and two years. Furthermore, the longitudinal alteration of CSF biomarkers was explored in each group using linear mixed models., Results: There was no significant difference in the level of CSF α-syn Aβ1-42, t-tau, and p-tau between HCs and SWEDD at different time points. Investigating the level of CSF α-syn in PD and SWEDD showed a significant difference at one ( p  = 0.016) and two years ( p  = 0.006). Also, we observed a significant difference in the level of CSF Aβ1-42 between SWEDD and PD at one year ( p  = 0.012). Moreover, there was a significant difference in the level of CSF t-tau between SWEDD and PD subjects at one ( p  = 0.013) and two years ( p  = 0.017). Furthermore, there was a significant difference in the level of CSF p-tau between SWEDD and PD groups at two years visits ( p  = 0.030). Longitudinal analysis showed a significant decrease after one ( p  = 0.029) and two years ( p  = 0.002) from baseline in the level of CSF α-syn only in the PD group. Also, we observed that the level of CSF Aβ1-42 significantly increased after one year in SWEDD ( p  = 0.031) and decreased after two years from baseline in PD subjects ( p  = 0.005). Moreover, there was a significant increase in the level of CSF t-tau after two years ( p  = 0.036) and CSF p-tau after six months from baseline in SWEDD subjects ( p  = 0.011)., Conclusion: This finding suggests a faster neurodegeneration process in PD patients compared to SWEDD at least based on these biomarkers. Future studies with longer follow-up duration and more sample sizes are necessary to validate our results., Competing Interests: The authors declare no conflict of interest regarding the publication of this paper., (© 2023 The Authors.)

Background: Several different endovascular and non-invasive treatment methods are suggested for the various types of intracranial aneurysms including simple, balloon-assisted, and stent-assisted coiling (SAC). Previous studies investigated the safety and efficacy of SAC versus non-stent-assisted coiling (non-SAC) but the results were controversial. We aim to perform a systematic review and meta-analysis to compare the efficacy and safety of SAC with non-SAC technique in stratifying by the ruptured and unruptured aneurysms., Methods: PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched in April 2022 for studies investigated the efficacy and safety of SAC versus non-SAC., Results: Overall, 26 studies entered into our qualitative and quantitative synthesis. We found that there was overall lower recurrence rate in SAC versus non-SAC significant (RR: 0.43, 95%CI: 0.33, 0.53). Furthermore, the comparisons were significant in unruptured (RR: 0.63, 95%CI: 0.40, 0.86), ruptured (RR: 0.29, 95%CI), and combination aneurysms (RR: 0.42, 95%CI: 0.30, 0.54). Also, we found higher risk of intraprocedural rupture for SAC versus non-SAC in unruptured aneurysms (RR: 1.40, 95%CI: 1.31, 1.50). Investigating hemorrhagic events risk showed that there was significant difference in ruptured (RR: 1.73, 95%CI: 1.12, 2.34) and combination aneurysms (RR: 0.60, 95%CI: 0.37, 0.82). There was no significant difference in immediate occlusion rate, complete occlusion, and risk of ischemic events in our analysis., Conclusion: Overall, our findings demonstrated that SAC may have higher efficacy in term of recurrence rate, but also may have a higher risk of complications in the treatment of intracranial aneurysms. As there are several factors affecting the outcomes and safety of these interventions, further RCTs controlled for multiple factors are required better guide the neurointerventionists choose the best strategy., Competing Interests: The authors declare no conflict of interest regarding the publication of this paper., (© 2023 The Authors.)

Background: Recent findings suggest that the plasma axonal structural protein, neurofilament light (NFL) chain, may serve as a potential blood biomarker for early signs of neurodegenerative diseases, such as Alzheimer's disease (AD). Given the need for early detection of neurodegenerative disorders, the current study investigated the associations between regional cerebral blood flow (rCBF) in brain regions associated with neurodegenerative disorders and memory function with plasma NFL in AD, mild cognitive impairment (MCI), and healthy controls (HCs). Methods: We recruited 29 AD, 76 MCI, and 39 HCs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database in the current cross-sectional study. We used Pearson's correlation models adjusted for the effect of age, sex, and APOE genotype to investigate the association between plasma NFL and rCBF. Results: We found non-significant differences in age (F (2, 141) = 1.304; P = 0.275) and years of education (F (2, 141) = 0.013; P = 0.987). Additionally, we found significant differences between groups in terms of MMSE scores (F (2, 141) = 100.953; P < 0.001). Despite the observation of significantly reduced rCBF in AD and MCI groups versus HCs, we did not detect significant differences in plasma NFL between these groups. We found significant negative associations between plasma NFL and rCBF in various AD-related regions, these findings were only observed after analyses in all participants, and were observed in HCs alone and no significant associations were observed in the AD or MCI groups. Conclusion: These outcomes add to our current understanding surrounding the use of rCBF and plasma NFL biomarkers as tools for early detection and diagnosis of neurodegenerative diseases. A conclusion might be that the association between NFL and impaired rCBF exists before the clinical symptoms appear. Further longitudinal studies with a large sample size should be performed to examine the correlation between plasma NFL and rCBF in order to understand these complex relationships., Competing Interests: The authors declare no conflict of interest in this study., (Copyright © 2023 Iranian Neurological Association, and Tehran University of Medical Sciences Published by Tehran University of Medical Sciences.)

Diffusion-weighted imaging has been applied to investigate alterations in multiple sclerosis (MS). In the last years, advanced diffusion models were used to identify subtle changes and early lesions in MS. Among these models, neurite orientation dispersion and density imaging (NODDI) is an emerging approach, quantifying specific neurite morphology in both grey (GM) and white matter (WM) tissue and increasing the specificity of diffusion imaging. In this systematic review, we summarized the NODDI findings in MS. A search was conducted on PubMed, Scopus, and Embase, which yielded a total number of 24 eligible studies. Compared to healthy tissue, these studies identified consistent alterations in NODDI metrics involving WM (neurite density index), and GM lesions (neurite density index), or normal-appearing WM tissue (isotropic volume fraction and neurite density index). Despite some limitations, we pointed out the potential of NODDI in MS to unravel microstructural alterations. These results might pave the way to a deeper understanding of the pathophysiological mechanism of MS. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 3., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Previously, several studies investigated the effect of cladribine among patients with multiple sclerosis (MS) as a treatment option. Due to the contradictory results of previous studies regarding the efficacy and safety of cladribine in the MS population, we aimed to conduct a systematic review and meta-analysis by including clinical trials and observational studies in terms of having more confirmative results to make a general decision., Methods: The three databases including PubMed, Scopus, and Web of Science were comprehensively searched in May 2022. We included the studies that investigated the efficacy and safety of cladribine in patients with MS. Eligible studies have to provide sufficient details on MS diagnosis and appropriate follow-up duration. We investigated the efficacy of cladribine with several outcomes including Expanded Disability Status Scale (EDSS) change, progression-free survival (PFS), relapse-free survival (RFS), and MRI-free activity survival (MFAS)., Results: After two-step reviewing, 23 studies were included in our qualitative and quantitative synthesis. The pooled SMD for EDSS before and after treatment was - 0.54 (95%CI: - 1.46, 0.39). Our analysis showed that the PFS after cladribine use is 79% (95%CI 71%, 86%). Also, 58% of patients with MS who received cladribine remained relapse-free (95%CI 31%, 83%). Furthermore, the MFAS after treatment was 60% (95%CI 36%, 81%). Our analysis showed that infection is the most common adverse event after cladribine treatment with a pooled prevalence of 10% (95%CI 4%, 18%). Moreover, the pooled prevalence of infusion-related adverse events was 9% (95%CI 4%, 15%). Also, the malignancies after cladribine were present in 0.4% of patients (95%CI 0.25%, 0.75%)., Conclusion: Our results showed acceptable safety and efficacy for cladribine for the treatment of MS except in terms of reducing EDSS. Combination of our findings with the results of previous studies which compared cladribine to other disease-modifying therapies (DMTs), cladribine seems to be a safe and effective drug in achieving better treatment for relapsing-remitting MS (RRMS) patients., (© 2023. Fondazione Società Italiana di Neurologia.)

Background: Association between traumatic brain injury (TBI) and Parkinson's disease (PD) has been a hot topic of discussion for a long time. Previous studies reported that the incidence of PD is significantly higher among elderly adults with a history of TBI. Due to contradictory results of previous investigations, we aimed to perform a systematic review and meta-analysis to investigate the role of TBI as a risk factor for PD., Methods: We conducted a systematic literature search in the electronic databases PubMed, Web of Science, and Scopus. In this study, we included published papers on the risk of PD in patients with previous TBI compared to the healthy control group., Results: After the screening, 15 studies entered our systematic review and meta-analysis. The risk ratio of TBI among PD and controls by a combination of 15 studies using a random-effect model was 1.48 (95% CI 1.22-1.74). The prevalence of TBI by a combination of 14 studies was 18% (95% CI 12-24%)., Conclusion: Our result suggests that TBI is a major risk factor for developing PD later in life. At this time, there is a lack of populous prospective cohort studies with sufficient follow-up period to provide a well-documented association between the onset of PD and severity, frequency, and location of prior TBI, which warrants special efforts and consideration for years to come., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background: Protein misfolding within specific brain regions is a common characteristic of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease (PD). Therefore, a common term often used for these disorders is "proteinopathy". Currently, there has been increasing attention toward the overlap of pathogenesis between proteinopathies., Aims: We aimed to explore the cross-sectional and longitudinal level of the CSF α-synuclein (α-syn), amyloid βeta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in PD subjects with tremor dominant (TD) and a non-tremor dominant (nonTD) subtype from the Parkinson Progression Markers Initiative (PPMI)., Methods: We enrolled 411 early-stage PD patients and 187 healthy controls (HCs) from the PPMI. We compared the level of CSF biomarkers at four time points including baseline, 6 months, 1 year, and 2 years. To investigate longitudinal changes in CSF proteins within each group, we used linear mixed models., Results: The level of CSF biomarkers was significantly lower in PD patients compared to HCs at any visit. Moreover, there was no statistically significant difference in the level of CSF α-syn, Aβ1-42, t-tau, and p-tau between PD-TD and PD-nonTD. Longitudinal analysis showed significant CSF α-syn reduction after one year from baseline in PD-TD patients (P = 0.047). Also, there was a significant reduction in the level of CSF Aβ1-42 after two years in PD-nonTD patients but not HCs and PD-TD (P = 0.033)., Conclusion: Our results indicate that different patterns in longitudinal changes of CSF biomarkers could be due to different pathophysiological mechanisms involved in each PD motor subtype., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background and Purpose: Previous studies investigating cardiovascular disorders in patients with Parkinson's disease (PD) showed heterogeneous results regarding whether there is a higher or lower risk of myocardial infarction (MI) in these patients compared to the general population. Because of the inconsistency in findings, herein the aim was to perform a systematic review and meta-analysis to investigate the risk of MI in patients with PD., Methods: A comprehensive literature search was performed using four databases, PubMed, Web of Science, Scopus and Embase, in June 2022. Peer-reviewed observational studies comprising case-controls, cohort, cross-sectional and longitudinal studies that reported MI in the PD population were included., Results: After the screening, 20 studies with a total of 80,441 patients with PD and 802,857 controls were included in our qualitative and quantitative synthesis. The pooled estimated odds ratio for MI in PD patients compared to controls was 0.80 (95% confidence interval [CI] 0.56-1.05) which indicates that there is no association. The pooled prevalence of MI was 5% (95% CI 3%-7%) with a range of 1%-20% amongst patients with PD. The men (6%, 95% CI 1%-13%) and women (6%, 95% CI 1%-14%, Q = 29.27, I 2 = 98.50%, p < 0.001) had similar MI prevalence., Conclusion: This comprehensive systematic review and meta-analysis provide compelling evidence that PD is associated with a reduced risk of MI. Whilst the exact mechanism underlying this association remains to be fully elucidated, it is clear that certain risk factors for cardiac events appear to be less present in PD patients, which may serve as a protective factor. However, given the reports of increased risk for cerebrovascular events in PD patients, it is possible that the major risk factors for MI and cardiovascular accidents in this population differ. These findings have important implications for clinical management and further research in this area is warranted., (© 2023 European Academy of Neurology.)

Background: Comorbidity is a current area of interest in multiple sclerosis (MS) and is essential for multidisciplinary management. Although recent studies suggest that patients with MS have an elevated risk of developing inflammatory bowel diseases (IBD), this systematic review and meta-analysis aimed to estimate the overall risk of developing ulcerative colitis (UC), specifically in patients with MS., Methods: In 2021, a comprehensive literature search was performed on PubMed, Scopus, Embase, and Web of Science to identify studies investigating the association between UC and MS. The selected papers were utilized to estimate the associations, risk ratios (RRs), and a 95% confidence interval (CI)., Results: The analysis revealed a slightly elevated risk of UC incidence in patients with MS compared to controls, but this finding was not statistically significant (RR: 1.27 [95% CI: 0.96-1.67]). In contrast, the study found that patients with UC have a significantly higher risk of developing MS than controls (RR: 1.66 [95% CI: 1.15-2.40])., Conclusion: Our findings highlight that the presence of UC increases the risk of developing MS by more than 50%, whereas the presence of MS does not increase the risk of UC occurrence. These results underscore the importance of considering the potential development of UC in the clinical management and early diagnosis of patients with MS, as it may contribute to better therapeutic outcomes., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

Background: The traditional approach to studying the neurobiological mechanisms of brain disorders and localizing brain function involves identifying brain abnormalities and comparing them to matched controls. This method has been instrumental in clinical neurology, providing insight into the functional roles of different brain regions. However, it becomes challenging when lesions in diverse regions produce similar symptoms. To address this, researchers have begun mapping brain lesions to functional or structural networks, a process known as lesion network mapping (LNM). This approach seeks to identify common brain circuits associated with lesions in various areas. In this review, we focus on recent studies that have utilized LNM to map neurological and psychiatric symptoms, shedding light on how this method enhances our understanding of brain network functions., Methods: We conducted a systematic search of four databases: PubMed, Scopus, and Web of Science, using the term "Lesion network mapping." Our focus was on observational studies that applied lesion network mapping in the context of neurological and psychiatric disorders., Results: Following our screening process, we included 52 studies, comprising a total of 6,814 subjects, in our systematic review. These studies, which utilized functional connectivity, revealed several regions and network overlaps across various movement and psychiatric disorders. For instance, the cerebellum was found to be part of a common network for conditions such as essential tremor relief, parkinsonism, Holmes tremor, freezing of gait, cervical dystonia, infantile spasms, and tics. Additionally, the thalamus was identified as part of a common network for essential tremor relief, Holmes tremor, and executive function deficits. The dorsal attention network was significantly associated with fall risk in elderly individuals and parkinsonism., Conclusion: LNM has proven to be a powerful tool in localizing a broad range of neuropsychiatric, behavioral, and movement disorders. It holds promise in identifying new treatment targets through symptom mapping. Nonetheless, the validity of these approaches should be confirmed by more comprehensive prospective studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nabizadeh and Aarabi.)

Background: There are contradictory findings regarding the effect of statin drugs on amyloid β (Aβ) deposition as one of the main hallmarks of Alzheimer's disease (AD), along with tau pathology. We aimed to longitudinally investigate the therapeutic and preventive role of statin drugs by examining the brain Aβ deposition and metabolism rate in AD, mild cognitive impairment (MCI), and healthy controls (HC)., Methods: The data of 828 subjects including 178 HC, 492 MCI, and 158 AD individuals were obtained from ADNI. The baseline and longitudinal [ 18 F] AV45 and 18-fluorodeoxyglucose (FDG) PET standard uptake value ratio (SUVR) measures were investigated among statin users and non-users., Results: Our results showed that there is no significant difference in baseline Aβ deposition and metabolism rate between statin users and non-users among HC, MCI, and AD subjects. While there was no significant effect of statin on metabolism rate, there was a significant difference in Aβ deposition change after 4 years (from baseline) between statin users and non-users within HC subjects (p = 0.011). The change of Aβ deposition at 4 years from baseline was -2.0 ± 6.3% for statin users and 1.4 ± 4.7% for non-users. There was no significant association between statin duration use with baseline and longitudinal Aβ deposition and metabolism rate. However, statin dosage was significantly associated with Aβ deposition in 2 years (r = -0.412, p = 0.021) in the HC group. Moreover, our analysis showed a significant correlation between total statin exposure (duration×dosage) and Aβ deposition in 2 years visit (r = -0.198, p = 0.037) in HC subjects. Furthermore, we investigated the longitudinal changes within each group of statin users and non-users separately in linear mixed models. Our findings showed that there are no significant changes in AV45 and FDG SUVR among both groups., Conclusion: The present longitudinal analysis revealed that using statins might be beneficial in slowing down or stabilizing the Aβ deposition due to aging in subjects without cognitive impairment. However, once the clinical symptoms of cognitive impairment appear, statins fail to slow down Aβ deposition. Overall, our findings revealed that statin users might have slower Aβ aggregation than non-users., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Although global vaccination against COVID-19 infection has its excellence, potential side effects are yet of concern. Several lines of evidence have proposed ADEM occurrence after SARS-CoV-2 infection. Moreover, a large number of case reports and case series have also suggested the casual association between ADEM and COVID-19 vaccination. To better understand the development of ADEM following COVID-19 vaccination and its potential association, we aimed to systematically review ADEM cases reported after COVID-19 vaccination., Methods: We conducted a comprehensive systematic search using three databases including PubMed, Scopus, and Web of Science. Studies that reported ADEM after COVID-19 vaccination were eligible to include in our study. Observational studies, case reports, and case series which reported cases of ADEM with sufficient detail to confirm clinical diagnosis following COVID-19 vaccination were eligible to enter our study., Results: Twenty studies were included in our systematic review after the abstract and full-text screening with a total of 54 cases. Among included patients, 45 (85.1 %) developed ADEM after the first dose of the COVID-19 vaccine, and seven (12.9 %) cases experienced ADEM after the second dose. The median time interval between vaccination and neurological symptoms was 14 days which ranged from 12 h to 63 days. Twelve (22.2 %) patients experienced symptoms of muscle weakness, ten (18.5 %) presented unconsciousness, nine (16.6 %) patients had urinary complaints, nine (16.6 %) had visual impairments, and five (9.2 %) experienced a seizure. After treatments, four (13.8 %) patients died. Forty-six patients had clinical improvement (85.1 %), also improvement in brain MRI was observed among 44 (81.4 %) patients., Conclusion: In conclusion, it is not clear that ADEM could be a potential complication of COVID-19 vaccination based on the current evidence and further studies are needed. However, this rare condition should not trigger stopping the mass vaccination programs since the only way to eradicate the current pandemic of COVID-19 is to extend the number of immunized people., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: The authors declare no conflict of interest in this study.

Background: According to a large number of scientific reports, the main problem is COVID-19 vaccine hesitancy which slowed down the vaccination program. Previous studies revealed that COVID-19 vaccine hesitancy is associated with lower cognitive performance. However, the neurobiology of such behavior is less known, and investigating the brain structural patterns in this regard can extend our knowledge on the basis of this behavior. This study aimed to investigate the link between brain structural features including cortical and subcortical volume with COVID-19 vaccine hesitancy in elderly individuals., Methods: A total of 221 healthy subjects without any cognitive impairment with a mean age of 63.7 ± 6.1 were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Overall, 87 vaccine-hesitant (VH) and 134 vaccine-accepted (VA) were entered into this study. The difference in the volume of cortical and subcortical regions was investigated between VH and VA groups., Results: There was no significant difference in cognitive status measured by MMSE, MoCA, ADAS-cog, and RAVLT between VA and VH groups ( P >0.05). The analysis showed that VA subjects had significantly higher left pars orbitalis ( P : 0.013), left precentral ( P : 0.042), right caudal anterior cingulate ( P : 0.044), and right isthmus cingulate ( P : 0.013) volume compared to the VH group. There was no significant difference in other cortical and subcortical regions., Conclusion: In conclusion, this finding demonstrated that in the era of complicated decision-making due to social media reports, elderly adults with smaller frontal and cingulate regions are more likely to be vaccine-hesitant. These findings can highlight the link between cortical regions and health-protective behaviors such as taking up the offer of vaccination., Competing Interests: Conflict of interest The author declares no conflict of interest regarding the publication of this paper.

Background: Studies revealed that serum neurofilament light chain (NFL) levels not only increase considerably over time in Parkinson's disease (PD) but also have a significant association with disease progression. However, there is no evidence of the level of serum NFL in PD patients with leucine-rich repeat kinase 2 (LRRK2) mutation (LRRK2-PD) which is the most common mutation that causes familial and sporadic PD., Aim: Here we aimed to investigate the difference and longitudinal alteration of the serum level of NFL in LRRK2-PD and idiopathic PD (iPD) patients., Methods: We entered 228 iPD and 103 LRRK2-PD patients and 176 healthy controls (HCs) from PPMI. We compared the level of serum NFL at baseline, six months, one year, two years, three years, and five years visits. Also, we used linear mixed models to assess longitudinal changes of serum NFL over six months, one year, two years, three years, and five years within groups., Results: We found a significant difference in the level of serum NFL between three groups at baseline, two years, three years, and five years time points. Also, our analysis showed that LRRK2-PD patients had significantly lower serum NFL compared to iPD subjects at baseline. In the longitudinal analysis, there was no significant change in the HCs group over five years. The level of serum NFL was significantly increased after two, three, and five years from baseline in LRRK2-PD patients. Also, we found similar results for iPD subjects after three and five years from baseline., Conclusion: We can conclude that the overall neurodegeneration might be similar in LRRK2-PD and healthy subjects and lower than the idiopathic form of PD at the early stages, which may disappear in the later stages. Moreover, our findings suggest that the serum NFL might be a more accurate biomarker to distinguish iPD from healthy subjects rather than all PD patients or LRRK2-PD from healthy subjects at the early stages., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The aim of this study was to the production of an active film based on Prangos ferulacea root gum, using its leaf's essential oil (PFEO) (0-3 %) and bismuth oxide nanoparticles (Bi 2 O 3 NPs) (0-3 %). Then, the developed film was used for packaging of quail fillet. Response surface methodology was used to evaluate the effect of PFEO and Bi 2 O 3 NPs on films' properties. Optimum formulation, including 1.5 % PFEO and 1 % Bi 2 O 3 NPs, was achieved based on numerical optimization. The optimum film was produced and compared with the control film (based on Prangos ferulacea root gum, without PFEO and Bi 2 O 3 NPs). According to the results, adding PFEO and Bi 2 O 3 NPs to the film formulation increased the thickness and antioxidant activity of the film and decreased moisture content, solubility, water vapor permeability, and whiteness index (p < 0.05). The optimum film indicated high antimicrobial effects on Escherichia coli and Staphylococcus aureus. The pH, TVBN, TBA values, coliform, and total bacterial counts of quail fillet packed with the optimum film were lower and sensorial scores were higher than the control samples during the storage(p < 0.05)., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background: The expansion of the availability of advanced imaging methods needs more time, expertise, and resources which is in contrast to the primary goal of the imaging techniques. To overcome most of these difficulties, artificial intelligence (AI) can be used. A number of studies used AI models for multiple sclerosis (MS) diagnosis and reported diverse results. Therefore, we aim to perform a comprehensive systematic review and meta-analysis study on the role of AI in the diagnosis of MS., Methods: We performed a systematic search using four databases including PubMed, Scopus, Web of Science, and IEEE. Studies that applied deep learning or AI to the diagnosis of MS based on any modalities were considered eligible in our study. The accuracy, sensitivity, specificity, precision, and area under curve (AUC) were pooled with a random-effects model and 95% confidence interval (CI)., Results: After the screening, 41 articles with 5989 individuals met the inclusion criteria and were included in our qualitative and quantitative synthesis. Our analysis showed that the overall accuracy among studies was 94% (95%CI: 93%, 96%). The pooled sensitivity and specificity were 92% (95%CI: 90%, 95%) and 93% (95%CI: 90%, 96%), respectively. Furthermore, our analysis showed 92% precision in MS diagnosis for AI studies (95%CI: 88%, 97%). Also, the overall pooled AUC was 93% (95%CI: 89%, 96%)., Conclusion: Overall, AI models can further improve our diagnostic practice in MS patients. Our results indicate that the use of AI can aid the clinicians in accurate diagnosis of MS and improve current diagnostic approaches as most of the parameters including accuracy, sensitivity, specificity, precision, and AUC were considerably high, especially when using MRI data., (© 2022. Fondazione Società Italiana di Neurologia.)

Background: Previous studies investigated CSF levels of α-synuclein (α-syn), amyloid-β (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) with clinical progression of Parkinson's disease (PD). However, there is limited data on the association between CSF biomarkers and dopamine uptake status in PD., Aim: In the current study, we aim to investigate the longitudinal association between striatal dopaminergic neuronal loss assessed by dopamine active transporter single photon emission computerized tomography (DaTSCAN) imaging with CSF α-syn, t-tau, p-tau, and Aβ1-42., Methods: A total of 413 early-stage PD patients and 187 healthy controls (HCs) from the PPMI. Striatal binding ratios (SBRs) of DaTSCAN images in caudate and putamen nuclei were calculated. We investigated the cross-sectional and longitudinal association between CSF biomarkers and dopamine uptake using partial correlation models adjusted for the effect of age, sex, and years of education over 24 months of follow-up., Results: The level of CSF α-syn, Aβ1-42, t-tau, and p-tau was significantly higher in HCs compared to PD groups at any time point. We found that higher CSF α-syn was associated with a higher SBR score in the left caudate at baseline (P = 0.038) and after 12 months (P = 0.012) in PD patients. Moreover, SBR scores in the left caudate and CSF Aβ1-42 were positively correlated at baseline (P = 0.021), 12 months (P = 0.006), and 24 months (P = 0.014) in patients with PD. Our findings demonstrated that change in CSF Aβ1-42 was positively correlated with change in SBR score in the left caudate after 24 months in the PD group (P = 0.043)., Conclusion: We found that cross-sectional levels of α-syn and Aβ1-42 could reflect the degree of dopaminergic neuron loss in the left caudate nucleus. Interestingly, longitudinal changes in CSF Aβ1-42 could predict the severity of left caudal dopaminergic neuron loss throughout the disease. This suggested that Aβ pathology might precede dopaminergic loss in striatal nuclei in this case left caudate and subsequently cognitive impairment in PD patients, although future studies are needed to confirm our results and expand the understanding of the pathophysiology of cognitive dysfunction in PD., (© 2022. Fondazione Società Italiana di Neurologia.)

Background: Multiple Sclerosis (MS) relapses are episodes of transient disease exacerbation. There are contradictory findings regarding seasonal variation in MS relapses. In this systematic review and meta-analysis, we aimed to investigate the seasonal and monthly variation in relapse rates among patients with MS., Methods: We systematically queried PubMed, Scopus, and Web of Science for published papers until February 30, 2022., Results: A total of 24 studies were included in this systematic review and meta-analysis with a total of 29,106 patients with MS. We found that the relapse rate was significantly lower in fall compared to the average relapse rate in other seasons with a risk ratio (RR) of 0.97 (95% CI 0.95-0.98). Furthermore, patients with MS experienced a higher number of relapses in April (RR: 1.06, 95% CI 1.01-1.11) and March (RR: 1.08, 95% CI 1.00-1.16) compared to other months. Also, the risk of relapse was lower in August (RR: 0.92, 95% CI.85-0.98), September (RR: 0.97, 95% CI.94-0.99), October (RR: 0.92, 95% CI.89-0.96), and November (RR: 0.93, 95% CI.89-0.97)., Conclusion: Our systematic review and meta-analysis confirm the temporal fluctuations in the relapse of MS through a comprehensive review of the existing literature, with a lower relapse rate during late summer and fall and a higher relapse rate during early spring., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background: In this study, the effects of seed weight (4, 8, and 12 g), extraction temperature (30, 60, and 90 °C), and pH (4, 7, and 10) on the yield of mucilage extraction from fenugreek seeds and its chemical properties were investigated using response-surface methodology., Results: The optimum condition for mucilage extraction was a seed weight of 8.30 g, a temperature of 86.10 °C, and pH 6.90. The results showed that the dry weight of extracted mucilage increased with increase and decrease of extraction temperature and pH respectively at high seed weight. Increasing temperature and pH increased the extraction yield, and the effect was more considerable at low seed weight. The maximum carbohydrate content of mucilage was achieved at average levels of variables. The protein, flavonoid, and total phenolic contents of extracted mucilage increased with increasing temperature. Both flavonoid and total phenolic contents were maximum at neutral pH, but they were maximum at moderate and low levels of seed weight respectively. Maximum antioxidant activity was obtained at the highest extraction temperature, seed weight of 8 g, and neutral pH. The study of rheological properties indicated that extracted mucilage solution showed mainly elastic and shear-thinning behavior., Conclusion: The Fourier transform infrared spectra of extracted mucilage exhibited the existence of polysaccharides and protein chains in fenugreek seeds mucilage. The X-ray diffraction corroborated the presence of crystals in the mucilage structure. The proton nuclear magnetic resonance spectra confirmed the polysaccharides and protein composition of extracted mucilage. The maximum mucilage mass loss was observed at 190-350 °C using thermogravimetric analysis. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

Introduction: In 1995, the use of autologous hematopoietic stem-cell transplantation (AHSCT), which was previously used to treat hematological tumors, was introduced for severe autoimmune diseases such as multiple sclerosis (MS). AHSCT has proven its safety over the past few years due to technical advances and careful patient selection in transplant centers. While most studies have reported that AHSCT led to decreased Expanded Disability Status Scale (EDSS) scores, some patients reported increased EDSS scores following the procedure. Given the contradictory results, we aimed to conduct a comprehensive systematic review and meta-analysis to investigate the efficacy and safety of AHSCT., Methods: PubMed, Web of Science, and Scopus were searched in March 2022 using a predefined search strategy. We included cohort studies, clinical trials, case-control studies, and case series that investigated the efficacy or safety of AHSCT in patients with MS. PICO in the present study was defined as follows: problem or study population (P): patients with MS; intervention (I): AHSCT; comparison (C): none; outcome (O): efficacy and safety., Results: After a two-step review process, 50 studies with a total of 4831 patients with MS were included in our study. Our analysis showed a significant decrease in EDSS score after treatment (standardized mean difference [SMD]: -0.48, 95% CI -0.75, -0.22). Moreover, the annualized relapse rate was also significantly reduced after AHSCT compared to the pretreatment period (SMD: -1.58, 95% CI -2.34, -0.78). The pooled estimate of progression-free survival after treatment was 73% (95% CI 69%, 77). Furthermore, 81% of patients with MS who received AHSCT remained relapse-free (95% CI 76%, 86%). Investigating event-free survival, which reflects the absence of any disease-related event, showed a pooled estimate of 63% (95% CI 54%, 73%). Also, the MRI activity-free survival was 89% (95% CI 84%) among included studies with low heterogeneity. New MRI lesions seem to appear in nearly 8% of patients who underwent AHSCT (95% CI 4%, 12%). Our meta-analysis showed that 68% of patients with MS experience no evidence of disease activity (NEDA) after AHSCT (95% CI 59%, 77). The overall survival after transplantation was 94% (95% CI 91%, 96%). In addition, 4% of patients died from transplant-related causes (95% CI 2%, 6%)., Conclusion: Current data encourages a broader application of AHSCT for treating patients with MS while still considering proper patient selection and transplant methods. In addition, with increasing knowledge and expertise in the field of stem-cell therapy, AHSCT has become a safer treatment approach for MS., (© 2022. The Author(s).)

Introduction: Treatment options for neuromyelitis optica spectrum disorder (NMOSD) are corticosteroids, immunosuppressive drugs, emerging monoclonal antibodies, rituximab, eculizumab, satralizumab, and inebilizumab. Due to disabling and deadly nature of NMOSD, there is a great motivation among physicians for finding new treatment options. Recently, several studies have been conducted on the therapeutic effects of autologous hematopoietic stem cell transplantation (AHSCT) on NMOSD patients., Methods: Several databases including PubMed, Scopus, Web of Science, and Google scholar were searched for studies on AHSCT in NMOSD patients., Results: After screening titles and abstracts, and reviewing full texts, nine studies with 39 severe cases of NMOSD met the criteria of our study. The pooled standardized mean difference (SMD) for EDSS score before and after treatment was -0.81 (95 %CI:-1.07, -0.15; Q = 1.99, P = 0.58, I 2  = 0 %). Also, the PFS and RFS were 69 % and 53 % respectively (PFS: 69 %, 95 %CI 42 %, 96 %; Q = 8.63, P = 0.01, I 2  = 73.07 %; RFS: 53 %, 95 %CI 27 %, 79 %; Q = 12.33, P = 0.01, I 2  = 71.87 %). Also, there were three cases with secondary autoimmune diseases including myasthenia gravis, hyperthyroidism, and thyroiditis., Conclusion: According to the present study, AHSCT could be an alternative therapy for NMOSD in severe cases instead of conventional immunotherapies. However, physicians should pay attention to its serious complications. The diversity of results from the published trials on the efficacy and safety of AHSCT calls for further investigations on determining the ideal AHSCT conditioning and the characteristics of patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The blood biomarker neurofilament light (NFL) is one of the most widely used for monitoring Alzheimer's disease (AD). According to recent research, a higher NFL plasma level has a substantial predictive value for cognitive deterioration in AD patients. Diffusion tensor imaging (DTI) is an MRI-based approach for detecting neurodegeneration, white matter (WM) disruption, and synaptic damage. There have been few studies on the relationship between plasma NFL and WM microstructure integrity., Aims: The goal of the current study is to assess the associations between plasma levels of NFL, CSF total tau, phosphorylated tau181 (P-tau181), and amyloid-β (Aβ) with WM microstructural alterations., Methods: We herein have investigated the cross-sectional association between plasma levels of NFL and WM microstructural alterations as evaluated by DTI in 92 patients with mild cognitive impairment (MCI) provided by Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. We analyzed the potential association between plasma NFL levels and radial diffusivity (RD), axial diffusivity (AxD), mean diffusivity (MD), and fractional anisotropy (FA) in each region of the Montreal Neurological Institute and Hospital (MNI) atlas, using simple linear regression models stratified by age, sex, and APOE ε4 genotype., Results: Our findings demonstrated a significant association between plasma NFL levels and disrupted WM microstructure across the brain. In distinct areas, plasma NFL has a negative association with FA in the fornix, fronto-occipital fasciculus, corpus callosum, uncinate fasciculus, internal capsule, and corona radiata and a positive association with RD, AxD, and MD values in sagittal stratum, corpus callosum, fronto-occipital fasciculus, corona radiata, internal capsule, thalamic radiation, hippocampal cingulum, fornix, and cingulum. Lower FA and higher RD, AxD, and MD values are related to demyelination and degeneration in WM., Conclusion: Our findings revealed that the level of NFL in the blood is linked to WM alterations in MCI patients. Plasma NFL has the potential to be a biomarker for microstructural alterations. However, further longitudinal studies are necessary to validate the predictive role of plasma NFL in cognitive decline., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Concerns about vaccination increased among patients with multiple sclerosis (MS) regarding side effects, efficacy, and disease exacerbation. Recently there were reports of MS relapses after the COVID-19 vaccination, which emerged the safety concerns. Therefore, we aimed to perform a systematic review of case reports and case series studies to investigate the MS relapses after COVID-19 vaccination with most details., Methods: We systematically searched three databases, including PubMed, Scopus, and Web of Science, in February 2022. Case reports and case series which reported relapse after COVID-19 vaccination in MS patients were eligible to include in our study., Results: Seven studies were included in our systematic review after the abstract and full-text screening with a total of 29 cases. The mean duration between COVID-19 vaccination and relapse appearance was 9.48 ± 7.29 days. Among patients, 22 cases experienced relapse after their first dosage of the COVID-19 vaccine, one after the second dose, and five after the booster dose. The type of vaccine was unknown for one patient. The most common symptoms of relapses were sensory deficits (paresthesia, numbness, dysesthesia, and hypoesthesia) and weakness., Conclusion: Overall, the COVID-19 vaccination may trigger relapses in some MS patients, but as the infection itself can stimulate relapse, the benefit of vaccination outweighs its risk in this population, and mass vaccination against COVID-19, especially in MS patients, should be continued and encouraged., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Proteinopathies as a consequence of cellular pathological pathways associated with Parkinson's disease (PD), leading to alteration of protein aggregation in cerebrospinal fluid (CSF). Rapid eye movement (REM) sleep behavior disorder (RBD is generally accepted as a prognostic factor predicting neurodegeneration, worse cognitive impairment, and the development of dementia PD., Aim: Here we aimed to investigate the difference and longitudinal alteration of the CSF level of α-synuclein (α-syn), amyloid βeta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in PD subjects with RBD and without RBD., Methods: We entered 413 early stage PD patients and 187 healthy controls (HCs) from PPMI. We compared the level of CSF biomarkers at baseline, 6 months, 1 year, and 2 years visits. In addition, we used linear mixed models to assess longitudinal changes of CSF proteins over 6 months, 1 year, and 2 years within groups., Results: The level of CSF α-syn, Aβ1-42, t-tau, and p-tau was significantly higher in HCs compared to PD groups at any timepoint. In addition, there was a significantly lower CSF Aβ1-42 in PD-RBD subjects at 2 years timepoint (p = 0.020). There was no difference in CSF Aβ1-42 at other timepoints. Furthermore, comparisons between PD subjects with RBD and without RBD did not show any significant difference in CSF α-syn, t-tau, and p-tau at timepoints. The longitudinal analysis demonstrated that there was only a significant change in CSF level of Aβ1-42 after 1 year in PD patients with RBD (p = 0.031)., Conclusions: In our study, baseline values and longitudinal changes in CSF α-syn, t-tau, and p-tau were not remarkable enough to distinguish PD patients with and without RBD. Both of these groups demonstrated a stable trend in the longitudinal changes of these biomarkers. However, CSF Aβ1-42 seems to decrease in short follow-up and represents a significant difference after a while in PD patients with and without RBD. These findings suggested that CSF Aβ1-42 could be a more sensitive biomarker for early neurodegeneration and cognitive impairment in PD patients. The stable trend in other CSF biomarkers such as α-syn, t-tau, and p-tau can be justified by the fact that severe neurodegeneration may not be predictable in the early stages of PD patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with dementia and is a serious concern for the health of individuals and government health care systems worldwide. Gray matter atrophy and white matter damage are major contributors to cognitive deficits in AD patients, as demonstrated by magnetic resonance imaging (MRI). Many of these brain changes associated with AD begin to occur about 15 years before the onset of initial clinical symptoms. Therefore, it is critical to find biomarkers reflective of these brain changes associated with AD to identify this disease and monitor its prognosis and development. The increased plasma level of hyperphosphorylated tau 181 (p-tau181) has been recently considered a novel biomarker for the diagnosis of AD, preclinical AD, and mild cognitive impairment (MCI). In the current study, we examined the association of cerebrospinal fluid (CSF) and plasma levels of p-tau181 with structural brain changes in cortical thickness, cortical volume, surface area, and subcortical volume in MCI patients. In this cross-sectional study, we included the information of 461 MCI patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. The results of voxel-wise partial correlation analyses showed a significant negative correlation between the increased levels of plasma p-tau181, CSF total tau, and CSF p-tau181 with structural changes in widespread brain regions. These results provide evidence for the use of plasma p-tau181 as a diagnostic marker for structural changes in the brain associated with the early stages of AD and neurodegeneration., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: There is a shred of growing evidence demonstrating that diabetic patients are at higher risk of developing Alzheimer's disease compared to the general population. The previous investigation showed the protective effect of metformin for delaying dementia in diabetic patients. However, there are limited data on the effect of metformin on structural changes. This study aims to investigate the effect of metformin on hippocampal and cortical volumes in non-demented diabetic individuals., Method: We entered 157 non-demented diabetic subjects including 89 mild cognitive impairment (MCI), and 68 cognitively healthy individuals from Alzheimer's disease Neuroimaging Initiative (ADNI) which were then categorized as metformin users and non-users. We used the ANCOVA model for measuring the association between metformin use and hippocampal and cortical volumes., Results: Among 157 subjects with a mean age of 71.8 (±7.7) included in this study, 76 individuals were stratified as metformin users. Results of the univariate model indicate that metformin users had a higher right (p = 0.003) and left parietal lobe volume (p = 0.004). Moreover, the volume of left cingulate was higher in those who used metformin compared to those not used it (p = 0.027). Our results were also significant for the right frontal lobe and indicated that metformin users had higher volume (p = 0.035). There were no significant differences in the hippocampus, occipital, and temporal regions., Conclusion: Our findings showed the protective effects of metformin on brain volumes in non-demented elderly individuals with diabetes. Comparing the groups show strong enough results regarding the lower atrophy in metformin users., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Some previous studies have shown that cerebrospinal fluid (CSF) levels of p-tau231 were significantly higher in patients with Alzheimer's disease (AD) compared to that in patients with mild cognitive impairment (MCI) and normal control (NC), whereas some other studies did not. Due to contradictory results, we aimed to conduct a systematic review and meta-analysis study on previous investigations to examine the potential role of CSF p-tau231 as a biomarker of AD and MCI., Method: PubMed, Scopus, and Web of Science were searched in March 2021 for studies on the CSF level of p-tau231 in AD, MCI, and NC. The statistical analysis was performed via standardized mean difference (SMD) methodology with a 95% confidence interval., Results: A total of 10 studies including 1141 subjects were included. The present study showed that CSF level of p-tau231 was significantly higher in AD patients compared to that in MCI patients (SMD = 160.94 [11.11, 310.78], P = 0.04) and NC patients (SMD = 436.21 [164.88, 707.54], P < 0.00). Moreover, comparison of MCI and NC showed a significantly higher level of CSF p-tau231 in MCI compared to NC (SMD = 341.44 [59.73, 623.14], P = 0.02)., Conclusion: P-tau231 showed to be a valuable biomarker of discrimination AD, MCI, and NC based on our findings. This meta-analysis showed that the CSF p-tau231 can reliably differentiate AD patients from MCI and NC patients. Furthermore, based on our findings the level of CSF p-tau231 was significantly higher in MCI compared to NC. Therefore, p-tau231 can be added to the list of potential biomarkers for the diagnosis of AD and MCI in further studies. However, further investigations are needed to confirm our findings., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Annals of Indian Academy of Neurology.)

Introduction: Autoimmune encephalitis (AE) is caused by the antibodies that target receptors and intracellular or surface proteins. To achieve the appropriate therapeutic results, early and proper diagnosis is still the most important issue. In this review, we provide an overview of FDG-PET imaging findings in AE patients and possible relation to different subtypes and clinical features., Methods: PubMed, Web of Science, and Scopus were searched in August 2021 using a predefined search strategy., Results: After two-step reviewing, 22 studies with a total of 332 participants were entered into our qualitative synthesis. In anti-NMDAR encephalitis, decreased activity in the occipital lobe was present, in addition, to an increase in frontal, parietal, and specifically medial temporal activity. Anti-VGKC patients showed altered metabolism in cortical and subcortical regions such as striata and cerebellum. Abnormal metabolism in patients with anti-LGI1 has been reported in diverse areas of the brain including medial temporal, hippocampus, cerebellum, and basal ganglia all of which had hypermetabolism. Hypometabolism in parietal, frontal, occipital lobes, temporal, frontal, and hippocampus was observed in AE patients with anti-GAD antibodies., Conclusion: Our results indicate huge diversity in metabolic patterns among different AE subtypes and it is hard to draw a firm conclusion. Moreover, the timing of imaging, seizures, and acute treatments can alter the PET patterns strongly. Further prospective investigations with specific inclusion and exclusion criteria should be carried out to identify the metabolic defect in different AE subtypes., (© 2022. Fondazione Società Italiana di Neurologia.)

Amyotrophic lateral sclerosis (ALS) is a paralytic, heterogeneous and progressive disease characterized by the degeneration of both upper and lower motor neurons. Several studies about the effects of statins drug on the risk of ALS showed contradictory results and evidence for this is inconclusive. So we aimed to perform a meta-analysis on previous studies to clarify the association between statin use and risk of ALS. The databases including PubMed, Scopus, and Web of science were searched in February 2021 for studies that reported the association between statin use and risk of ALS. The eligible studies had to provide a report on the effect of statin and the incidence of ALS while comparing it to the control group. Articles that had low statin exposure time, the absence of a control group and an unknown number of ALS patients were excluded. The rate ratio and 95% confidence interval (CI) were used for association measures in case-control and cohort studies. After full-text and abstract review, data from 8 studies with a total of 547,622 participants and 13,890 cases of ALS were entered in the present meta-analysis. We combined eight studies using a random-effect model and the RR for statin users among groups was 0.98 (95% CI 0.80-1.20) which indicates no association between statin and incidence of ALS. Also high heterogeneity was detected across the studies (Q value = 26.62, P = .00; I 2  = 72.71%). In our meta-analysis study, we found no association between statin use and an increase in ALS incidence. This result is in line with some previous studies and provides strong evidence that denies the possible association between statin uptake and disease induction., (© 2021. Belgian Neurological Society.)