Publications by authors named "Dafin Muresanu"

140 Publications

Manganese nanoparticles induce blood-brain barrier disruption, cerebral blood flow reduction, edema formation and brain pathology associated with cognitive and motor dysfunctions.

Prog Brain Res 2021 13;265:385-406. Epub 2021 Aug 13.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

Nanoparticles affect blood-brain barrier (BBB) and brain edema formation resulting in sensory-motor dysfunction. Exposure of Mn nanoparticles from industrial sources in humans could target basal ganglia resulting in Parkinson's disease. In present investigation, Mn exposure on brain pathology in a rat model was examined. Rats received Mn nanoparticles (30-40nm size) in a dose of 10 or 20mg/kg, i.p. once daily for 7 days and behavioral dysfunctions on Rota Rod performance, inclined plane angle and grid-walking tests as well as gait performances were examined. In addition, BBB breakdown to Evans blue and radioiodine, brain edema formation and neural injuries were also evaluated. Mn nanoparticles treated rats exhibited cognitive and motor dysfunction on the 8th day. At this time, BBB disruption, reduction in cerebral blood flow (CBF), brain edema formation and brain pathology were most marked in the sensory-motor cortex, hippocampus, caudate putamen, cerebellum and thalamus followed by hypothalamus, pons, medulla and spinal cord. In these brain areas, neuronal injuries using Nissl staining was clearly seen. These effects of Mn nanoparticle are dose dependent. These results are the first to demonstrate that Mn nanoparticles induce selective brain pathology resulting in cognitive and motor dysfunction, not reported earlier.
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http://dx.doi.org/10.1016/bs.pbr.2021.06.015DOI Listing
August 2021

Upregulation of hemeoxygenase enzymes HO-1 and HO-2 following ischemia-reperfusion injury in connection with experimental cardiac arrest and cardiopulmonary resuscitation: Neuroprotective effects of methylene blue.

Prog Brain Res 2021 12;265:317-375. Epub 2021 Aug 12.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

Oxidative stress plays an important role in neuronal injuries after cardiac arrest. Increased production of carbon monoxide (CO) by the enzyme hemeoxygenase (HO) in the brain is induced by the oxidative stress. HO is present in the CNS in two isoforms, namely the inducible HO-1 and the constitutive HO-2. Elevated levels of serum HO-1 occurs in cardiac arrest patients and upregulation of HO-1 in cardiac arrest is seen in the neurons. However, the role of HO-2 in cardiac arrest is not well known. In this review involvement of HO-1 and HO-2 enzymes in the porcine brain following cardiac arrest and resuscitation is discussed based on our own observations. In addition, neuroprotective role of methylene blue- an antioxidant dye on alterations in HO under in cardiac arrest is also presented. The biochemical findings of HO-1 and HO-2 enzymes using ELISA were further confirmed by immunocytochemical approach to localize selective regional alterations in cardiac arrest. Our observations are the first to show that cardiac arrest followed by successful cardiopulmonary resuscitation results in significant alteration in cerebral concentrations of HO-1 and HO-2 levels indicating a prominent role of CO in brain pathology and methylene blue during CPR followed by induced hypothermia leading to superior neuroprotection after return of spontaneous circulation (ROSC), not reported earlier.
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http://dx.doi.org/10.1016/bs.pbr.2021.06.009DOI Listing
August 2021

Nanodelivery of traditional Chinese Gingko Biloba extract EGb-761 and bilobalide BN-52021 induces superior neuroprotective effects on pathophysiology of heat stroke.

Prog Brain Res 2021 12;265:249-315. Epub 2021 Aug 12.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

Military personnel often exposed to high summer heat are vulnerable to heat stroke (HS) resulting in abnormal brain function and mental anomalies. There are reasons to believe that leakage of the blood-brain barrier (BBB) due to hyperthermia and development of brain edema could result in brain pathology. Thus, exploration of suitable therapeutic strategies is needed to induce neuroprotection in HS. Extracts of Gingko Biloba (EGb-761) is traditionally used in a variety of mental disorders in Chinese traditional medicine since ages. In this chapter, effects of TiO2 nanowired EGb-761 and BN-52021 delivery to treat brain pathologies in HS is discussed based on our own investigations. We observed that TiO2 nanowired delivery of EGb-761 or TiO2 BN-52021 is able to attenuate more that 80% reduction in the brain pathology in HS as compared to conventional drug delivery. The functional outcome after HS is also significantly improved by nanowired delivery of EGb-761 and BN-52021. These observations are the first to suggest that nanowired delivery of EGb-761 and BN-52021 has superior therapeutic effects in HS not reported earlier. The clinical significance in relation to the military medicine is discussed.
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http://dx.doi.org/10.1016/bs.pbr.2021.06.007DOI Listing
August 2021

Nanodelivery of oxiracetam enhances memory, functional recovery and induces neuroprotection following concussive head injury.

Prog Brain Res 2021 12;265:139-230. Epub 2021 Aug 12.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

Military personnel are the most susceptible to concussive head injury (CHI) caused by explosion, blast or missile or blunt head trauma. Mild to moderate CHI could induce lifetime functional and cognitive disturbances causing significant decrease in quality of life. Severe CHI leads to instant death and lifetime paralysis. Thus, further exploration of novel therapeutic agents or new features of known pharmacological agents are needed to enhance quality of life of CHI victims. Previous reports from our laboratory showed that mild CHI induced by weight drop technique causing an impact of 0.224N results in profound progressive functional deficit, memory impairment and brain pathology from 5h after trauma that continued over several weeks of injury. In this investigation we report that TiO2 nanowired delivery of oxiracetam (50mg/kg, i.p.) daily for 5 days after CHI resulted in significant improvement of functional deficit on the 8th day. This was observed using Rota Rod treadmill, memory improvement assessed by the time spent in finding hidden platform under water. The motor function improvement is seen in oxiracetam treated CHI group by placing forepaw on an inclined mesh walking and foot print analysis for stride length and distance between hind feet. TiO2-nanowired oxiracetam also induced marked improvements in the cerebral blood flow, reduction in the BBB breakdown and edema formation as well as neuroprotection of neuronal, glial and myelin damages caused by CHI at light and electron microscopy on the 7th day after 5 days TiO2 oxiracetam treatment. Adverse biochemical events such as upregulation of CSF nitrite and nitrate, IL-6, TNF-a and p-Tau are also reduced significantly in oxiracetam treated CHI group. On the other hand post treatment of 100mg/kg dose of normal oxiracetam in identical conditions after CHI is needed to show slight but significant neuroprotection together with mild recovery of memory function and functional deficits on the 8th day. These observations are the first to point out that nanowired delivery of oxiracetam has superior neuroprotective ability in CHI. These results indicate a promising clinical future of TiO2 oxiracetam in treating CHI patients for better quality of life and neurorehabilitation, not reported earlier.
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http://dx.doi.org/10.1016/bs.pbr.2021.06.004DOI Listing
August 2021

Alzheimer's disease neuropathology is exacerbated following traumatic brain injury. Neuroprotection by co-administration of nanowired mesenchymal stem cells and cerebrolysin with monoclonal antibodies to amyloid beta peptide.

Prog Brain Res 2021 12;265:1-97. Epub 2021 Aug 12.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

Military personnel are prone to traumatic brain injury (TBI) that is one of the risk factors in developing Alzheimer's disease (AD) at a later stage. TBI induces breakdown of the blood-brain barrier (BBB) to serum proteins into the brain and leads to extravasation of plasma amyloid beta peptide (ΑβP) into the brain fluid compartments causing AD brain pathology. Thus, there is a need to expand our knowledge on the role of TBI in AD. In addition, exploration of the novel roles of nanomedicine in AD and TBI for neuroprotection is the need of the hour. Since stem cells and neurotrophic factors play important roles in TBI and in AD, it is likely that nanodelivery of these agents exert superior neuroprotection in TBI induced exacerbation of AD brain pathology. In this review, these aspects are examined in details based on our own investigations in the light of current scientific literature in the field. Our observations show that TBI exacerbates AD brain pathology and TiO nanowired delivery of mesenchymal stem cells together with cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments, and monoclonal antibodies to amyloid beta protein thwarted the development of neuropathology following TBI in AD, not reported earlier.
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http://dx.doi.org/10.1016/bs.pbr.2021.04.008DOI Listing
August 2021

Community-acquired systemic infection complicated with rhombencephalitis.

Clin Case Rep 2021 Aug 13;9(8). Epub 2021 Aug 13.

Iuliu Hațieganu University of Medicine and Pharmacy Cluj-Napoca Cluj-Napoca Romania.

Rhombencephalitis is a rapidly progressing disease that should be taken into consideration in a patient with abrupt onset of cerebellar ataxia with rapid neurologic deterioration (tetraparesis, coma) after vascular etiology has been ruled out.
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http://dx.doi.org/10.1002/ccr3.3666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385686PMC
August 2021

Real-World Data Regarding Long-Term Administration of Natalizumab from a Neurology Department along Literature Review.

CNS Neurol Disord Drug Targets 2021 Aug 26. Epub 2021 Aug 26.

Department of Clinical Neurosciences, "Carol Davila" University of Medicine and Pharmacy, Bucharest. Romania.

Background: Natalizumab is a humanized monoclonal antibody with high efficacy and an acceptable safety profile used in the treatment of patients with multiple sclerosis (MS).

Objectives: Our aim was to report data regarding long-term administration of Natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) from our clinic.

Methods: A retrospective observational study was performed including RRMS patients who underwent treatment with ≥ 24 Natalizumab infusions. We analyzed the EDSS values, the relapse rate and the rate and type of adverse events related to Natalizumab administration.

Results: 51 subjects were included with a predominance of women (62.74%), an average age of 40.43±1.49 years, a mean disease duration of 9.86±0.7 years and mean number of Natalizumab infusions of 45.58±2.74. An increased number of patients (80.39%) were relapse-free and there was observed a mild reduction of the mean EDSS value following Natalizumab initiation in patients who had not been treated with other disease modifying therapies anteriorly. Among the encountered adverse events we registered: increased liver transaminases (13.72%), local infections (7.84%) and dysmenorrhea in one patient. The rate of severe adverse events was 3.92 and there were registered no cases of Progressive Multifocal Leukoencephalopathy (PML).

Conclusions: Natalizumab proves to be effective, has an adequate safety profile and can be administered with good tolerability for a rather extended period of time, provided that the patients are closely monitored.
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http://dx.doi.org/10.2174/1871527320666210827113733DOI Listing
August 2021

IL27 T4730C Polymorphism and Serology in Multiple Sclerosis: A Pilot Study.

In Vivo 2021 Sep-Oct;35(5):2845-2853

Department of Medical Biochemistry, Iuliu Hațieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania.

Background: Multiple sclerosis (MS) is one of the most debilitating neurological diseases of young adults. The presence of a single nucleotide polymorphism in the promoter regions of the interleukin 27 gene (IL27 T4730C, rs181206) may alter the transcription and the production of cytokine levels, leading to MS.

Patients And Methods: We performed a case-control study including 82 individuals: 51 patients diagnosed with MS and 31 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism was used in order to determine the genotypes for the IL27 T4730С polymorphism and enzyme-linked immunosorbent assay to measure the serum IL27 level.

Results: Carriers of the T4730С polymorphism were found to have a 6-fold [95% confidence intervaI (CI)=1.83-19.63, p=0.002] increased risk for MS. Univariate logistic regression analysis showed an increased frequency of the TC4730 heterozygous genotype (39.2% vs. 9.7%) and also of the C4730 allele (27.45% vs. 8.06) in patients compared to controls, with a 6.02-fold increased risk (95% CI=1.61-22.46, p=0.006) and a 4.31-fold increased risk (95% CI=1.57-11.87, p=0.002) of developing MS. IL27 levels were significantly lower in patients compared to controls (12.35 versus 14.34 pg/ml, p=0.039), without significant differences between genotypes. Multivariate logistic analysis showed that IL27 T4730C polymorphism (odds ratio=6.272, 95% CI=1.84-21.40, p=0.003) and smoking (odds ratio=4.214, 95% CI=1.39-12.74, p=0.011) represented independent risk factors for MS.

Conclusion: Our study provides a possible link between IL27 level and IL27 T4730C gene polymorphism and the risk for developing MS in a Romanian population.
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http://dx.doi.org/10.21873/invivo.12572DOI Listing
August 2021

RGC-32 Acts as a Hub to Regulate the Transcriptomic Changes Associated With Astrocyte Development and Reactive Astrocytosis.

Front Immunol 2021 29;12:705308. Epub 2021 Jul 29.

Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States.

Response Gene to Complement 32 (RGC-32) is an important mediator of the TGF-β signaling pathway, and an increasing amount of evidence implicates this protein in regulating astrocyte biology. We showed recently that spinal cord astrocytes in mice lacking RGC-32 display an immature phenotype reminiscent of progenitors and radial glia, with an overall elongated morphology, increased proliferative capacity, and increased expression of progenitor markers when compared to their wild-type (WT) counterparts that make them incapable of undergoing reactive changes during the acute phase of experimental autoimmune encephalomyelitis (EAE). Here, in order to decipher the molecular networks underlying RGC-32's ability to regulate astrocytic maturation and reactivity, we performed next-generation sequencing of RNA from WT and RGC-32 knockout (KO) neonatal mouse brain astrocytes, either unstimulated or stimulated with the pleiotropic cytokine TGF-β. Pathway enrichment analysis showed that RGC-32 is critical for the TGF-β-induced up-regulation of transcripts encoding proteins involved in brain development and tissue remodeling, such as axonal guidance molecules, transcription factors, extracellular matrix (ECM)-related proteins, and proteoglycans. Our next-generation sequencing of RNA analysis also demonstrated that a lack of RGC-32 results in a significant induction of WD repeat and FYVE domain-containing protein 1 (Wdfy1) and stanniocalcin-1 (Stc1). Immunohistochemical analysis of spinal cords isolated from normal adult mice and mice with EAE at the peak of disease showed that RGC-32 is necessary for the expression of ephrin receptor type A7 in reactive astrocytes, and that the lack of RGC-32 results in a higher number of homeodomain-only protein homeobox (HOPX) and CD133 radial glia cells. Collectively, these findings suggest that RGC-32 plays a major role in modulating the transcriptomic changes in astrocytes that ultimately lead to molecular programs involved in astrocytic differentiation and reactive changes during neuroinflammation.
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http://dx.doi.org/10.3389/fimmu.2021.705308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358671PMC
July 2021

Coffee and Tea Consumption Impact on Amyotrophic Lateral Sclerosis Progression: A Multicenter Cross-Sectional Study.

Front Neurol 2021 28;12:637939. Epub 2021 Jul 28.

Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

Amyotrophic lateral sclerosis (ALS) is a devastating and still untreatable motor neuron disease. The causes of ALS are unknown, but nutritional factors may impact the rate of disease progression. We aimed to ascertain the influence of coffee and tea consumption on ALS progression rate. In this multicenter cross-sectional study, we recruited 241 patients, 96 females, and 145 males; the mean age at onset was 59.9 ± 11.8 years. According to El Escorial criteria, 74 were definite ALS, 77 probable, 55 possible, and 35 suspected; 187 patients had spinal onset and 54 bulbar. Patients were categorized into three groups, according to their ΔFS (derived from ALS Functional Rating Scale-Revised score and disease duration from onset): slow (81), intermediate (80), and fast progressors (80). Current coffee consumers were 179 (74.3%), 34 (14.1%) were non-consumers, and 22 (9.1%) were former consumers, whereas six (2.5%) consumed decaffeinated coffee only. The log-ΔFS was weakly correlated with the duration of coffee consumption ( = 0.034), but not with the number of cup-years, or the intensity of coffee consumption (cups/day). Current tea consumers were 101 (41.9%), 6 (2.5%) were former consumers, and 134 (55.6%) were non-consumers. Among current and former consumers, 27 (25.2%) consumed only green tea, 51 (47.7%) only black tea, and 29 (27.1%) both. The log-ΔFS was weakly correlated only with the consumption duration of black tea ( = 0.028) but not with the number of cup-years. Our study does not support the hypothesis that coffee or tea consumption is associated with the ALS progression rate.
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http://dx.doi.org/10.3389/fneur.2021.637939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356721PMC
July 2021

Prognostic Factors in COVID-19 Patients With New Neurological Manifestations: A Retrospective Cohort Study in a Romanian Neurology Department.

Front Aging Neurosci 2021 17;13:645611. Epub 2021 Jun 17.

Neurology Department, Colentina Clinical Hospital, Bucharest, Romania.

The emerging Coronavirus Disease (COVID-19) pandemic caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious public health issue due to its rapid spreading, high mortality rate and lack of specific treatment. Given its unpredictable clinical course, risk assessment, and stratification for severity of COVID-19 are required. Apart from serving as admission criteria, prognostic factors might guide future therapeutic strategies. We aimed to compare clinical features and biological parameters between elderly (age ≥ 65 years) and non-elderly (age <65 years) patients with COVID-19 and new neurological symptoms/conditions. We also aimed to determine factors independently associated with all-cause in-hospital mortality. All consecutive patients with COVID-19 and new neurological symptoms/conditions admitted in our Neurology Department between April 1 and August 23, 2020 were enrolled in this observational retrospective cohort study. Patient characteristics such as demographic data, comorbidities, biological parameters, imaging findings and clinical course were recorded. All-cause in-hospital mortality was the main outcome, whereas COVID-19 severity, hospitalization duration and the levels of supplemental oxygen were the secondary outcomes. One hundred forty-eight patients were included, out of which 54.1% were women. The average age was 59.84 ± 19.06 years and 47.3% were elderly, the majority having cardiovascular and metabolic comorbidities. In the elderly group, the most frequent neurological symptoms/manifestations responsible for hospitalization were stroke symptoms followed by confusion, whereas in the non-elderly, headache prevailed. The final neurological diagnosis significantly varied between the two groups, with acute cerebrovascular events and acute confusional state in dementia most commonly encountered in the elderly (65.71 and 14.28%, respectively) and secondary headache attributed to SARS-CoV-2 infection often experienced by the non-elderly (38.46%). The elderly had statistically significant higher median values of white blood cell (8,060 vs. 6,090/μL) and neutrophil count (6,060 vs. 4,125/μL), C-reactive protein (29.2 vs. 5.72 mg/L), ferritin (482 vs. 187 mg/dL), fibrinogen (477 vs. 374 mg/dL), D-dimer (1.16 vs. 0.42), prothrombin time (151.15 vs. 13.8/s), aspartate transaminase (26.8 vs. 20.8 U/l), creatinine (0.96 vs. 0.77 mg/dL), and blood urea nitrogen level (51.1 vs. 27.65 mg/dL), as well as lower median value of hemoglobin (13.05 vs. 13.9 g/dL) and lymphocyte count (1,245 vs. 1,670/μL). Moreover, advanced age was significantly associated with more extensive lung involvement (25 vs. 10%) and higher fatality rate (40 vs. 9%). Overall, the mortality rate was 23.6%. Age as well as neutrophil count, C-reactive protein, fibrinogen, and activated partial thromboplastin time levels were independently associated with mortality. Older age, higher neutrophil count, C-reactive protein, fibrinogen, and activated partial thromboplastin time levels are independent predictors of mortality in COVID-19 patients with new neurological manifestations/conditions at admission.
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http://dx.doi.org/10.3389/fnagi.2021.645611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245846PMC
June 2021

N-Pep-12 supplementation after ischemic stroke positively impacts frequency domain QEEG.

Neurol Sci 2021 Jun 25. Epub 2021 Jun 25.

Department of Neuroscience, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Background: N-Pep-12 is a dietary supplement with neuroprotective and pro-cognitive effects, as shown in experimental models and clinical studies on patients after ischemic stroke. We tested the hypothesis that N-Pep-12 influences quantitative electroencephalography (QEEG) parameters in patients with subacute to chronic supratentorial ischemic lesions.

Methods: We performed secondary data analysis on an exploratory clinical trial (ISRCTN10702895), assessing the efficacy and safety of 90 days of once-daily treatment with 90 mg N-Pep-12 on neurocognitive function and neurorecovery outcome in patients with post-stroke cognitive impairment against a control group. All participants performed two 32-channel QEEG in resting and active states at baseline (30-120 days after stroke) and 90 days later. Power spectral density on the alpha, beta, theta, delta frequency bands, delta/alpha power ratio (DAR), and (delta+theta)/(alpha+beta) ratio (DTABR) were computed and compared across study groups using means comparison and descriptive methods. Secondarily, associations between QEEG parameters and available neuropsychological tests were explored.

Results: Our analysis showed a statistically significant main effect of EEG segments (p<0.001) in alpha, beta, delta, theta, DA, and DTAB power spectral density. An interaction effect between EEG segments and time was noticed in the alpha power. There was a significant difference in theta spectral power between patients with N-Pep-12 supplementation versus placebo at 0.05 alpha level (p=0.023), independent of time points.

Conclusion: A 90-day, 90 mg daily administration of N-Pep-12 had significant impact on some QEEG indicators in patients after supratentorial ischemic stroke, confirming possible enhancement of post-stroke neurorecovery. Further research is needed to consolidate our findings.
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http://dx.doi.org/10.1007/s10072-021-05406-9DOI Listing
June 2021

European Academy of Neurology and European Federation of Neurorehabilitation Societies guideline on pharmacological support in early motor rehabilitation after acute ischaemic stroke.

Eur J Neurol 2021 Sep 21;28(9):2831-2845. Epub 2021 Jun 21.

RoNeuro Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania.

Background And Purpose: Early pharmacological support for post-stroke neurorehabilitation has seen an abundance of mixed results from clinical trials, leaving practitioners at a loss regarding the best options to improve patient outcomes. The objective of this evidence-based guideline is to support clinical decision-making of healthcare professionals involved in the recovery of stroke survivors.

Methods: This guideline was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. PubMed, Cochrane Library and Embase were searched (from database inception to June 2018, inclusive) to identify studies on pharmacological interventions for stroke rehabilitation initiated in the first 7 days (inclusive) after stroke, which were delivered together with neurorehabilitation. A sensitivity analysis was conducted on identified interventions to address results from breaking studies (from end of search to February 2020).

Results: Upon manually screening 17,969 unique database entries (of 57,001 original query results), interventions underwent meta-analysis. Cerebrolysin (30 ml/day, intravenous, minimum 10 days) and citalopram (20 mg/day, oral) are recommended for clinical use for early neurorehabilitation after acute ischaemic stroke. The remaining interventions identified by our systematic search are not recommended for clinical use: amphetamine (5, 10 mg/day, oral), citalopram (10 mg/day, oral), dextroamphetamine (10 mg/day, oral), Di-Huang-Yi-Zhi (2 × 18 g/day, oral), fluoxetine (20 mg/day, oral), lithium (2 × 300 mg/day, oral), MLC601(3 × 400 mg/day, oral), phosphodiesterase-5 inhibitor PF-03049423 (6 mg/day, oral). No recommendation 'for' or 'against' is provided for selegiline (5 mg/day, oral). Issues with safety and tolerability were identified for amphetamine, dextroamphetamine, fluoxetine and lithium.

Conclusions: This guideline provides information for clinicians regarding existing pharmacological support in interventions for neurorecovery after acute ischaemic stroke. Updates to this material will potentially elucidate existing conundrums, improve current recommendations, and hopefully expand therapeutic options for stroke survivors.
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http://dx.doi.org/10.1111/ene.14936DOI Listing
September 2021

Widening access in the European Union Higher Education Arena: Introducing Neurotech.

J Med Life 2021 Mar-Apr;14(2):125-126

Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.

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http://dx.doi.org/10.25122/jml-2021-1002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169133PMC
June 2021

The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Amyotrophic Lateral Sclerosis Progression: A Cross-Sectional Study.

Life (Basel) 2021 Apr 17;11(4). Epub 2021 Apr 17.

Neurology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Background-Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease; smoking and alcohol drinking may impact its progression rate. Objective-To ascertain the influence of smoking and alcohol consumption on ALS progression rates. Methods-Cross-sectional multicenter study, including 241 consecutive patients (145 males); mean age at onset was 59.9 ± 11.8 years. Cigarette smoking and alcohol consumption data were collected at recruitment through a validated questionnaire. Patients were categorized into three groups according to ΔFS (derived from the ALS Functional Rating Scale-Revised and disease duration from onset): slow ( = 81), intermediate (80), and fast progressors (80). Results-Current smokers accounted for 44 (18.3%) of the participants, former smokers accounted for 10 (4.1%), and non-smokers accounted for 187 (77.6%). The age of ALS onset was lower in current smokers than non-smokers, and the ΔFS was slightly, although not significantly, higher for smokers of >14 cigarettes/day. Current alcohol drinkers accounted for 147 (61.0%) of the participants, former drinkers accounted for 5 (2.1%), and non-drinkers accounted for 89 (36.9%). The log(ΔFS) was weakly correlated only with the duration of alcohol consumption ( = 0.028), but not with the mean number of drinks/day or the drink-years. Conclusions: This cross-sectional multicenter study suggested a possible minor role for smoking in worsening disease progression. A possible interaction with alcohol drinking was suggested.
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http://dx.doi.org/10.3390/life11040352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072690PMC
April 2021

Severe cervical compressive polydiscopathic myelopathy with features of motor neuron disease: A case report.

Clin Case Rep 2021 Mar 9;9(3):1266-1272. Epub 2021 Jan 9.

Department of Clinical Neurosciences "Iuliu Hațieganu" University of Medicine and Pharmacy Cluj-Napoca Romania.

Cervical myelopathy is part of ALS mimic syndrome and should be considered in patients with clinical signs of motor neuron disease.
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http://dx.doi.org/10.1002/ccr3.3740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981701PMC
March 2021

A new chapter for the Journal of Medicine and Life in 2021.

J Med Life 2021 Jan-Mar;14(1)

Department of Neurosciences, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

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http://dx.doi.org/10.25122/jml-2021-1001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982261PMC
March 2021

Cerebrolysin after moderate to severe traumatic brain injury: prospective meta-analysis of the CAPTAIN trial series.

Neurol Sci 2021 Feb 23. Epub 2021 Feb 23.

Department of Neurosciences, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Introduction: This prospective meta-analysis summarizes results from the CAPTAIN trial series, evaluating the effects of Cerebrolysin for moderate-severe traumatic brain injury, as an add-on to usual care.

Materials And Methods: The study included two phase IIIb/IV prospective, randomized, double-blind, placebo-controlled clinical trials. Eligible patients with a Glasgow Coma Score (GCS) between 6 and 12 received study medication (50 mL of Cerebrolysin or physiological saline solution per day for ten days, followed by two additional treatment cycles with 10 mL per day for 10 days) in addition to usual care. The meta-analysis comprises the primary ensembles of efficacy criteria for 90, 30, and 10 days after TBI with a priori ordered hypotheses based on multivariate, directional tests.

Results: A total 185 patients underwent meta-analysis (mean admission GCS = 10.3, mean age = 45.3, and mean Baseline Prognostic Risk Score = 2.8). The primary endpoint, a multidimensional ensemble of functional and neuropsychological outcome scales indicated a "small-to-medium" sized effect in favor of Cerebrolysin, statistically significant at Day 30 and at Day 90 (Day 30: MW = 0.60, 95%CI 0.52 to 0.66, p = 0.0156; SMD = 0.31; OR = 1.69; Day 90: MW = 0.60, 95%CI 0.52 to 0.68, p = 0.0146; SMD = 0.34, OR = 1.77). Treatment groups showed comparable safety and tolerability profiles.

Discussion: The meta-analysis of the CAPTAIN trials confirms the safety and efficacy of Cerebrolysin after moderate-severe TBI, opening a new horizon for neurorecovery in this field. Integration of Cerebrolysin into existing guidelines should be considered after careful review of internationally applicable criteria.
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http://dx.doi.org/10.1007/s10072-020-04974-6DOI Listing
February 2021

RGC-32 Regulates Generation of Reactive Astrocytes in Experimental Autoimmune Encephalomyelitis.

Front Immunol 2020 25;11:608294. Epub 2021 Jan 25.

Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States.

Astrocytes are increasingly recognized as critical contributors to multiple sclerosis pathogenesis. We have previously shown that lack of Response Gene to Complement 32 (RGC-32) alters astrocyte morphology in the spinal cord at the peak of experimental autoimmune encephalomyelitis (EAE), suggesting a role for RGC-32 in astrocyte differentiation. In this study, we analyzed the expression and distribution of astrocytes and astrocyte progenitors by immunohistochemistry in spinal cords of wild-type (WT) and RGC-32-knockout (KO) mice with EAE and of normal adult mice. Our analysis showed that during acute EAE, WT astrocytes had a reactive morphology and increased GFAP expression, whereas RGC-32 KO astrocytes had a morphology similar to that of radial glia and an increased expression of progenitor markers such as vimentin and fatty acid binding protein 7 (FABP7). In control mice, GFAP expression and astrocyte density were also significantly higher in the WT group, whereas the number of vimentin and FABP7-positive radial glia was significantly higher in the RGC-32 KO group. studies on cultured neonatal astrocytes from WT and RGC-32 KO mice showed that RGC-32 regulates a complex array of molecular networks pertaining to signal transduction, growth factor expression and secretion, and extracellular matrix (ECM) remodeling. Among the most differentially expressed factors were insulin-like growth factor 1 (IGF1), insulin-like growth factor binding proteins (IGFBPs), and connective tissue growth factor (CTGF); their expression was downregulated in RGC-32-depleted astrocytes. The nuclear translocation of STAT3, a transcription factor critical for astrogliogenesis and driving glial scar formation, was also impaired after RGC-32 silencing. Taken together, these data suggest that RGC-32 is an important regulator of astrocyte differentiation during EAE and that in the absence of RGC-32, astrocytes are unable to fully mature and become reactive astrocytes.
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http://dx.doi.org/10.3389/fimmu.2020.608294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868332PMC
June 2021

Binswanger's disease: Case presentation and differential diagnosis.

Clin Case Rep 2020 Dec 27;8(12):3450-3457. Epub 2020 Oct 27.

Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca Cluj-Napoca Romania.

Establishing a diagnosis of Binswanger's disease requires a multimodal approach. As new pathophysiological mechanisms are revealed, tests that should yield greater specificity will become available in the years to come.
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http://dx.doi.org/10.1002/ccr3.3459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752439PMC
December 2020

Cerebrolysin enhances spinal cord conduction and reduces blood-spinal cord barrier breakdown, edema formation, immediate early gene expression and cord pathology after injury.

Prog Brain Res 2020 12;258:397-438. Epub 2020 Nov 12.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

Spinal cord evoked potentials (SCEP) are good indicators of spinal cord function in health and disease. Disturbances in SCEP amplitudes and latencies during spinal cord monitoring predict spinal cord pathology following trauma. Treatment with neuroprotective agents preserves SCEP and reduces cord pathology after injury. The possibility that cerebrolysin, a balanced composition of neurotrophic factors improves spinal cord conduction, attenuates blood-spinal cord barrier (BSCB) disruption, edema formation, and cord pathology was examined in spinal cord injury (SCI). SCEP is recorded from epidural space over rat spinal cord T9 and T12 segments after peripheral nerves stimulation. SCEP consists of a small positive peak (MPP), followed by a prominent negative peak (MNP) that is stable before SCI. A longitudinal incision (2mm deep and 5mm long) into the right dorsal horn (T10 and T11 segments) resulted in an immediate long-lasting depression of the rostral MNP with an increase in the latencies. Pretreatment with either cerebrolysin (CBL 5mL/kg, i.v. 30min before) alone or TiO nanowired delivery of cerebrolysin (NWCBL 2.5mL/kg, i.v.) prevented the loss of MNP amplitude and even enhanced further from the pre-injury level after SCI without affecting latencies. At 5h, SCI induced edema, BSCB breakdown, and cell injuries were significantly reduced by CBL and NWCBL pretreatment. Interestingly this effect on SCEP and cord pathology was still prominent when the NWCBL was delivered 2min after SCI. Moreover, expressions of c-fos and c-jun genes that are prominent at 5h in untreated SCI are also considerably reduced by CBL and NWCBL treatment. These results are the first to show that CBL and NWCBL enhanced SCEP activity and thwarted the development of cord pathology after SCI. Furthermore, NWCBL in low doses has superior neuroprotective effects on SCEP and cord pathology, not reported earlier. The functional significance and future clinical potential of CBL and NWCBL in SCI are discussed.
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http://dx.doi.org/10.1016/bs.pbr.2020.09.012DOI Listing
November 2020

Diabetes exacerbates brain pathology following a focal blast brain injury: New role of a multimodal drug cerebrolysin and nanomedicine.

Prog Brain Res 2020 9;258:285-367. Epub 2020 Nov 9.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

Blast brain injury (bBI) is a combination of several forces of pressure, rotation, penetration of sharp objects and chemical exposure causing laceration, perforation and tissue losses in the brain. The bBI is quite prevalent in military personnel during combat operations. However, no suitable therapeutic strategies are available so far to minimize bBI pathology. Combat stress induces profound cardiovascular and endocrine dysfunction leading to psychosomatic disorders including diabetes mellitus (DM). This is still unclear whether brain pathology in bBI could exacerbate in DM. In present review influence of DM on pathophysiology of bBI is discussed based on our own investigations. In addition, treatment with cerebrolysin (a multimodal drug comprising neurotrophic factors and active peptide fragments) or H-290/51 (a chain-breaking antioxidant) using nanowired delivery of for superior neuroprotection on brain pathology in bBI in DM is explored. Our observations are the first to show that pathophysiology of bBI is exacerbated in DM and TiO-nanowired delivery of cerebrolysin induces profound neuroprotection in bBI in DM, not reported earlier. The clinical significance of our findings with regard to military medicine is discussed.
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http://dx.doi.org/10.1016/bs.pbr.2020.09.004DOI Listing
November 2020

Protein kinase inhibitors in traumatic brain injury and repair: New roles of nanomedicine.

Prog Brain Res 2020 24;258:233-283. Epub 2020 Oct 24.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.

Traumatic brain injury (TBI) causes physical injury to the cell membranes of neurons, glial and axons causing the release of several neurochemicals including glutamate and cytokines altering cell-signaling pathways. Upregulation of mitogen associated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) occurs that is largely responsible for cell death. The pharmacological blockade of these pathways results in cell survival. In this review role of several protein kinase inhibitors on TBI induced oxidative stress, blood-brain barrier breakdown, brain edema formation, and resulting brain pathology is discussed in the light of current literature.
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http://dx.doi.org/10.1016/bs.pbr.2020.09.009DOI Listing
October 2020

Mild traumatic brain injury exacerbates Parkinson's disease induced hemeoxygenase-2 expression and brain pathology: Neuroprotective effects of co-administration of TiO nanowired mesenchymal stem cells and cerebrolysin.

Prog Brain Res 2020 9;258:157-231. Epub 2020 Nov 9.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

Mild traumatic brain injury (mTBI) is one of the leading predisposing factors in the development of Parkinson's disease (PD). Mild or moderate TBI induces rapid production of tau protein and alpha synuclein (ASNC) in the cerebrospinal fluid (CSF) and in several brain areas. Enhanced tau-phosphorylation and ASNC alters the molecular machinery of the brain leading to PD pathology. Recent evidences show upregulation of constitutive isoform of hemeoxygenase (HO-2) in PD patients that correlates well with the brain pathology. mTBI alone induces profound upregulation of HO-2 immunoreactivity. Thus, it would be interesting to explore whether mTBI exacerbates PD pathology in relation to tau, ASNC and HO-2 expression. In addition, whether neurotrophic factors and stem cells known to reduce brain pathology in TBI could induce neuroprotection in PD following mTBI. In this review role of mesenchymal stem cells (MSCs) and cerebrolysin (CBL), a well-balanced composition of several neurotrophic factors and active peptide fragments using nanowired delivery in PD following mTBI is discussed based on our own investigation. Our results show that mTBI induces concussion exacerbates PD pathology and nanowired delivery of MSCs and CBL induces superior neuroprotection. This could be due to reduction in tau, ASNC and HO-2 expression in PD following mTBI, not reported earlier. The functional significance of our findings in relation to clinical strategies is discussed.
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http://dx.doi.org/10.1016/bs.pbr.2020.09.010DOI Listing
November 2020

Co-administration of TiO-nanowired dl-3-n-butylphthalide (dl-NBP) and mesenchymal stem cells enhanced neuroprotection in Parkinson's disease exacerbated by concussive head injury.

Prog Brain Res 2020 9;258:101-155. Epub 2020 Nov 9.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

dl-3-n-butylphthalide (dl-NBP) is a powerful antioxidant compound with profound neuroprotective effects in stroke and brain injury. However, its role in Parkinson's disease (PD) is not well known. Traumatic brain injury (TBI) is one of the key factors in precipitating PD like symptoms in civilians and particularly in military personnel. Thus, it would be interesting to explore the possible neuroprotective effects of NBP in PD following concussive head injury (CHI). In this chapter effect of nanowired delivery of NBP together with mesenchymal stem cells (MSCs) in PD with CHI is discussed based on our own investigations. It appears that CHI exacerbates PD pathophysiology in terms of p-tau, α-synuclein (ASNC) levels in the cerebrospinal fluid (CSF) and the loss of TH immunoreactivity in substantia niagra pars compacta (SNpc) and striatum (STr) along with dopamine (DA), dopamine decarboxylase (DOPAC). And homovanillic acid (HVA). Our observations are the first to show that a combination of NBP with MSCs when delivered using nanowired technology induces superior neuroprotective effects in PD brain pathology exacerbated by CHI, not reported earlier.
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http://dx.doi.org/10.1016/bs.pbr.2020.09.011DOI Listing
November 2020

Concussive head injury exacerbates neuropathology of sleep deprivation: Superior neuroprotection by co-administration of TiO-nanowired cerebrolysin, alpha-melanocyte-stimulating hormone, and mesenchymal stem cells.

Prog Brain Res 2020 2;258:1-77. Epub 2020 Nov 2.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

Sleep deprivation (SD) is common in military personnel engaged in combat operations leading to brain dysfunction. Military personnel during acute or chronic SD often prone to traumatic brain injury (TBI) indicating the possibility of further exacerbating brain pathology. Several lines of evidence suggest that in both TBI and SD alpha-melanocyte-stimulating hormone (α-MSH) and brain-derived neurotrophic factor (BDNF) levels decreases in plasma and brain. Thus, a possibility exists that exogenous supplement of α-MSH and/or BDNF induces neuroprotection in SD compounded with TBI. In addition, mesenchymal stem cells (MSCs) are very portent in inducing neuroprotection in TBI. We examined the effects of concussive head injury (CHI) in SD on brain pathology. Furthermore, possible neuroprotective effects of α-MSH, MSCs and neurotrophic factors treatment were explored in a rat model of SD and CHI. Rats subjected to 48h SD with CHI exhibited higher leakage of BBB to Evans blue and radioiodine compared to identical SD or CHI alone. Brain pathology was also exacerbated in SD with CHI group as compared to SD or CHI alone together with a significant reduction in α-MSH and BDNF levels in plasma and brain and enhanced level of tumor necrosis factor-alpha (TNF-α). Exogenous administration of α-MSH (250μg/kg) together with MSCs (1×10) and cerebrolysin (a balanced composition of several neurotrophic factors and active peptide fragments) (5mL/kg) significantly induced neuroprotection in SD with CHI. Interestingly, TiO nanowired delivery of α-MSH (100μg), MSCs, and cerebrolysin (2.5mL/kg) induced enhanced neuroprotection with higher levels of α-MSH and BDNF and decreased the TNF-α in SD with CHI. These observations are the first to show that TiO nanowired administration of α-MSH, MSCs and cerebrolysin induces superior neuroprotection following SD in CHI, not reported earlier. The clinical significance of our findings in light of the current literature is discussed.
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http://dx.doi.org/10.1016/bs.pbr.2020.09.003DOI Listing
November 2020

Paraneoplastic Stiff Person Syndrome in Early-Stage Breast Cancer with Positive Anti-Amphiphysin Antibodies.

Case Rep Neurol 2020 Sep-Dec;12(3):339-347. Epub 2020 Oct 2.

Department of Neuroscience, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Stiff person syndrome (SPS) is a rare neurologic disorder, characterized by muscle rigidity and spasms. Anti-glutamic acid decarboxylase (anti-GAD) antibodies are associated with the classic form of SPS, while antibodies against amphiphysin are associated with the paraneoplastic form of the disease. We present the case of a patient with paraneoplastic SPS, presenting with muscle cramps of lower extremities that progressed to severe muscle rigidity and spasms, associated with a right breast tumor and positive anti-amphiphysin antibodies. Paraneoplastic SPS is a rare neurological disorder, challenging for the physicians both to diagnose and treat.
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http://dx.doi.org/10.1159/000508942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588701PMC
October 2020

Added Value of QEEG for the Differential Diagnosis of Common Forms of Dementia.

Clin EEG Neurosci 2021 May 8;52(3):201-210. Epub 2020 Nov 8.

Department of Neurosciences, 37576"Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Cluj, Romania.

Introduction: Quantitative electroencephalography (QEEG) has been documented as a helpful tool in the differential diagnosis of Alzheimer's disease (AD) with common forms of dementia. The main objective of the study was to assess the role of QEEG in AD differential diagnosis with other forms of dementia: Lewy body dementia (LBD), Parkinson's disease dementia (PDD), frontotemporal dementia (FTD), and vascular dementia (VaD).

Methods: We searched PubMed, Embase, and PsycNET, for articles in English published in peer-reviewed journals from January 1, 1980 to April 23, 2019 using adapted search strategies containing keywords and . The risk of bias was assessed by applying the QUADAS tool. The systematic review was conducted in line with the PRISMA methodology.

Results: We identified 10 articles showcasing QEEG features used in diagnosing dementia, EEG slowing phenomena in AD and PDD, coherence changes in AD and VaD, the role of LORETA in dementia, and the controversial QEEG pattern in FTD. Results vary significantly in terms of sociodemographic features of the studied population, neuropsychological assessment, signal acquisition and processing, and methods of analysis.

Discussion: This article provides a comparative synthesis of existing evidence on the role of QEEG in diagnosing dementia, highlighting some specific features for different types of dementia (eg, the slow-wave activity has been remarked in both AD and PDD, but more pronounced in PDD patients, a diminution in anterior and posterior alpha coherence was noticed in AD, and a lower alpha coherence in the left temporal-parietal-occipital regions was observed in VaD).

Conclusion: QEEG may be a useful investigation for settling the diagnosis of common forms of dementia. Further research of quantitative analyses is warranted, particularly on the association between QEEG, neuropsychological, and imaging features. In conjunction, these methods may provide superior diagnostic accuracy in the diagnosis of dementia.
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http://dx.doi.org/10.1177/1550059420971122DOI Listing
May 2021
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