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Article: The Role of Glymphatic System in Alzheimer's and Parkinson's Disease Pathogenesis.

Buccellato, Francesca R / D'Anca, Marianna / Serpente, Maria / Arighi, Andrea / Galimberti, Daniela

2022 Volume 10, Issue 9

Abstract: Alzheimer's disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson's disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological ... ...

Abstract	Alzheimer's disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson's disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative diseases has led to the hypothesis of new pathogenic mechanisms to target and design new potential therapeutic approaches. The recent observation that the glymphatic system is supposed to be responsible for the movement of cerebrospinal fluid into the brain and clearance of metabolic waste has led to study its involvement in the pathogenesis of these classic proteinopathies. Aquaporin-4 (AQP4), a water channel located in the endfeet of astrocyte membrane, is considered a primary driver of the glymphatic clearance system, and defective AQP4-mediated glymphatic drainage has been linked to proteinopathies. The objective of the present review is to present the recent body of knowledge that links the glymphatic system to the pathogenesis of AD and PD disease and other lifestyle factors such as sleep deprivation and exercise that may influence glymphatic system function. We will also focus on the potential neuroimaging approaches that could identify a neuroimaging marker to detect glymphatic system changes.
Language	English
Publishing date	2022-09-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10092261
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Article ; Online: Role of Genetics and Epigenetics in the Pathogenesis of Alzheimer's Disease and Frontotemporal Dementia.

Fenoglio, Chiara / Scarpini, Elio / Serpente, Maria / Galimberti, Daniela

Journal of Alzheimer's disease : JAD

2018 Volume 62, Issue 3, Page(s) 913–932

Abstract: Alzheimer's disease (AD) and frontotemporal dementia (FTD) represent the first cause of dementia in senile and pre-senile population, respectively. A percentage of cases have a genetic cause, inherited with an autosomal dominant pattern of transmission. ... ...

Abstract	Alzheimer's disease (AD) and frontotemporal dementia (FTD) represent the first cause of dementia in senile and pre-senile population, respectively. A percentage of cases have a genetic cause, inherited with an autosomal dominant pattern of transmission. The majority of cases, however, derive from complex interactions between a number of genetic and environmental factors. Gene variants may act as risk or protective factors. Their combination with a variety of environmental exposures may result in increased susceptibility to these diseases or may influence their course. The scenario is even more complicated considering the effect of epigenetics, which encompasses mechanisms able to alter the expression of genes without altering the DNA sequence. In this review, an overview of the current genetic and epigenetic progresses in AD and FTD will be provided, with particular focus on 1) causative genes, 2) genetic risk factors and disease modifiers, and 3) epigenetics, including methylation, non-coding RNAs and chromatin remodeling.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Animals ; Epigenesis, Genetic ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Genetic Predisposition to Disease ; Humans
Language	English
Publishing date	2018-03-21
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-170702
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Article ; Online: miRNA Expression Is Increased in Serum from Patients with Semantic Variant Primary Progressive Aphasia.

Serpente, Maria / Ghezzi, Laura / Fenoglio, Chiara / Buccellato, Francesca R / Fumagalli, Giorgio G / Rotondo, Emanuela / Arcaro, Marina / Arighi, Andrea / Galimberti, Daniela

International journal of molecular sciences

2022 Volume 23, Issue 15

Abstract: Primary progressive aphasia (PPA) damages the parts of the brain that control speech and language. There are three clinical PPA variants: nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). The pathophysiology underlying PPA variants ... ...

Abstract	Primary progressive aphasia (PPA) damages the parts of the brain that control speech and language. There are three clinical PPA variants: nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). The pathophysiology underlying PPA variants is not fully understood, including the role of micro (mi)RNAs which were previously shown to play a role in several neurodegenerative diseases. Using a two-step analysis (array and validation through real-time PCR), we investigated the miRNA expression pattern in serum from 54 PPA patients and 18 controls. In the svPPA cohort, we observed a generalized upregulation of miRNAs with miR-106b-5p and miR-133a-3p reaching statistical significance (miR-106b-5p: 2.69 ± 0.89 mean ± SD vs. 1.18 ± 0.28, p < 0.0001; miR-133a-3p: 2.09 ± 0.10 vs. 0.74 ± 0.11 mean ± SD, p = 0.0002). Conversely, in lvPPA, the majority of miRNAs were downregulated. GO enrichment and KEGG pathway analyses revealed that target genes of both miRNAs are involved in pathways potentially relevant for the pathogenesis of neurodegenerative diseases. This is the first study that investigates the expression profile of circulating miRNAs in PPA variant patients. We identified a specific miRNA expression profile in svPPA that could differentiate this pathological condition from other PPA variants. Nevertheless, these preliminary results need to be confirmed in a larger independent cohort.
MeSH term(s)	Aphasia, Primary Progressive/genetics ; Aphasia, Primary Progressive/pathology ; Brain/pathology ; Humans ; Language ; MicroRNAs/genetics ; Semantics
Chemical Substances	MicroRNAs
Language	English
Publishing date	2022-07-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23158487
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Article ; Online: Altered Extracellular Vesicle miRNA Profile in Prodromal Alzheimer's Disease.

Visconte, Caterina / Fenoglio, Chiara / Serpente, Maria / Muti, Paola / Sacconi, Andrea / Rigoni, Marta / Arighi, Andrea / Borracci, Vittoria / Arcaro, Marina / Arosio, Beatrice / Ferri, Evelyn / Golia, Maria Teresa / Scarpini, Elio / Galimberti, Daniela

International journal of molecular sciences

2023 Volume 24, Issue 19

Abstract: Extracellular vesicles (EVs) are nanosized vesicles released by almost all body tissues, representing important mediators of cellular communication, and are thus promising candidate biomarkers for neurodegenerative diseases like Alzheimer's disease (AD). ...

Abstract	Extracellular vesicles (EVs) are nanosized vesicles released by almost all body tissues, representing important mediators of cellular communication, and are thus promising candidate biomarkers for neurodegenerative diseases like Alzheimer's disease (AD). The aim of the present study was to isolate total EVs from plasma and characterize their microRNA (miRNA) contents in AD patients. We isolated total EVs from the plasma of all recruited subjects using ExoQuickULTRA exosome precipitation solution (SBI). Subsequently, circulating total EVs were characterized using Nanosight nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and Western blotting. A panel of 754 miRNAs was determined with RT-qPCR using TaqMan OpenArray technology in a QuantStudio 12K System (Thermo Fisher Scientific). The results demonstrated that plasma EVs showed widespread deregulation of specific miRNAs (miR-106a-5p, miR-16-5p, miR-17-5p, miR-195-5p, miR-19b-3p, miR-20a-5p, miR-223-3p, miR-25-3p, miR-296-5p, miR-30b-5p, miR-532-3p, miR-92a-3p, and miR-451a), some of which were already known to be associated with neurological pathologies. A further validation analysis also confirmed a significant upregulation of miR-16-5p, miR-25-3p, miR-92a-3p, and miR-451a in prodromal AD patients, suggesting these dysregulated miRNAs are involved in the early progression of AD.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; MicroRNAs/genetics ; Biomarkers ; Extracellular Vesicles/genetics ; Exosomes/genetics
Chemical Substances	MicroRNAs ; Biomarkers ; MIRN296 microRNA, human ; MIRN532 microRNA, human
Language	English
Publishing date	2023-09-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241914749
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Article ; Online: Klotho Gene Expression Is Decreased in Peripheral Blood Mononuclear Cells in Patients with Alzheimer's Disease and Frontotemporal Dementia.

Sorrentino, Federica / Fenoglio, Chiara / Sacchi, Luca / Serpente, Maria / Arighi, Andrea / Carandini, Tiziana / Arosio, Beatrice / Ferri, Evelyn / Arcaro, Marina / Visconte, Caterina / Rotondo, Emanuela / Scarpini, Elio / Galimberti, Daniela

Journal of Alzheimer's disease : JAD

2023 Volume 94, Issue 3, Page(s) 1225–1231

Abstract: Background: The longevity gene Klotho (KL) was recently associated with neurodegenerative diseases including Alzheimer's disease (AD). Its role in the brain has not been completely elucidated, although evidence suggests that KL-VS heterozygosity is ... ...

Abstract	Background: The longevity gene Klotho (KL) was recently associated with neurodegenerative diseases including Alzheimer's disease (AD). Its role in the brain has not been completely elucidated, although evidence suggests that KL-VS heterozygosity is associated with a reduced risk of AD in Apolipoprotein E ɛ4 carriers. Conversely, no data about genetic association with frontotemporal dementia (FTD) are available so far. Objective: To investigate the involvement of KL in AD and FTD by the determination of the genetic frequency of KL-VS variant and the expression analysis of KL gene. Methods: A population consisting of 438 patients and 240 age-matched controls was enrolled for the study. KL-VS and APOE genotypes were assessed by allelic discrimination through a QuantStudio 12K system. KL gene expression analysis was performed in a restricted cohort of patients consisting of 43 AD patients, 41 FTD patients and 19 controls. KL gene expression was assessed in peripheral blood mononuclear cells with specific TaqMan assay. Statistical analysis was performed using GraphPad 9 Prims software. Results: KL-VS frequency was comparable to the ones found in literature and no differences were found in both allelic and genotypic frequencies between patients and controls were found. Conversely, KL expression levels were significantly lower in AD and FTD patients compared with controls (mean fold regulation - 4.286 and - 6.561 versus controls in AD and FTD, respectively, p = 0.0037). Conclusion: This is the first study investigating KL in FTD. We showed a decreased expression of the gene in AD and FTD, independent of the genotype, suggesting a role of Klotho in common steps during neurodegeneration.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Frontotemporal Dementia/genetics ; Gene Expression ; Genotype ; Leukocytes, Mononuclear
Chemical Substances	KL protein, human (EC 3.2.1.31)
Language	English
Publishing date	2023-06-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-230322
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Article ; Online: Analysis of C9orf72 Intermediate Alleles in a Retrospective Cohort of Neurological Patients: Risk Factors for Alzheimer's Disease?

Serpente, Maria / Fenoglio, Chiara / Arighi, Andrea / Fumagalli, Giorgio G / Arcaro, Marina / Sorrentino, Federica / Visconte, Caterina / Scarpini, Elio / Galimberti, Daniela

Journal of Alzheimer's disease : JAD

2021 Volume 81, Issue 4, Page(s) 1445–1451

Abstract: Background: C9orf72 hexanucleotide GGGGCC (G4C2) large repeat expansions within the first intron of the gene are a major cause of familial frontotemporal dementia, but also of apparently sporadic cases. Alleles with > 30 repeats are often considered ... ...

Abstract	Background: C9orf72 hexanucleotide GGGGCC (G4C2) large repeat expansions within the first intron of the gene are a major cause of familial frontotemporal dementia, but also of apparently sporadic cases. Alleles with > 30 repeats are often considered pathogenic, but the repeat length threshold is still undefined. It is also unclear if C9orf72 intermediate alleles (9-30 repeats) have clinically significant effects. Objectives: We correlated the presence of C9orf72 intermediate alleles with clinical diagnoses in a perspective cohort referred to a secondary memory clinic. Methods: All samples were genotyped with AmplideXPCR/CE C9ORF72 Kit (Asuragen, Inc), an optimized C9orf72 PCR amplification reagent. Results: We showed that in patients with Alzheimer's disease (AD) the frequency of the intermediate repeat alleles was significantly increased versus controls (34/54, 63%AD versus 16/39, 41%CTRLs, p = 0.01, OR 2.91 CI 95%1.230-6.077), whereas no significant differences (p > 0.05) were observed when comparing all other dementias with non-demented individuals. Conclusion:* Our findings suggest that C9orf72 intermediate repeat units may represent a genetic risk factor, contributing to the occurrence of AD. Nevertheless, further longitudinal studies, including larger cohort of subjects with intermediate alleles with long-term follow-up, would be needed to confirm these results.
Language	English
Publishing date	2021-05-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-210249
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Article: Association between enlarged perivascular spaces and cerebrospinal fluid aquaporin-4 and tau levels: report from a memory clinic.

Sacchi, Luca / Arcaro, Marina / Carandini, Tiziana / Pietroboni, Anna Margherita / Fumagalli, Giorgio Giulio / Fenoglio, Chiara / Serpente, Maria / Sorrentino, Federica / Visconte, Caterina / Pintus, Manuela / Conte, Giorgio / Contarino, Valeria Elisa / Scarpini, Elio / Triulzi, Fabio / Galimberti, Daniela / Arighi, Andrea

Frontiers in aging neuroscience

2023 Volume 15, Page(s) 1191714

Abstract: Background: Perivascular spaces (PVS) are fluid-filled compartments that dilate in response to many different conditions. A high burden of enlarged PVS (EPVS) in the centrum semiovale (CSO) has been linked to neurodegeneration. Moreover, an increase in ... ...

Abstract	Background: Perivascular spaces (PVS) are fluid-filled compartments that dilate in response to many different conditions. A high burden of enlarged PVS (EPVS) in the centrum semiovale (CSO) has been linked to neurodegeneration. Moreover, an increase in cerebrospinal fluid (CSF) levels of aquaporin-4 (AQP4), a water channel expressed on PVS-bounding astrocytes, has been described in patients with neurodegenerative dementia. Our aim was to investigate the relationship between neurodegenerative diseases and two putative glymphatic system biomarkers: AQP4 and EPVS. Methods: We included 70 individuals, 54 patients with neurodegenerative diseases and 16 subjects with non-degenerative conditions. EPVS were visually quantified on MRI-scans applying Paradise's scale. All subjects underwent lumbar puncture for the measurement of AQP4 levels in the cerebrospinal fluid (CSF). CSF levels of amyloid-β-1-42, phosphorylated and total tau (tTau) were also measured. Linear regression analyses were adjusted for age, sex, education and disease duration, after excluding outliers. Results: Cerebrospinal fluid (CSF)-AQP4 levels were independent predictors of total (β = 0.28, standard error [SE] = 0.08, Conclusion: We provide evidence that CSO-EPVS and CSF-AQP4 might be clinically meaningful biomarkers of glymphatic dysfunction and associated neurodegeneration.
Language	English
Publishing date	2023-07-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2023.1191714
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Article: A Novel Automated Chemiluminescence Method for Detecting Cerebrospinal Fluid Amyloid-Beta 1-42 and 1-40, Total Tau and Phosphorylated-Tau: Implications for Improving Diagnostic Performance in Alzheimer's Disease.

Arcaro, Marina / Fenoglio, Chiara / Serpente, Maria / Arighi, Andrea / Fumagalli, Giorgio G / Sacchi, Luca / Floro, Stefano / D'Anca, Marianna / Sorrentino, Federica / Visconte, Caterina / Perego, Alberto / Scarpini, Elio / Galimberti, Daniela

Biomedicines

2022 Volume 10, Issue 10

Abstract: Recently, a fully automated instrument for the detection of the Cerebrospinal Fluid (CSF) biomarker for Alzheimer’s disease (AD) (low concentration of Amyloid-beta 42 (Aβ42), high concentration of total tau (T-tau) and Phosphorylated-tau (P-tau181)), has ...

Abstract	Recently, a fully automated instrument for the detection of the Cerebrospinal Fluid (CSF) biomarker for Alzheimer’s disease (AD) (low concentration of Amyloid-beta 42 (Aβ42), high concentration of total tau (T-tau) and Phosphorylated-tau (P-tau181)), has been implemented, namely CLEIA. We conducted a comparative analysis between ELISA and CLEIA methods in order to evaluate the analytical precision and the diagnostic performance of the novel CLEIA system on 111 CSF samples. Results confirmed a robust correlation between ELISA and CLEIA methods, with an improvement of the accuracy with the new CLEIA methodology in the detection of the single biomarkers and in their ratio values. For Aβ42 regression analysis with Passing−Bablok showed a Pearson correlation coefficient r = 0.867 (0.8120; 0.907% 95% CI p < 0.0001), T-tau analysis: r = 0.968 (0.954; 0.978% 95% CI p < 0.0001) and P-tau181: r = 0.946 (0.922; 0.962 5% 95% CI p < 0.0001). The overall ROC AUC comparison between ROC in ELISA and ROC in CLEIA confirmed a more accurate ROC AUC with the new automatic method: T-tau AUC ELISA = 0.94 (95% CI 0.89; 0.99 p < 0.0001) vs. AUC CLEIA = 0.95 (95% CI 0.89; 1.00 p < 0.0001), and P-tau181 AUC ELISA = 0.91 (95% CI 0.85; 0.98 p < 0.0001) vs. AUC CLEIA = 0.98 (95% CI 0.95; 1.00 p < 0.0001). The performance of the new CLEIA method in automation is comparable and, for tau and P-tau181, even better, as compared with standard ELISA. Hopefully, in the future, automation could be useful in clinical diagnosis and also in the context of clinical studies.
Language	English
Publishing date	2022-10-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10102667
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Article ; Online: Circulating Non-Coding RNA Levels Are Altered in Autosomal Dominant Frontotemporal Dementia.

Fenoglio, Chiara / Serpente, Maria / Visconte, Caterina / Arcaro, Marina / Sorrentino, Federica / D'Anca, Marianna / Arighi, Andrea / Rotondo, Emanuela / Vimercati, Roberto / Rossi, Giacomina / Scarpini, Elio / Galimberti, Daniela

International journal of molecular sciences

2022 Volume 23, Issue 23

Abstract: Frontotemporal Dementia (FTD) represents a highly heritable neurodegenerative disorder. Most of the heritability is caused by autosomal dominant mutations in the Microtubule-Associated Protein Tau ( ...

Abstract	Frontotemporal Dementia (FTD) represents a highly heritable neurodegenerative disorder. Most of the heritability is caused by autosomal dominant mutations in the Microtubule-Associated Protein Tau (
MeSH term(s)	Humans ; C9orf72 Protein/genetics ; Frontotemporal Dementia/metabolism ; MicroRNAs/genetics ; Mutation ; Pick Disease of the Brain/genetics ; Progranulins/genetics ; RNA, Long Noncoding/genetics ; tau Proteins/genetics
Chemical Substances	C9orf72 Protein ; MicroRNAs ; Progranulins ; RNA, Long Noncoding ; tau Proteins
Language	English
Publishing date	2022-11-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232314723
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Article ; Online: Aquaporin-4 cerebrospinal fluid levels are higher in neurodegenerative dementia: looking at glymphatic system dysregulation.

Arighi, Andrea / Arcaro, Marina / Fumagalli, Giorgio Giulio / Carandini, Tiziana / Pietroboni, Anna Margherita / Sacchi, Luca / Fenoglio, Chiara / Serpente, Maria / Sorrentino, Federica / Isgrò, Giovanni / Turkheimer, Federico / Scarpini, Elio / Galimberti, Daniela

Alzheimer's research & therapy

2022 Volume 14, Issue 1, Page(s) 135

Abstract: Aquaporin-4 (AQP4) is a channel protein that plays a fundamental role in glymphatic system, a newly described pathway for fluid exchange in the central nervous system, as well as a central figure in a fascinating new theory for the pathophysiology of ... ...

Abstract	Aquaporin-4 (AQP4) is a channel protein that plays a fundamental role in glymphatic system, a newly described pathway for fluid exchange in the central nervous system, as well as a central figure in a fascinating new theory for the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). In this study, cerebrospinal fluid (CSF) concentration of AQP4, amyloid-β, total tau and P-tau were determined in 103 CSF samples from patients affected by neurodegenerative dementias (AD and FTD) or psychiatric diseases and 21 controls. Significantly higher levels of AQP4 were found in AD and FTD patients compared to subjects not affected by neurodegenerative diseases, and a significant, positive correlation between AQP4 and total tau levels was found. This evidence may pave the way for future studies focused on the role of this channel protein in the clinical assessment of the glymphatic function and degree of neurodegeneration.
MeSH term(s)	Alzheimer Disease/cerebrospinal fluid ; Alzheimer Disease/metabolism ; Aquaporin 4/cerebrospinal fluid ; Aquaporin 4/metabolism ; Frontotemporal Dementia/cerebrospinal fluid ; Frontotemporal Dementia/metabolism ; Glymphatic System/metabolism ; Humans ; Neurodegenerative Diseases/cerebrospinal fluid ; Neurodegenerative Diseases/metabolism ; tau Proteins/cerebrospinal fluid ; tau Proteins/metabolism
Chemical Substances	AQP4 protein, human ; Aquaporin 4 ; tau Proteins
Language	English
Publishing date	2022-09-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-022-01077-6
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