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Article ; Online: Mixed Pathologies in a Subject with a Novel PSEN1 G206R Mutation.

Libard, Sylwia / Giedraitis, Vilmantas / Kilander, Lena / Ingelsson, Martin / Alafuzoff, Irina

2022 Volume 90, Issue 4, Page(s) 1601–1614

Abstract: Background: There are more than 300 presenilin-1 (PSEN1) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed.: Objective: To assess neuropathological changes (NC) in a 73-year-old ... ...

Abstract	Background: There are more than 300 presenilin-1 (PSEN1) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed. Objective: To assess neuropathological changes (NC) in a 73-year-old subject with the novel PSEN1 G206R mutation suffering from cognitive decline in over 20 years. To compare these findings with an age- and gender-matched subject with sporadic Alzheimer's disease (sAD). Methods: The brains were assessed macro- and microscopically and the proteinopathies were staged according to current recommendations. Results: The AD neuropathological change (ADNC) was more extensive in the mutation carrier, although both individuals reached a high level of ADNC. The transactive DNA binding protein 43 pathology was at the end-stage in the index subject, a finding not previously described in familial AD. This pathology was moderate in the sAD subject. The PSEN1 G206R subject displayed full-blown alpha-synuclein pathology, while this proteinopathy was absent in the sAD case. Additionally, the mutation carrier displayed pronounced neuroinflammation, not previously described in association with PSEN1 mutations. Conclusion: Our findings are exceptional, as the PSEN1 G206R subject displayed an end-stage pathology of every common proteinopathy. It is unclear whether the observed alterations are caused by the mutation or are related to a cross-seeding mechanisms. The pronounced neuroinflammation in the index patient can be reactive to the extensive NC or a contributing factor to the proteinopathies. Thorough postmortem neuropathological and genetic assessment of subjects with familial AD is warranted, for further understanding of a dementing illness.
Language	English
Publishing date	2022-10-31
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-220655
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Article ; Online: Dual-Task Interference of Gait Parameters During Different Conditions of the Timed Up-and-Go Test Performed by Community-Dwelling Older Adults.

Åberg, Anna Cristina / Larsson, Liss Elin / Giedraitis, Vilmantas / Berglund, Lars / Halvorsen, Kjartan

Journal of aging and physical activity

2023 Volume 31, Issue 5, Page(s) 823–832

Abstract: The Timed Up-and-Go (TUG) test has been combined with different verbal/cognitive tasks (i.e., TUG dual task [TUGdt]) as a form of motor-cognitive testing. However, it is still unclear how different TUGdt conditions affect gait among older adults. Thirty ... ...

Abstract	The Timed Up-and-Go (TUG) test has been combined with different verbal/cognitive tasks (i.e., TUG dual task [TUGdt]) as a form of motor-cognitive testing. However, it is still unclear how different TUGdt conditions affect gait among older adults. Thirty community-dwelling older adults, with mean age of 73 years, participated in the study. Data were collected using marker-free video recordings. Gait parameters were extracted using a semiautomatic deep learning system. Comparisons of execution time and gait parameter outcomes were made under TUG and three types of TUGdt test conditions: TUGdt-naming animals, TUGdt-months backwards, and TUGdt-serial 7s. Statistical analyses were based on mean values of the gait parameters for each participant and TUG condition, including TUGdt gait cost, that is, the relative difference between TUGdt and TUG. All the investigated TUGdt conditions resulted in varying degrees of gait parameter changes. Under TUGdt conditions, participants took shorter and slower steps, with TUGdt-serial 7s causing the largest interference.
MeSH term(s)	Humans ; Independent Living ; Gait
Language	English
Publishing date	2023-04-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1543-267X
ISSN (online)	1543-267X
DOI	10.1123/japa.2022-0304
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Article ; Online: Prediction of conversion to dementia disorders based on timed up and go dual-task test verbal and motor outcomes: a five-year prospective memory-clinic-based study.

Åberg, Anna Cristina / Petersson, Johanna R / Giedraitis, Vilmantas / McKee, Kevin J / Rosendahl, Erik / Halvorsen, Kjartan / Berglund, Lars

BMC geriatrics

2023 Volume 23, Issue 1, Page(s) 535

Abstract: Background: While assessment tools can increase the detection of cognitive impairment, there is currently insufficient evidence regarding clinical outcomes based on screening for cognitive impairment in older adults.: Methods: The study purpose was ... ...

Abstract	Background: While assessment tools can increase the detection of cognitive impairment, there is currently insufficient evidence regarding clinical outcomes based on screening for cognitive impairment in older adults. Methods: The study purpose was to investigate whether Timed Up and Go dual-task test (TUGdt) results, based on TUG combined with two different verbal tasks (name different animals, TUGdt-NA, and recite months in reverse order, TUGdt-MB), predicted dementia incidence over a period of five years among patients (N = 186, mean = 70.7 years; 45.7% female) diagnosed with Subjective Cognitive Impairment (SCI) and Mild Cognitive Impairment (MCI) following assessment at two memory clinics. Associations between TUG parameters and dementia incidence were examined in Cox regression models. Results: During follow-up time (median (range) 3.7 (0.1-6.1) years) 98 participants converted to dementia. Novel findings indicated that the TUGdt parameter words/time, after adjustment for age, gender, and education, can be used for the prediction of conversion to dementia in participants with SCI or MCI over a period of five years. Among the TUG-related parameters investigated, words/time showed the best predictive capacity, while time scores of TUG and TUGdt as well as TUGdt cost did not produce significant predictive results. Results further showed that the step parameter step length during TUGdt predicts conversion to dementia before adjustment for age, gender, and education. Optimal TUGdt cutoffs for predicting dementia at 2- and 4-year follow-up based on words/time were calculated. The sensitivity of the TUGdt cutoffs was high at 2-year follow-up: TUGdt-NA words/time, 0.79; TUGdt-MB words/time, 0.71; reducing respectively to 0.64 and 0.65 at 4-year follow-up. Conclusions: TUGdt words/time parameters have potential as cost-efficient tools for conversion-to-dementia risk assessment, useful for research and clinical purposes. These parameters may be able to bridge the gap of insufficient evidence for such clinical outcomes. Trial registration: ClinicalTrials.gov Identifier: NCT05893524: https://www. Clinicaltrials: gov/study/NCT05893524?id=NCT05893524&rank=1 .
MeSH term(s)	Female ; Humans ; Animals ; Male ; Memory, Episodic ; Educational Status ; Ambulatory Care Facilities ; Cognitive Dysfunction/diagnosis ; Cognitive Dysfunction/epidemiology ; Dementia/diagnosis ; Dementia/epidemiology
Language	English
Publishing date	2023-09-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2059865-8
ISSN	1471-2318 ; 1471-2318
ISSN (online)	1471-2318
ISSN	1471-2318
DOI	10.1186/s12877-023-04262-w
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Article ; Online: Correction: Prediction of conversion to dementia disorders based on timed up and go dual-task test verbal and motor outcomes: a five-year prospective memory-clinic-based study.

Åberg, Anna Cristina / R Petersson, Johanna / Giedraitis, Vilmantas / McKee, Kevin J / Rosendahl, Erik / Halvorsen, Kjartan / Berglund, Lars

BMC geriatrics

2023 Volume 23, Issue 1, Page(s) 714

Language	English
Publishing date	2023-11-02
Publishing country	England
Document type	Published Erratum
ZDB-ID	2059865-8
ISSN	1471-2318 ; 1471-2318
ISSN (online)	1471-2318
ISSN	1471-2318
DOI	10.1186/s12877-023-04427-7
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Article ; Online: Mutation analysis of disease causing genes in patients with early onset or familial forms of Alzheimer's disease and frontotemporal dementia.

Pagnon de la Vega, María / Näslund, Carl / Brundin, RoseMarie / Lannfelt, Lars / Löwenmark, Malin / Kilander, Lena / Ingelsson, Martin / Giedraitis, Vilmantas

BMC genomics

2022 Volume 23, Issue 1, Page(s) 99

Abstract: Background: Most dementia disorders have a clear genetic background and a number of disease genes have been identified. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genes for the amyloid-β precursor ... ...

Abstract	Background: Most dementia disorders have a clear genetic background and a number of disease genes have been identified. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genes for the amyloid-β precursor protein (APP) and the presenilins (PSEN1, PSEN2) cause early-onset, dominantly inherited forms of Alzheimer's disease (AD). Even if mutations causing Mendelian forms of these diseases are uncommon, elucidation of the pathogenic effects of such mutations have proven important for understanding the pathogenic processes. Here, we performed a screen to identify novel pathogenic mutations in known disease genes among patients undergoing dementia investigation. Results: Using targeted exome sequencing we have screened all coding exons in eleven known dementia genes (PSEN1, PSEN2, APP, MAPT, APOE, GRN, TARDBP, CHMP2B, TREM2, VCP and FUS) in 102 patients with AD, FTD, other dementia diagnoses or mild cognitive impairment. We found three AD patients with two previously identified pathogenic mutations in PSEN1 (Pro264Leu and Met146Val). In this screen, we also identified the recently reported APP mutation in two siblings with AD. This mutation, named the Uppsala mutation, consists of a six amino acid intra-amyloid β deletion. In addition, we found several potentially pathogenic mutations in PSEN2, FUS, MAPT, GRN and APOE. Finally, APOE ε4 was prevalent in this patient group with an allele frequency of 54%. Conclusions: Among the 102 screened patients, we found two disease causing mutations in PSEN1 and one in APP, as well as several potentially pathogenic mutations in other genes related to neurodegenerative disorders. Apart from giving important information to the clinical investigation, the identification of disease mutations can contribute to an increased understanding of disease mechanisms.
MeSH term(s)	Alzheimer Disease/genetics ; Amyloid beta-Peptides ; Frontotemporal Dementia/genetics ; Humans ; Membrane Glycoproteins ; Mutation ; Presenilin-1/genetics ; Presenilin-2/genetics ; Receptors, Immunologic
Chemical Substances	Amyloid beta-Peptides ; Membrane Glycoproteins ; Presenilin-1 ; Presenilin-2 ; Receptors, Immunologic ; TREM2 protein, human
Language	English
Publishing date	2022-02-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2041499-7
ISSN	1471-2164 ; 1471-2164
ISSN (online)	1471-2164
ISSN	1471-2164
DOI	10.1186/s12864-022-08343-9
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Article ; Online: Corrigendum to "Extraction of gait parameters from marker-free video recordings of timed up-and-go tests: Validity, inter- and intra-rater reliability" [Gait Posture 90 (2021) 489-495].

Åberg, Anna Cristina / Olsson, Fredrik / Åhman, Hanna Bozkurt / Tarassova, Olga / Arndt, Anton / Giedraitis, Vilmantas / Berglund, Lars / Halvorsen, Kjartan

Gait & posture

2022 Volume 94, Page(s) 195–197

Language	English
Publishing date	2022-03-28
Publishing country	England
Document type	Published Erratum
ZDB-ID	1162323-8
ISSN	1879-2219 ; 0966-6362
ISSN (online)	1879-2219
ISSN	0966-6362
DOI	10.1016/j.gaitpost.2022.03.015
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Article ; Online: Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion.

Pagnon de la Vega, María / Syvänen, Stina / Giedraitis, Vilmantas / Hooley, Monique / Konstantinidis, Evangelos / Meier, Silvio R / Rokka, Johanna / Eriksson, Jonas / Aguilar, Ximena / Spires-Jones, Tara L / Lannfelt, Lars / Nilsson, Lars N G / Erlandsson, Anna / Hultqvist, Greta / Ingelsson, Martin / Sehlin, Dag

Acta neuropathologica communications

2024 Volume 12, Issue 1, Page(s) 22

Abstract: Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer's disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the ... ...

Abstract	Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer's disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5-6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [
MeSH term(s)	Animals ; Humans ; Mice ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Brain/pathology ; Disease Models, Animal ; Gliosis/pathology ; Ligands ; Mice, Transgenic
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Ligands
Language	English
Publishing date	2024-02-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-024-01734-x
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Article ; Online: Extraction of gait parameters from marker-free video recordings of Timed Up-and-Go tests: Validity, inter- and intra-rater reliability.

Åberg, Anna Cristina / Olsson, Fredrik / Åhman, Hanna Bozkurt / Tarassova, Olga / Arndt, Anton / Giedraitis, Vilmantas / Berglund, Lars / Halvorsen, Kjartan

Gait & posture

2021 Volume 90, Page(s) 489–495

Abstract: Background: We study dual-task performance with marker-free video recordings of Timed Up-and-Go tests (TUG) and TUG combined with a cognitive/verbal task (TUG dual-task, TUGdt).: Research question: Can gait parameters be accurately estimated from ... ...

Abstract	Background: We study dual-task performance with marker-free video recordings of Timed Up-and-Go tests (TUG) and TUG combined with a cognitive/verbal task (TUG dual-task, TUGdt). Research question: Can gait parameters be accurately estimated from video-recorded TUG tests by a new semi-automatic method aided by a technique for human 2D pose estimation based on deep learning? Methods: Thirty persons aged 60-85 years participated in the study, conducted in a laboratory environment. Data were collected by two synchronous video-cameras and a marker-based optoelectronic motion capture system as gold standard, to evaluate the gait parameters step length (SL), step width (SW), step duration (SD), single-stance duration (SSD) and double-stance duration (DSD). For reliability evaluations, data processing aided by a deep neural network model, involved three raters who conducted three repetitions of identifying anatomical keypoints in recordings of one randomly selected step from each of the participants. Validity was analysed using 95 % confidence intervals (CI) and p-values for method differences and Bland-Altman plots with limits of agreement. Inter- and intra-rater reliability were calculated as intraclass correlation coefficients (ICC) and standard errors of measurement. Smallest detectable change was calculated for inter-rater reliability. Results: Mean ddifferences between video and the motion capture system data for SW, DSD, and SSD were significant (p < 0.001). However, mean differences for all parameters were small (-6.4%-13.0% of motion capture system) indicating good validity. Concerning reliability, almost all 95 % CI of the ICC estimates exceeded 0.90, indicating excellent reliability. Only inter-rater reliability for SW (95 % CI = 0.892;0.973) and one rater's intra-rater reliability for SSD (95 % CI = 0.793;0.951) were lower, but still showed good to excellent reliability. Significance: The presented method for extraction of gait parameters from video appears suitable for valid and reliable quantification of gait. This opens up for analyses that may contribute to the knowledge of cognitive-motor interference in dual-task testing.
MeSH term(s)	Gait ; Humans ; Physical Therapy Modalities ; Reproducibility of Results ; Task Performance and Analysis ; Video Recording
Language	English
Publishing date	2021-08-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1162323-8
ISSN	1879-2219 ; 0966-6362
ISSN (online)	1879-2219
ISSN	0966-6362
DOI	10.1016/j.gaitpost.2021.08.004
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Article ; Online: Timed "Up & Go" Dual-Task Tests: Age- and Sex-Specific Reference Values and Test-Retest Reliability in Cognitively Healthy Controls.

Åhman, Hanna B / Berglund, Lars / Cedervall, Ylva / Giedraitis, Vilmantas / McKee, Kevin J / Rosendahl, Erik / Åberg, Anna Cristina

Physical therapy

2021 Volume 101, Issue 10

Abstract: Objective: The purpose of the study was to establish reference values for the Uppsala-Dalarna Dementia and Gait (UDDGait) Timed "Up & Go" dual-task (TUGdt) test variables in cognitively healthy adults and to assess these variables' test-retest ... ...

Abstract	Objective: The purpose of the study was to establish reference values for the Uppsala-Dalarna Dementia and Gait (UDDGait) Timed "Up & Go" dual-task (TUGdt) test variables in cognitively healthy adults and to assess these variables' test-retest reliability. Methods: For reference values, 166 participants were recruited with approximately equal numbers and proportions of women and men in the age groups 50 to 59, 60 to 69, 70 to 79, and 80+ years (mean age = 70 years, age range = 50-91 years, 51% women). For reliability testing, 43 individuals (mean age = 69 years, age range = 50-89 years, 51% women) were recruited. Two dt tests were carried out: TUGdt naming animals and TUGdt months backward, representing 8 test variables: time scores, costs (the relative difference between single-task and dt time scores), "number of animals," "number of months," "animals/10 seconds ," and "months/10 seconds ." Reference ranges for the variables were established by quantile regression in age- and sex-specific groups. For reliability, intraclass correlation coefficients (ICCs), standard error of measurement, minimal detectable change, and Bland-Altman plots were used. Results: Reference values for the TUGdt test variables are presented for the 2.5th and 97.5th percentiles. The reliability of TUGdt time scores was excellent (ICCs between 0.85 and 0.86). "Number of animals" and "animals/10 seconds" as well as "months/10 seconds" showed fair to good levels of reliability (ICCs between 0.45 and 0.58), whereas the reliability for both cost measures and "number of months" was poor (ICCs between 0.34 and 0.39). Conclusion: Normative reference values, potentially useful for clinical and research purposes, were presented in 4 age- and sex-specific groups from 50 years and older. Reliability for the test variables varied between poor and excellent, the lower estimates partly explained by some variables being the ratio of 2 other variables. In UDDGait, TUGdt tests are intended for diagnostic and predictive purposes, for which these tests are promising and require further investigations. Impact: Normative reference values and test-retest reliability results for the UDDGait TUGdt test variables were presented. These results should be useful for both clinical and research purposes.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Cognition/physiology ; Female ; Gait ; Healthy Volunteers ; Humans ; Male ; Middle Aged ; Physical Therapy Modalities ; Postural Balance/physiology ; Psychometrics/methods ; Reference Values ; Reproducibility of Results ; Sex Factors ; Task Performance and Analysis ; Walking/physiology
Language	English
Publishing date	2021-07-13
Publishing country	United States
Document type	Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	415886-6
ISSN	1538-6724 ; 0031-9023
ISSN (online)	1538-6724
ISSN	0031-9023
DOI	10.1093/ptj/pzab179
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Article: CRISPR-Cas9 treatment partially restores amyloid-β 42/40 in human fibroblasts with the Alzheimer's disease

Konstantinidis, Evangelos / Molisak, Agnieszka / Perrin, Florian / Streubel-Gallasch, Linn / Fayad, Sarah / Kim, Daniel Y / Petri, Karl / Aryee, Martin J / Aguilar, Ximena / György, Bence / Giedraitis, Vilmantas / Joung, J Keith / Pattanayak, Vikram / Essand, Magnus / Erlandsson, Anna / Berezovska, Oksana / Ingelsson, Martin

Molecular therapy. Nucleic acids

2022 Volume 28, Page(s) 450–461

Abstract: Presenilin 1 (PS1) is a central component of γ-secretase, an enzymatic complex involved in the generation of the amyloid-β (Aβ) peptide that deposits as plaques in the Alzheimer's disease (AD) brain. The M146L mutation in the PS1 gene ( ...

Abstract	Presenilin 1 (PS1) is a central component of γ-secretase, an enzymatic complex involved in the generation of the amyloid-β (Aβ) peptide that deposits as plaques in the Alzheimer's disease (AD) brain. The M146L mutation in the PS1 gene (
Language	English
Publishing date	2022-03-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2662631-7
ISSN	2162-2531
ISSN	2162-2531
DOI	10.1016/j.omtn.2022.03.022
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