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  • 1
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    Online Resource
    Ultrasound‐assisted lumbar puncture in Alzheimer's disease and related disorders research: A pilot study
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S5 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S5 ( 2021-12)
    Abstract: Lumbar puncture (LP) and collection of cerebrospinal fluid (CSF) are increasingly essential in Alzheimer’s disease and related disorders (ADRD) research. Ultrasound‐assisted lumbar puncture (Us‐LP) has not been studied in ADRD research and could improve LP success rates through more accurate anatomical site selection, precise planning, and individualized intra‐procedure adjustments. This pilot study assessed the feasibility, utility, and tolerability of Us‐LP in ADRD research. Method LP clinician‐researchers from ADRD centers completed simulation‐based Us‐LP training using the Philips Lumify system, a portable hand‐held transducer connecting to a tablet. Thereafter, clinician‐researchers had the option to use Us‐LP during research LPs. Participant demographics and attitudes about LP were obtained prior to LP. The clinician‐researchers completed a post‐LP questionnaire assessing procedural details, choices, and LP performance. Result Following training, four clinician‐researchers implemented Us‐LP into their practices. Between August 2019‐March 2020, 58 research participants (Table 1) underwent LP. Clinician‐researchers used Us‐LP on 37/58 (64%) participants. Compared to conventional‐LP, Us‐LP choice was associated with higher/highest BMI and older/oldest age categories (Tables 2,3). A U‐shaped relationship between BMI and Age in Us‐LP choice was noted (Figure 1). Us‐LP was also the choice in all who were most obese; in most who were moderately overweight‐to‐obese; and in all who were oldest and moderately overweight‐to‐obese. There were no differences between those receiving conventional‐LP compared to US‐LP with respect to participant history of chronic pain or headache, prior attitudes about LP, success rate, or post‐LP complications. Conclusion Training clinician‐researchers in Us‐LP and implementing portable hand‐held Us‐LP for ADRD research studies demonstrated feasibility, utility and tolerability. Pilot data indicated that clinician‐researchers were more likely to use Us‐LP in perceived challenging cases including the most obese, and those oldest and moderately overweight‐to‐obese. More studies are needed to determine if using Us‐LP in ADRD research will improve LP success rates, tolerability, and participant willingness to undergo LP. Improving these factors will accelerate CSF biomarker, aging and ADRD research. Furthermore, with potential availability of AD disease‐modifying treatments in the coming years, LP and CSF collection are likely to play a crucial role in patient selection for treatment.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S5
    DOI: 10.1002/alz.056636
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 2
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    Higher systolic and diastolic blood pressures in recently postmenopausal women are associated with higher white matter hyperintensity volume more than a decade later in the keeps continuation study
    Wiley ; 2023
    In:  Alzheimer's & Dementia Vol. 19, No. S8 ( 2023-06)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 19, No. S8 ( 2023-06)
    Abstract: Women have higher rates of hypertension at the time of menopausal transition than men. Although elevated systolic and diastolic blood pressures (SBP and DBP) are risk factors for white matter (WM) injury both in women and men, WM hyperintensities (WMH), a marker of WM injury, are more common in women than in men after the age of 60. Thus, women may be vulnerable to the effects of elevated BP on WM integrity during menopausal transition. We investigated the association of BP in recently postmenopausal women with good cardiovascular health with WMH volume assessed 13 years later. Method Women (n = 212; median age = 67; range 58‐72), who were previously enrolled in a multi‐site randomized menopausal hormone therapy trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59). Participants who were on antihypertensive medications at KEEPS baseline were excluded from the analysis (n = 34). Approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions, WM integrity was assessed with automated WMH volume measurements from 3D‐FLAIR MRI. Associations of baseline SBP and DBP with logWMH volume measured 13 years later were tested by linear regression analyses. Model 1 was adjusted for age, study site, and total intracranial volume. Model 2 was adjusted for covariates of model 1, triglycerides, low density lipoproteins, and waist/hip ratio. Result The median SBP was 116 (range 83‐158) and DBP was 74 (range 56‐98). Higher SBP was associated with greater WMH volume (model 1:p = 0.005; model 2:p = 0.005). Similarly, higher DBP was associated with greater WMH volume (model 1:p = 0.008; model 2:p = 0.006) (Figure 1). Neither menopausal hormone therapies versus placebo, nor having high/low SBP (≥120/ 〈 120) modified these associations. Voxel‐based analyses demonstrate the association of BPs with the spatial distribution of WMHs (Figure 2). Conclusion Higher BPs in recently menopausal women were associated with greater WM injury more than a decade later after adjusting for CVD risk factors. Early postmenopausal stage is a critical time for BP control in women, which may reduce the risk of WM injury later in life.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v19.S8
    DOI: 10.1002/alz.064187
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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  • 3
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    Baseline demographic, clinical, and cognitive characteristics of the Alzheimer's Prevention Initiative (API) Autosomal‐Dominant Alzheimer's Disease Colombia Trial
    Wiley ; 2020
    In:  Alzheimer's & Dementia Vol. 16, No. 7 ( 2020-07), p. 1023-1030
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. 7 ( 2020-07), p. 1023-1030
    Abstract: The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo‐controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60‐year‐old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non‐carriers who receive placebo. Methods Of the 252 enrolled, we present data on a total of 242 mutation carriers and non‐carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. Results We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non‐carriers, 30 to 53 years of age. Carriers were significantly younger than non‐carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. Discussion Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non‐carriers. Their demographic characteristics are representative of the local population.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.7
    DOI: 10.1002/alz.12109
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 4
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    A novel longitudinal approach in individual subjects to investigate the movement of tau over time using graph theory in clinical and preclinical stages of Alzheimer’s disease : Neuroimaging / New imaging methods
    Wiley ; 2020
    In:  Alzheimer's & Dementia Vol. 16, No. S4 ( 2020-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S4 ( 2020-12)
    Abstract: We previously introduced an index characterizing inter‐regional tau deposition variability based on graph theory. Extending our method to additionally characterize the longitudinal tau spread for individual subjects based on directed graph theory, we examined the difference between longitudinal network measures and the regional tau deposit measures over time with respect to 1) differentiation of patients with AD, MCI, and cognitively unimpaired(CU) subjects, 2) correlation with memory measures in Aβ+ CU, and 3) sample size needed for a prevention trial for Aβ+/‐ CU. Method The longitudinal tau PET data is from 13 AD, 42 MCI, and 72 CU in ADNI . Using cerebellar grey reference region, we calculated the difference over two time points (1.1 years ± 0.2 (0.6‐1.6)) for the entorhinal, inferior temporal and metaROI SUVR, and the difference for indices, in‐strength and out‐strength each based on the directed tau longitudinal network using predefined nodes(inferior temporal and limbic). We examined regional/network based indices in term of the group differences, their correlation with AVLT‐LTM change. In addition, we also calculated sample size for a prevention clinical trial for Aβ+/‐ subjects separately with 80% power and 25% treatment effect. Result The longitudinal tau network measures(instrength and outstrength) are significantly different between the three groups (p 〈 0.004) but not the SUVR change at entorhinal(p=0.62), inferior temporal(p=0.36) or tau meta ROI rates(p=0.21). In CU Aβ+ subjects, limbic outstrength significantly correlated to AVLT‐LTM rate(rs=‐0.52, p=0.013). The most significant regional value(tau metaROI) rate is not significantly correlated with AVLT LTM rate(rs=‐0.25,p=0.26). For a clinical trial, the Inferior temporal in‐out strength(net influx) requires a sample size of 584 subjects in CU Aβ+ group and a sample size of 26448 subjects in CU Aβ‐ Entorhinal tau SUVR, inferior temporal and tau metaROI SUVR needs a sample size for CU Aβ+ is 1623, 2450,2629 respectively. For CU Aβ‐ subjects, the sample size is 53537 for entorhinal SUVR, 50605 for inferior temporal SUVR and 916184 for tau metaROI SUVR Conclusion The network based longitudinal indices provide better power for differentiating patients at different stages, for examining tau’s effects on memory and for detecting a treatment effects in prevention trial.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.S4
    DOI: 10.1002/alz.044004
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 5
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    Meta‐Analysis of Animal Fluency Performance in Amnestic Mild Cognitive Impairment and Cognitively Unimpaired Older Adults.
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S7 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S7 ( 2022-12)
    Abstract: Animal fluency is a commonly used neuropsychological measure that is used in the diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Although most individuals with MCI have clinically normal scores on this test, several studies have shown the MCI individuals’ performance is significantly lower than that of cognitively unimpaired (CU) individuals. The aim of this meta‐analysis will be to characterize the effect size of animal fluency performance differences between MCI and CU individuals. Method Literature search with search terms used were: “animal fluency and mild cognitive impairment”, “semantic fluency and mild cognitive impairment”, “category fluency and mild cognitive impairment”. Data was extracted only from studies that met the following criteria: 1. It was to be an observational study (interventional studies were excluded; 2. Peterson criteria was used for diagnosis of the MCI individuals; 3. The study had raw data available animal fluency performance. Both the standardized mean difference (SMD) and the raw mean difference (RMD) were derived from random effects analyses. Demographically adjusted z‐scores for Animal fluency performance for the MCI groups were obtained to determine normative performance. Result Twenty studies were included in the analysis. The SMD for animal fluency performance between CU and MCI was 0.89 (95% confidence interval: [0.73; 1.04], p 〈 0.001), I^2 = 68.6% [50.2%; 80.2%], which reflects a large effect size with moderate heterogeneity. The RMD was ‐4.09 [‐4.78; ‐3.40] , p 〈 0.001 indicating that MCI individuals generated significantly fewer animals than CU individuals. The mean z‐score for MCI groups’ animal fluency scores was z = ‐0.75 indicating performance in the Low Average range. Conclusion This study found a large effect size for differences on animal fluency performance between MCI and CU individuals. On average, the MCI groups’ normative performance did not fall into the Impaired range indicating that there are important sub‐clinical differences on animal fluency performance between CU and MCI individuals. These findings are relevant to the use of composite efficacy measures for AD prevention trials. Specifically, the inclusion of animal fluency in these composite scores may help increase their sensitivity to change and yield greater statistical power for these trials.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S7
    DOI: 10.1002/alz.060092
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 6
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    White Matter Hyperintensity and PET‐Based Amyloid Load Correlations: A Meta‐Analysis
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: White matter hyperintensities (WMHs) are prevalent vascular pathologies that often co‐occur with amyloid plaque deposition in Alzheimer’s disease (AD). Previous research has shown that antemortem WMHs correlate well with post‐mortem findings of cerebral amyloid angiopathy (CAA). PET‐amyloid imaging is widely used to assess in‐vivo amyloid load, however the extent to which CAA‐binding of amyloid tracers contributes to global measures of amyloid load is unclear. The aim of this meta‐analysis was to determine the strength of the correlation between amyloid load and WMHs in AD subjects. Method Thirteen studies that reported either a correlation or regression coefficient between amyloid load and WMHs were included. Age, education level, sample size, correlation, study setting (community, clinic, Alzheimer’s Disease Neuroimaging Initiative [ADNI]), amyloid tracer type (florbetapir vs. Pittsburgh compound B [PiB] ), and method of WMH quantification (visual vs. volumetric) were extracted. Random effects results were reported for the main and subgroup analyses. Between‐study heterogeneity was quantified using I 2 with 95% confidence intervals. Result The overall correlation for amyloid load and WMH load was r=.25, 95% CI[.15, .35], p 〈 .001; I 2 =80%, 95% CI[66%, 88%]. The combined effect size of community and clinic‐based studies (r =0.30) was larger than that of ADNI studies (r=0.21) and had substantially less heterogeneity (I 2 =67% vs. I 2 =86%). Florbetapir had a stronger correlation with WMHs (r=0.28) than PiB (r=0.20), with less heterogeneity (I 2 =71%, I 2 =87%). Visual methods of WMH quantification yielded a stronger correlation with amyloid load (r=0.38) than volumetric methods (r=0.20), however between‐study heterogeneity was similar for both methods (I 2 =80%, I 2 =82%). Conclusion WMHs correlate significantly with amyloid load, but this relationship is strongly influenced by amyloid tracer type and WMH quantification method. A high level of heterogeneity was noted for ADNI studies which further indicates the impact that methodologic and analytic techniques may have on a study’s findings. Although CAA‐related binding cannot be distinguished from parenchymal binding in amyloid‐PET studies, these results provide a general estimate of CAA’s contribution to PET‐based estimates of global amyloid load.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.060372
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 7
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    CSF amyloid‐beta, tau, and neurodegenerative and inflammatory biomarkers in cognitively unimpaired late middle‐aged and older adult APOE ε4 homozygotes, heterozygotes, and non‐carriers from the Arizona APOE Cohort
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S5 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S5 ( 2021-12)
    Abstract: APOE4 gene dose, the number of apolipoprotein E ‐ɛ4 (APOE4) ɛ4 alleles in a person’s genotype, is associated with higher Alzheimer’s disease (AD) risk and younger median age at dementia onset. We previously found relationships between PET, plasma, and CSF measurements of amyloid‐β (Aβ) pathophysiology in APOE4 gene dose. Here, we characterize the core AD CSF biomarkers (Aβ 42/40 , pTau 181 , tTau), the neurodegeneration marker neurofilament light chain (NfL) and the glial biomarkers soluble TREM2 (sTREM2), and glial fibrillary acidic protein (GFAP) measurements in age‐matched 48‐70 year‐old cognitively unimpaired (CU) APOE4 homozygotes (HMs), heterozygotes (HTs) and non‐carriers (NCs) from the Arizona cohort. Method CSF biomarker measurements were performed at the University of Gothenburg using Lumipulse and ELISA immunoassays. CSF biomarker measurements were characterized and compared using linear‐tend ANOVAs in 12 HMs, 17 HTs, and 20 NCs who were CU, 48‐70 years old and did not differ significantly in their age, sex, or educational level. Result As expected, CSF Aβ 42/40 ratios were inversely associated with APOE4 gene dose (linear trend, HM 〈 HT 〈 NC, p 〈 0.05), and tTau/Aβ 42 and pTau 181 /Aβ 42 ratios were directly associated with APOE4 gene dose (HM 〉 HT 〉 NC p 〈 0.05). Non‐significant trends suggested that CSF sTREM2 and sTREM2/pTau 181 measurements were inversely associated with APOE4 gene dose (HM 〈 HT≤NC, (0.05 〈 p≤0.06). We failed to detect significant differences or linear trends in CSF pTau 181 , tTau, GFAP, or NfL measurements among these small subject groups. Conclusion APOE4 gene dose is associated with measures of CSF Aβ 42/40 and Aβ‐related tau pathophysiology, reflecting higher Aβ plaque burden in CU subjects close to their estimated ages at clinical onset. Additional studies are needed to clarify relationships between different Aβ, tau, neurodegenerative, inflammatory, and other CSF, or blood‐based biomarkers, and APOE4 gene dose in larger subject groups and at other ages.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S5
    DOI: 10.1002/alz.057242
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 8
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    Frontal Cortex and Hippocampal γ-Secretase Activating Protein Levels in Prodromal Alzheimer Disease
    S. Karger AG ; 2017
    In:  Neurodegenerative Diseases Vol. 17, No. 6 ( 2017), p. 235-241
    Details
    In: Neurodegenerative Diseases, S. Karger AG, Vol. 17, No. 6 ( 2017), p. 235-241
    Abstract: 〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 β-Amyloid (Aβ) is the product of concerted cleavage of the amyloid precursor protein (APP) by β- and & #x03B3;-secretases. However, the molecular mechanisms that regulate this process are not well understood. Recently, evidence was reported that & #x03B3;-secretase activating protein (GSAP, 16 kDa), derived from a larger precursor protein (98 kDa), plays a role in Aβ metabolism through a mechanism involving its interaction with both & #x03B3;-secretase and APP. However, a detailed evaluation of GSAP protein levels and their association with clinical and neuropathological variables are lacking during the clinical progression of Alzheimer disease (AD). 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 We quantified levels of the GSAP precursor (98 kDa) and its active form (16 kDa) in the frontal cortex and hippocampus, areas displaying extensive Aβ and neurofibrillary tangle (NFT) pathology, in subjects who came to autopsy with a premortem clinical diagnosis of noncognitive impairment, mild cognitive impairment, mild to moderate AD, and severe AD using Western blotting. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Analysis found that 98-kDa GSAP levels were increased, while those of 16 kDa were reduced in the frontal cortex of severe-AD subjects. By contrast, GSAP levels remained stable in the hippocampus. Frontal cortex and hippocampal GSAP 98- and 16-kDa levels were not associated with Aβ, NFT, and neuropathological criteria across clinical groups. Interestingly, only neocortical 98-kDa GSAP values showed a significant correlation with the Mini-Mental State Examination and episodic memory scores. 〈 b 〉 〈 i 〉 Conclusions: 〈 /i 〉 〈 /b 〉 These data demonstrate that GSAP proteins are differentially dysregulated in severe AD, but only the full-length form was associated with cognitive test scores in AD.
    Type of Medium: Online Resource
    ISSN: 1660-2854 , 1660-2862
    URL: Article
    DOI: 10.1159/000477937
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2017
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  • 9
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    Sex differences in cognitive resilience in preclinical autosomal‐dominant Alzheimer's disease carriers and non‐carriers: Baseline findings from the API ADAD Colombia Trial
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. 11 ( 2022-11), p. 2272-2282
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. 11 ( 2022-11), p. 2272-2282
    Abstract: Females may have greater susceptibility to Alzheimer's disease (AD)‐pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively‐unimpaired Presenilin‐1 ( PSEN1 ) E280A mutation carriers and non‐carriers. Methods We analyzed baseline data from 167 mutation carriers and 75 non‐carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir‐ and fludeoxyglucose‐PET, MRI based hippocampal volume and cognitive testing. Results Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory. Discussion Our findings suggest that, among cognitively‐unimpaired individuals at genetic risk for autosomal‐dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex‐specific differences in autosomal‐dominant AD is key to elucidating mechanisms of AD risk and resilience.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.11
    DOI: 10.1002/alz.12552
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 10
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    PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer’s disease-causing Presenilin-1 E280A mutation carriers
    Elsevier BV ; 2021
    In:  NeuroImage: Clinical Vol. 31 ( 2021), p. 102749-
    Details
    In: NeuroImage: Clinical, Elsevier BV, Vol. 31 ( 2021), p. 102749-
    Type of Medium: Online Resource
    ISSN: 2213-1582
    URL: Article
    DOI: 10.1016/j.nicl.2021.102749
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2701571-3
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