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  • 1
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    METACOHORTS for the study of vascular disease and its contribution to cognitive decline and neurodegeneration: An initiative of the Joint Programme for Neurodegenerative Disease Research
    Wiley ; 2016
    In:  Alzheimer's & Dementia Vol. 12, No. 12 ( 2016-12), p. 1235-1249
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 12, No. 12 ( 2016-12), p. 1235-1249
    Abstract: Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegeneration and dementia, particularly by small vessel disease, is hampered by imprecise data, including the incidence and prevalence of symptomatic and clinically “silent” cerebrovascular disease, long‐term outcomes (cognitive, stroke, or functional), and risk factors. New large collaborative studies with long follow‐up are expensive and time consuming, yet substantial data to advance the field are available. In an initiative funded by the Joint Programme for Neurodegenerative Disease Research, 55 international experts surveyed and assessed available data, starting with European cohorts, to promote data sharing to advance understanding of how vascular disease affects brain structure and function, optimize methods for cerebrovascular disease in neurodegeneration research, and focus future research on gaps in knowledge. Here, we summarize the results and recommendations from this initiative. We identified data from over 90 studies, including over 660,000 participants, many being additional to neurodegeneration data initiatives. The enthusiastic response means that cohorts from North America, Australasia, and the Asia Pacific Region are included, creating a truly global, collaborative, data sharing platform, linked to major national dementia initiatives. Furthermore, the revised World Health Organization International Classification of Diseases version 11 should facilitate recognition of vascular‐related brain damage by creating one category for all cerebrovascular disease presentations and thus accelerate identification of targets for dementia prevention.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Article
    DOI: 10.1016/j.jalz.2016.06.004
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2201940-6
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  • 2
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    Correction: The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1–6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7–34 pathogenic variant
    Elsevier BV ; 2019
    In:  Genetics in Medicine Vol. 21, No. 8 ( 2019-08), p. 1895-
    Details
    In: Genetics in Medicine, Elsevier BV, Vol. 21, No. 8 ( 2019-08), p. 1895-
    Type of Medium: Online Resource
    ISSN: 1098-3600
    URL: Article
    DOI: 10.1038/s41436-018-0306-z
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2063504-7
    SSG: 12
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  • 3
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    Shape of the Central Sulcus and Disability After Subcortical Stroke : A Motor Reserve Hypothesis
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Stroke Vol. 47, No. 4 ( 2016-04), p. 1023-1029
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 47, No. 4 ( 2016-04), p. 1023-1029
    Abstract: Both brain and cognitive reserves modulate the clinical impact of chronic brain diseases. Whether a motor reserve also modulates the relationships between stroke and disability is unknown. We aimed to determine whether the shape of the central sulcus, a marker of the development of underlying motor connections, is independently associated with disability in patients with a positive history of small subcortical ischemic stroke. Methods— Shapes of central sulci were reconstructed from high-resolution magnetic resonance imaging and ordered without supervision according to a validated algorithm in 166 patients with a positive history of small subcortical ischemic stroke caused by CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), a severe monogenic cerebral small vessel disease affecting young patients. Ordinal logistic regression modeling was used to test the relationships between modified Rankin scale, a disability scale strongly weighted toward motor disability, and sulcal shape. Results— Modified Rankin scale was strongly associated with sulcal shape, independent of age, sex, and level of education (proportional odds ratio =1.19, 95% confidence interval =1.06–1.35; P =0.002). Results remained significant after further adjustment for brain atrophy, volume of lacunes, and volume of white matter hyperintensities of presumed vascular origin. Conclusions— The severity of disability in patients with a positive history of small subcortical ischemic stroke caused by a severe cerebral small vessel disease is related to the shape of the central sulcus, independently of the main determinants of disability. These results support the concept of a motor reserve that could modulate the clinical severity in patients with a positive history of small subcortical ischemic stroke.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.115.012562
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1467823-8
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  • 4
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    NIHSS Scores in Ischemic Small Vessel Disease: A Study in CADASIL
    S. Karger AG ; 2012
    In:  Cerebrovascular Diseases Vol. 34, No. 5-6 ( 2012), p. 419-423
    Details
    In: Cerebrovascular Diseases, S. Karger AG, Vol. 34, No. 5-6 ( 2012), p. 419-423
    Abstract: 〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 The National Institutes of Health Stroke Scale (NIHSS) is widely used to measure neurological deficits, evaluate the effectiveness of treatment and predict outcome in acute ischemic stroke. It has also been used to measure the residual neurological deficit at the chronic stage after ischemic events. However, the value of NIHSS in ischemic cerebral small vessel disease has not been specifically evaluated. The purpose of this study was to investigate the link between the NIHSS score and clinical severity in a large population of subjects with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a unique model to investigate the pathophysiology and natural history of ischemic small vessel disease. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 Demographic and clinical data of 220 patients with one or more lacunar infarcts confirmed by MRI examination and enrolled from a prospective cohort study were analyzed. Detailed neurological examinations, including evaluation of the NIHSS and modified Rankin Scale score (mRS) for evaluating the clinical severity, were performed in all subjects. The sensitivity, specificity, positive and negative predictive values of various NIHSS thresholds to capture the absence of significant disability (mRS 〈 3) were calculated. General linear models, controlling for age, educational level and different clinical manifestations frequently observed in CADASIL, were used to evaluate the relationships between NIHSS and clinical severity. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 In the whole cohort, 45 (20.5%) subjects presented with mRS ≥3, but only 16 (7.3%) had NIHSS 〉 5. All but 1 subject with NIHSS 〉 5 showed mRS ≥3. NIHSS ≤5 had an 85.3% positive predictive value for no or slight disability with only 33.3% specificity. The NIHSS, MMSE score and presence or absence of gait disturbances were found to be strongly and independently correlated with disability (all p 〈 0.001). Altogether, they accounted for 73% of the variance of mRS in contrast with the NIHSS alone accounting for only 50% of this variance. Among patients with NIHSS ≤5, subjects with mRS ≥3 showed a lower MMSE score than those with mRS 〈 3 (p 〈 0.001). All patients with NIHSS ≤5 but with mRS ≥3 presented either with gait disturbances or MMSE score 〈 25. 〈 b 〉 〈 i 〉 Conclusions: 〈 /i 〉 〈 /b 〉 The present results suggest that the NIHSS cannot reflect the extent of neurological deficit and clinical severity in subjects with lacunar infarctions in the context of a chronic and diffuse small vessel disease. A specific and global neurological scale, including the assessment of cognitive and gait performances, should be developed for ischemic cerebral microangiopathy.
    Type of Medium: Online Resource
    ISSN: 1015-9770 , 1421-9786
    URL: Article
    DOI: 10.1159/000345067
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2012
    detail.hit.zdb_id: 1482069-9
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  • 5
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    Extensive White Matter Hyperintensities May Increase Brain Volume in Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Stroke Vol. 43, No. 12 ( 2012-12), p. 3252-3257
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. 12 ( 2012-12), p. 3252-3257
    Abstract: The extent of white matter hyperintensities (WMH) is associated with cerebral atrophy in elderly people. WMH is a radiological hallmark of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), but their relationship with brain volume remains poorly understood. The association between WMH and brain volume was analyzed in a large population of patients with CADASIL. Methods— Demographic and MRI data of 278 patients recruited from a prospective cohort study were analyzed. Volumes of WMH and lacunar infarcts, number of cerebral microbleeds, and brain parenchymal fraction were measured. Multivariate analysis was used to study the impact of WMH on brain volume at baseline. Results— In univariate analyses, brain parenchymal fraction was negatively associated with age, male sex, and all MRI markers. Multiple regression modeling showed that brain parenchymal fraction was inversely related to age, number of cerebral microbleeds, and normalized volume of lacunar infarcts but positively related to normalized volume of WMH ( P 〈 0.001). This positive relationship was independent of the presence/absence of lacunar infarcts or of cerebral microbleeds. Subgroup analysis showed that this association was significant in subjects having normalized volume of WMH ≥6.13 or brain parenchymal fraction ≥86.37% (median values, both P ≤0.001). Conclusion— The results of the present study suggest that extensive WMH may be associated with increase of brain volume in CADASIL. In this disorder, WMH may be related not only to loss of white matter components, but also to a global increase of water content in the cerebral tissue.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.112.664854
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467823-8
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  • 6
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    Genome-Wide Genotyping Demonstrates a Polygenic Risk Score Associated With White Matter Hyperintensity Volume in CADASIL
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Stroke Vol. 45, No. 4 ( 2014-04), p. 968-972
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. 4 ( 2014-04), p. 968-972
    Abstract: White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease. Methods— We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background. Results— Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden ( P =0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance. Conclusions— We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.113.004461
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1467823-8
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  • 7
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    Predictors and Clinical Impact of Incident Lacunes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Stroke Vol. 48, No. 2 ( 2017-02), p. 283-289
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 48, No. 2 ( 2017-02), p. 283-289
    Abstract: Previous studies in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy showed that accumulation of lacunes strongly relate to clinical severity. However, the potential predictors of incident lacunes and their clinical consequences over a short time frame have not been investigated. This study aimed to determine the predictors and clinical impact of such lesions in a large cohort of patients. Methods— Two hundred and six NOTCH3 mutation carriers (mean age, 49.5±10.6 years) were followed up over 3 years. Incident lacunes were identified using difference imaging from 3-dimensional T1 images. Clinical events and change in different clinical scores such as the Mattis Dementia Rating Scale, Modified Rankin Scale, Barthel index, and time to complete part A and part B of Trail Making Test were recorded. Associations were analyzed with multivariable logistic regression analysis and ANCOVA. Results— Over a mean period of 3.4±0.7 years, incident lacunes occurred in 51 of 206 patients. Both the number of lacunes ( P 〈 0.0001) and systolic blood pressure at baseline ( P 〈 0.01) were independent predictors of incident lacunes during follow-up. The results were still significant after excluding patients with systolic blood pressure 〉 140 mm Hg. Incident lacunes were also associated with incident stroke and with change in time to complete Trail Making Test part B, initiation/perseveration subscale of the Mattis Dementia Rating Scale and Barthel Index over the study period. Conclusions— Systolic blood pressure and the number of prevalent lacunes are independent predictors of incident lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These lesions mainly impact executive performances and functional independence over 3 years.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.116.015750
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1467823-8
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  • 8
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    Cortical folding influences migraine aura symptoms in CADASIL
    BMJ ; 2012
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 83, No. 2 ( 2012-02), p. 213-216
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 83, No. 2 ( 2012-02), p. 213-216
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2011-300825
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2012
    detail.hit.zdb_id: 1480429-3
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  • 9
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    APOE ɛ 2 is associated with white matter hyperintensity volume in CADASIL
    SAGE Publications ; 2016
    In:  Journal of Cerebral Blood Flow & Metabolism Vol. 36, No. 1 ( 2016-01), p. 199-203
    Details
    In: Journal of Cerebral Blood Flow & Metabolism, SAGE Publications, Vol. 36, No. 1 ( 2016-01), p. 199-203
    Abstract: Apolipoprotein E ( APOE) increases the risk for Alzheimer’s disease ( ɛ4 allele) and cerebral amyloid angiopathy ( ɛ2 and ɛ4), but its role in small vessel disease (SVD) is debated. Here we studied the effects of APOE on white matter hyperintensity volume (WMHV) in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a nonamyloidogenic angiopathy and inherited early-onset form of pure SVD. Four hundred and eighty-eight subjects were recruited through a multicenter consortium. Compared with APOE ɛ3/ ɛ3, WMHV was increased in APOE ɛ2 ( P = 0.02) but not APOE ɛ4. The results remained significant when controlled for genome-wide genetic background variation. Our findings suggest a modifying influence of APOE ɛ2 on WMHV caused by pure SVD.
    Type of Medium: Online Resource
    ISSN: 0271-678X , 1559-7016
    URL: Article
    DOI: 10.1038/jcbfm.2015.85
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2016
    detail.hit.zdb_id: 2039456-1
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  • 10
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    Harmonizing brain magnetic resonance imaging methods for vascular contributions to neurodegeneration
    Wiley ; 2019
    In:  Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring Vol. 11, No. 1 ( 2019-12), p. 191-204
    Details
    In: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Wiley, Vol. 11, No. 1 ( 2019-12), p. 191-204
    Abstract: Many consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease. Methods Surveys, teleconferences, and an in‐person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis. Results A framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at www.harness‐neuroimaging.org with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository. Conclusions The HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.
    Type of Medium: Online Resource
    ISSN: 2352-8729 , 2352-8729
    URL: Article
    DOI: 10.1016/j.dadm.2019.01.002
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2832898-X
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