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- Dichgans, Martin, et al.
(author)
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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
- 2016
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 12:12, s. 1235-1249
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Journal article (peer-reviewed)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.
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| 3. |
- Ohta, Yasuyuki, et al.
(author)
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Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis
- 2016
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In: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 25:21, s. 4771-4786
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Journal article (peer-reviewed)abstract
- Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)(P413L) allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHG(BP413L) variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGB(L413) protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGB(L413) transgene in SOD1(G37R) mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGB(L413) variant also slowed down disease progression in SOD1(G37R) mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1(D90A) alleles and two variant CHGB(P413)L and CHGB(R458Q) alleles. In contrast, overexpression of the common CHGB(P413) allele in SOD1(G37R) mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGB(P413L) allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGB(L413) allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.
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