| 1. |
- Dichgans, Martin, et al.
(författare)
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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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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 12:12, s. 1235-1249
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Franzmeier, Nicolai, et al.
(författare)
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Earlier Alzheimer's disease onset is associated with a shift of tau pathology towards brain hubs which facilitates tau spreading
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Tidskriftsartikel (refereegranskat)abstract
- Background: In Alzheimer’s disease (AD), younger symptom onset is associated accelerated cognitive decline and tau spreading, yet the drivers of faster disease manifestation in patients with earlier symptom onset are unknown. Earlier symptom onset is associated with stronger tau pathology in fronto-parietal regions which typically harbor globally connected hubs that are central for cognition. Since tau spreads across connected regions, globally connected hubs may accelerate tau spreading due to their large number of connections to other brain regions. Thus, we hypothesized that a pattern shift of tau pathology towards globally connected brain hubs may facilitate tau spreading and earlier symptom manifestation in AD. Method: We included two independent samples with longitudinal Flortaucipir tau-PET covering the AD spectrum (ADNI: n(controls/AD-preclinical/AD-symptomatic)=93/60/89, BioFINDER, n(controls/AD-preclinical/AD-symptomatic)=16/16/25). In addition, we included resting-state fMRI from human connectome project participants (n=1000), applying a 200-ROI brain atlas to obtain a global connectivity map for assessing brain hubs (Fig.1A-D). Applying the same atlas to tau-PET we transformed SUVRs to tau positivities using a pre-established gaussian-mixture modeling approach (Fig.1E-F). By mapping tau-PET positivities to the fMRI-derived global connectivity map (Fig.1G-L), we assessed the degree to which subject specific tau-PET patterns were shifted towards globally connected hubs or non-hubs, while adjusting for global tau levels. Using linear regression, we then tested whether a stronger shift of tau towards hubs was associated with earlier symptom manifestation and faster longitudinal tau accumulation. Result: In symptomatic AD patients, younger age was associated with a stronger shift of tau-PET towards globally connected brain hubs (p[ADNI/BiOFINDER]=0.024/0.018, Fig.2A&B), and with higher global connectivity of epicenters with highest tau pathology (p[ADNI/BiOFINDER]<0.001/0.001, Fig.2C&D). In symptomatic AD, younger age (p[ADNI/BiOFINDER]=0.009/0.001) and a stronger shift of tau-PET towards hubs predicted faster subsequent tau accumulation (p[ADNI/BiOFINDER]=0.004/0.002), supporting the view that that hubs facilitate tau spreading (Fig.3). Further, a stronger shift of tau-PET towards globally connected brain hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients (p[ADNI/BiOFINDER]=0.039/0.046). Conclusion: Younger AD symptom onset is associated with stronger tau pathology in globally connected brain hubs, which facilitates faster tau spreading.
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| 3. |
- Franzmeier, Nicolai, et al.
(författare)
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The BIN1 rs744373 Alzheimer's disease risk SNP is associated with faster Aβ-associated tau accumulation and cognitive decline
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:1, s. 103-115
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The BIN1 rs744373 single nucleotide polymorphism (SNP) is a key genetic risk locus for Alzheimer's disease (AD) associated with tau pathology. Because tau typically accumulates in response to amyloid beta (Aβ), we tested whether BIN1 rs744373 accelerates Aβ-related tau accumulation. Methods: We included two samples (Alzheimer's Disease Neuroimaging Initiative [ADNI], n = 153; Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably [BioFINDER], n = 63) with longitudinal 18F-Flortaucipir positron emission tomography (PET), Aβ biomarkers, and longitudinal cognitive assessments. We assessed whether BIN1 rs744373 was associated with faster tau-PET accumulation at a given level of Aβ and whether faster BIN1 rs744373-associated tau-PET accumulation mediated cognitive decline. Results: BIN1 rs744373 risk-allele carriers showed faster global tau-PET accumulation (ADNI/BioFINDER, P <.001/P <.001). We found significant Aβ by rs744373 interactions on global tau-PET change (ADNI: β/standard error [SE] = 0.42/0.14, P = 0.002; BioFINDER: β/SE = –0.35/0.15, P =.021), BIN1 risk-allele carriers showed accelerated tau-PET accumulation at higher Aβ levels. In ADNI, rs744373 effects on cognitive decline were mediated by faster global tau-PET accumulation (β/SE = 0.20/0.07, P =.005). Discussion: BIN1-associated AD risk is potentially driven by accelerated tau accumulation in the face of Aβ.
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| 4. |
- Hachinski, Vladimir, et al.
(författare)
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Preventing dementia by preventing stroke : The Berlin Manifesto
- 2019
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:7, s. 961-984
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Forskningsöversikt (refereegranskat)abstract
- The incidence of stroke and dementia are diverging across the world, rising for those in low- and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action.
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