| 1. |
- Morenas-Rodriguez, E., et al.
(författare)
-
Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer acute accent s disease: a longitudinal observational study
- 2022
-
Ingår i: LANCET NEUROLOGY. - 1474-4422. ; 21:4, s. 329-341
-
Tidskriftsartikel (refereegranskat)abstract
- Background Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid beta (A beta) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease. Methods We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1 , PSEN2 , and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR > 0). CSF concentrations of A beta 40, A beta 42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models. Findings In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF A beta 42 (beta=-4.28 x 10(-2) [SE 0.013], p=0.0012), but not high cortical uptake in PiB-PET (beta=-5.51 x 10(-3) [0.011], p=0.63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by A beta 42 in CSF (r=0.56 [0.22], p=0.011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=-0.67 [0.25], p=0.0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0.45 [0.21], p=0.035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between A beta 42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0.46 [0.22]), p=0.040) and diminished cognitive decline (r=0.67 [0.22], p=0.0020). Interpretation Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in A beta aggregation and further support the role of TREM2 on A beta plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on A beta deposition, A beta-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing. Funding German Research Foundation, US National Institutes of Health.Copyright (C) 2022 Elsevier Ltd. All rights reserved.
|
|
| 2. |
- Levin, Johannes, et al.
(författare)
-
α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden
- 2024
-
Ingår i: Alzheimer's and Dementia. - 1552-5260.
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. Highlights: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.
|
|
| 3. |
- De Frenne, Pieter, et al.
(författare)
-
Forest microclimates and climate change : Importance, drivers and future research agenda
- 2021
-
Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 27:11, s. 2279-2297
-
Forskningsöversikt (refereegranskat)abstract
- Forest microclimates contrast strongly with the climate outside forests. To fully understand and better predict how forests' biodiversity and functions relate to climate and climate change, microclimates need to be integrated into ecological research. Despite the potentially broad impact of microclimates on the response of forest ecosystems to global change, our understanding of how microclimates within and below tree canopies modulate biotic responses to global change at the species, community and ecosystem level is still limited. Here, we review how spatial and temporal variation in forest microclimates result from an interplay of forest features, local water balance, topography and landscape composition. We first stress and exemplify the importance of considering forest microclimates to understand variation in biodiversity and ecosystem functions across forest landscapes. Next, we explain how macroclimate warming (of the free atmosphere) can affect microclimates, and vice versa, via interactions with land-use changes across different biomes. Finally, we perform a priority ranking of future research avenues at the interface of microclimate ecology and global change biology, with a specific focus on three key themes: (1) disentangling the abiotic and biotic drivers and feedbacks of forest microclimates; (2) global and regional mapping and predictions of forest microclimates; and (3) the impacts of microclimate on forest biodiversity and ecosystem functioning in the face of climate change. The availability of microclimatic data will significantly increase in the coming decades, characterizing climate variability at unprecedented spatial and temporal scales relevant to biological processes in forests. This will revolutionize our understanding of the dynamics, drivers and implications of forest microclimates on biodiversity and ecological functions, and the impacts of global changes. In order to support the sustainable use of forests and to secure their biodiversity and ecosystem services for future generations, microclimates cannot be ignored.
|
|
| 4. |
- Kemppinen, Julia, et al.
(författare)
-
Microclimate, an important part of ecology and biogeography
- 2024
-
Ingår i: GLOBAL ECOLOGY AND BIOGEOGRAPHY. - 1466-822X .- 1466-8238. ; 33:6
-
Tidskriftsartikel (refereegranskat)abstract
- Brief introduction: What are microclimates and why are they important?Microclimate science has developed into a global discipline. Microclimate science is increasingly used to understand and mitigate climate and biodiversity shifts. Here, we provide an overview of the current status of microclimate ecology and biogeography in terrestrial ecosystems, and where this field is heading next.Microclimate investigations in ecology and biogeographyWe highlight the latest research on interactions between microclimates and organisms, including how microclimates influence individuals, and through them populations, communities and entire ecosystems and their processes. We also briefly discuss recent research on how organisms shape microclimates from the tropics to the poles.Microclimate applications in ecosystem managementMicroclimates are also important in ecosystem management under climate change. We showcase new research in microclimate management with examples from biodiversity conservation, forestry and urban ecology. We discuss the importance of microrefugia in conservation and how to promote microclimate heterogeneity.Methods for microclimate scienceWe showcase the recent advances in data acquisition, such as novel field sensors and remote sensing methods. We discuss microclimate modelling, mapping and data processing, including accessibility of modelling tools, advantages of mechanistic and statistical modelling and solutions for computational challenges that have pushed the state-of-the-art of the field.What's next?We identify major knowledge gaps that need to be filled for further advancing microclimate investigations, applications and methods. These gaps include spatiotemporal scaling of microclimate data, mismatches between macroclimate and microclimate in predicting responses of organisms to climate change, and the need for more evidence on the outcomes of microclimate management.
|
|
| 5. |
- Lauwers, E., et al.
(författare)
-
Potential human transmission of amyloid beta pathology: surveillance and risks
- 2020
-
Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 19:10, s. 872-878
-
Tidskriftsartikel (refereegranskat)abstract
- Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid beta after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid beta through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid beta might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid beta transmission and to clarify whether other similar proteopathic seeds, such as tau or alpha-synuclein, can also be transferred iatrogenically.
|
|
| 6. |
|
|
| 7. |
- Tanrioever, Gaye, et al.
(författare)
-
Prominent microglial inclusions in transgenic mouse models of alpha-synucleinopathy that are distinct from neuronal lesions
- 2020
-
Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated alpha-synuclein (alpha S). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of alpha S but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study alpha S conformers among different transgenic (TG) mouse models of alpha-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]alpha S; Thy1-h[A53T]alpha S; Thy1-h[A30P]alpha S; Thy1-m alpha S) that overexpress human or murine alpha S and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal alpha S pathology as evidenced by accumulation of alpha S serine 129 (p-alpha S) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study alpha S conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal alpha S pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of alpha S, but were largely p-alpha S-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded alpha S aggregation. Although nature and significance of microglial inclusions for human alpha-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of alpha-synucleinopathy bears importance for mechanistic and preclinical-translational studies.
|
|
| 8. |
- Wagner, Jessica, et al.
(författare)
-
Medin co-aggregates with vascular amyloid-beta in Alzheimers disease
- 2022
-
Ingår i: Nature. - : Nature Portfolio. - 0028-0836 .- 1476-4687. ; 612, s. 123-131
-
Tidskriftsartikel (refereegranskat)abstract
- Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age(1,)(2), making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction(3). Here we demonstrate in amyloid-beta precursor protein (APP) transgenic mice and in patients with Alzheimers disease that medin co-localizes with vascular amyloid-beta deposits, and that in mice, medin deficiency reduces vascular amyloid-beta deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-beta burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimers disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-beta to promote its aggregation, as medin forms heterologous fibrils with amyloid-beta, affects amyloid-beta fibril structure, and cross-seeds amyloid-beta aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-beta deposition in the blood vessels of the brain.
|
|
