| 1. |
|
|
| 2. |
- Ackum, Susanne, et al.
(författare)
-
Vi tar fram en handfast plan för en omstart av Sverige
- 2020
-
Ingår i: Dagens Nyheter. - 1101-2447. ; :27 april
-
Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Det är /.../ fullt möjligt att tänka strategiskt och systematiskt även i brinnande kris. Omstartskommissionen hoppas kunna bidra till fokus, analys och konkreta policyförslag för att stödja Sveriges långsiktiga inriktning. Vi kommer att under våren och sommaren anordna seminarier och hearings om vårt arbete, delrapporter ska läggas fram – och när budgetarbetet börjar och Riksdagen öppnar, vill vi kunna bidra med en rejäl och handfast plan för hur vi omstartar Sverige.
|
|
| 3. |
- Ahmad, Shahzad, et al.
(författare)
-
CDH6 and HAGH protein levels in plasma associate with Alzheimer’s disease in APOE ε4 carriers
- 2020
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Many Alzheimer’s disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aβ) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (β = 0.638, P = 3.33 × 10−4) and HAGH (β = 0.481, P = 7.20 × 10−4), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10−3) and HAGH proteins (β = 0.506, P = 9.31 × 10−7) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10−3). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10−9). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.
|
|
| 4. |
- Andersson, Emelie, et al.
(författare)
-
Blood and cerebrospinal fluid neurofilament light differentially detect neurodegeneration in early Alzheimer's disease
- 2020
-
Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 95, s. 143-153
-
Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) neurofilament light (NfL) concentration has reproducibly been shown to reflect neurodegeneration in brain disorders, including Alzheimer's disease (AD). NfL concentration in blood correlates with the corresponding CSF levels, but few studies have directly compared the reliability of these 2 markers in sporadic AD. Herein, we measured plasma and CSF concentrations of NfL in 478 cognitively unimpaired (CU) subjects, 227 patients with mild cognitive impairment, and 113 patients with AD dementia. We found that the concentration of NfL in CSF, but not in plasma, was increased in response to Aβ pathology in CU subjects. Both CSF and plasma NfL concentrations were increased in patients with mild cognitive impairment and AD dementia. Furthermore, only NfL in CSF was associated with reduced white matter microstructure in CU subjects. Finally, in a transgenic mouse model of AD, CSF NfL increased before serum NfL in response to the development of Aβ pathology. In conclusion, NfL in CSF may be a more reliable biomarker of neurodegeneration than NfL in blood in preclinical sporadic AD.
|
|
| 5. |
- Andersson, Emelie, et al.
(författare)
-
CSF Aβ42 and Aβ40 and their relation to brain soluble and insoluble Aβ in the 5xFAD mouse model of Alzheimer's disease
- 2021
-
Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - 1552-5279. ; 17
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In patients with AD, CSF Aβ42 is reduced while Aβ40 remains unchanged. It has been suggested that altered CSF Aβ42 is due to aggregation of this peptide into insoluble plaques, resulting in less soluble Aβ42 available for secretion to the CSF. However, the relations between soluble and insoluble Aβ42 and Aβ40 in the brain and the concentrations of these Aβ peptides in CSF are not well studied. METHODS: CSF and cortical brain tissue was collected from 2, 4, 6, and 12 months old male and female 5xFAD mice (n=45). CSF Aβ42 and Aβ40 concentrations were measured using Single molecule array (Simoa) technology. Brain sections were prepared and immunohistochemically (IHC) stained using antibodies specific for Aβ42 and Aβ40. The concentrations of Aβ42 and Aβ40 in soluble (extracted with TBS) and insoluble (extracted with formic acid) cortical brain fractions were determined by the Meso Scale Discovery technique. RESULTS: CSF Aβ42 was decreased over time whereas CSF Aβ40 remained unaltered (Fig 1). In the same mice, IHC revealed an age-related increased deposition of both Aβ42 and Aβ40 in insoluble plaques from 2 months of age (Fig 2). Moreover, measurements of Aβ42 and Aβ40 in soluble and insoluble cortical brain fractions showed increased concentrations of both peptides over time (Fig 3). CSF Aβ42 correlated inversely with cortical deposition of Aβ42 determined with IHC and the concentrations of Aβ42 in soluble and insoluble brain fractions. In contrast, no such correlations were found for Aβ40 (Fig 4). Although cortical levels of the two Aβ peptides were higher in females than in males, these sex differences were not reflected in CSF (Fig 5). CONCLUSIONS: Although significant depositions of both Aβ42 and Aβ40 were found in the brain, only Aβ42 was altered in CSF. Together with the finding that Aβ42 was increased, and not reduced, in soluble cortical brain fractions, this may suggest that mechanisms other than aggregation of Aβ42 into insoluble plaques contribute to decreased CSF concentrations of this Aβ peptide in 5xFAD mice. However, additional characterization of Aβ in the soluble brain fraction is needed to further understand its relation to the concentrations in CSF.
|
|
| 6. |
- Ashton, Nicholas J., et al.
(författare)
-
A multicentre validation study of the diagnostic value of plasma neurofilament light
- 2021
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-12
-
Tidskriftsartikel (refereegranskat)abstract
- Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
|
|
| 7. |
- Ashton, Nicholas J., et al.
(författare)
-
Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer's trial selection and disease monitoring.
- 2022
-
Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 28:12, s. 2555-2562
-
Tidskriftsartikel (refereegranskat)abstract
- Blood biomarkers indicative of Alzheimer's disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4-6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer's Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.
|
|
| 8. |
- Ayton, Scott, et al.
(författare)
-
Acute phase markers in CSF reveal inflammatory changes in Alzheimer's disease that intersect with pathology, APOE ε4, sex and age
- 2021
-
Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082. ; 198
-
Tidskriftsartikel (refereegranskat)abstract
- It is unknown how neuroinflammation may feature in the etiology of Alzheimer's disease (AD). We profiled acute phase response (APR) proteins (α1-antitrypsin, α1-antichymotrypsin, ceruloplasmin, complement C3, ferritin, α-fibrinogen, β-fibrinogen, γ-fibrinogen, haptoglobin, hemopexin) in CSF of 1291 subjects along the clinical and biomarker spectrum of AD to investigate the association between inflammatory changes, disease outcomes, and demographic variables. Subjects were stratified by Aβ42/t-tau as well as the following clinical diagnoses: cognitively normal (CN); subjective cognitive decline (SCD); mild cognitive impairment (MCI); and AD dementia. In separate multiple regressions (adjusting for diagnosis, age, sex, APOE-ε4) of each APR protein and a composite of all APR proteins, CSF Aβ42/t-tau status was associated with elevated ferritin, but not any other APR protein in CN and SCD subjects. Rather, the APR was elevated along with symptomatic progression (CN < SCD < MCI < AD), and this was elevation was mediated by CSF p-tau181. APOE ε4 status did not affect levels of any APR proteins in CSF, while these were elevated in males and with increased age. The performance of the APR in predicting clinical diagnosis was influenced by APOE ε4 status, sex, and age. These data provide new insight into inflammatory changes in AD and how this intersects with pathology changes and patient demographics.
|
|
| 9. |
- Ayton, Scott, et al.
(författare)
-
The Neuroinflammatory Acute Phase Response in Parkinsonian-Related Disorders
- 2022
-
Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 37:5, s. 993-1003
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Neuroinflammation is implicated in the pathophysiology of Parkinson's disease (PD) and related conditions, yet prior clinical biomarker data report mixed findings. Objectives: The aim was to measure a panel of neuroinflammatory acute phase response (APR) proteins in the cerebrospinal fluid (CSF) of participants with PD and related disorders. Methods: Eleven APR proteins were measured in the CSF of 867 participants from the BioFINDER cohort who were healthy (612) or had a diagnosis of PD (155), multiple system atrophy (MSA) (26), progressive supranuclear palsy (PSP) (22), dementia with Lewy bodies (DLB) (23), or Parkinson’s disease with dementia (PDD) (29). Results: CSF APR proteins were mostly unchanged in PD, with only haptoglobin and α1-antitrypsin significantly elevated compared to controls. These proteins were variably increased in the other disorders. Certain protein components yielded unique signatures according to diagnosis: ferritin and transthyretin were selectively elevated in MSA and discriminated these patients from all others. Haptoglobin was selectively increased in PSP, discriminating this disease from MSA when used in combination with ferritin and transthyretin. This panel of proteins did not correlate well with severity of motor impairment in any disease category, but several (particularly ceruloplasmin and ferritin) were associated with memory performance (Mini-Mental State Examination) in patients with DLB and PDD. Conclusions: These findings provide new insights into inflammatory changes in PD and related disorders while also introducing biomarkers of potential clinical diagnostic utility.
|
|
| 10. |
- Berron, David, et al.
(författare)
-
Early stages of tau pathology and its associations with functional connectivity, atrophy and memory
- 2021
-
Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2771-2783
-
Tidskriftsartikel (refereegranskat)abstract
- In Alzheimer's disease, post-mortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with Brodmann area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 amyloid-β- cognitively unimpaired, 81 amyloid-β+ cognitively unimpaired and 87 amyloid-β+ individuals with mild cognitive impairment, who each underwent 18F-RO948 tau and 18F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and Brodmann area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, Brodmann area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, Brodmann area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease stage-specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.
|
|
