| 1. |
- 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.
|
|
| 2. |
- Blennow, Kaj, 1958, et al.
(författare)
-
Predicting clinical decline and conversion to Alzheimer's disease or dementia using novel Elecsys Aβ(1-42), pTau and tTau CSF immunoassays.
- 2019
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- We evaluated the performance of CSF biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients with cognitive symptoms. CSF samples from patients in two multicentre longitudinal studies (ADNI, n = 619; BioFINDER, n = 431) were analysed. Aβ(1-42), tTau and pTau CSF concentrations were measured using Elecsys CSF immunoassays, and tTau/Aβ(1-42) and pTau/Aβ(1-42) ratios calculated. Patients were classified as biomarker (BM)-positive or BM-negative at baseline. Ability of biomarkers to predict risk of clinical decline and conversion to AD/dementia was assessed using pre-established cut-offs for Aβ(1-42) and ratios; tTau and pTau cut-offs were determined. BM-positive patients showed greater clinical decline than BM-negative patients, demonstrated by greater decreases in MMSE scores (all biomarkers: -2.10 to -0.70). Risk of conversion to AD/dementia was higher in BM-positive patients (HR: 1.67 to 11.48). Performance of Tau/Aβ(1-42) ratios was superior to single biomarkers, and consistent even when using cut-offs derived in a different cohort. Optimal pTau and tTau cut-offs were approximately 27 pg/mL and 300 pg/mL in both BioFINDER and ADNI. Elecsys pTau/Aβ(1-42) and tTau/Aβ(1-42) are robust biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients, and may support AD diagnosis in clinical practice.
|
|
| 3. |
- Cullen, Nicholas C., et al.
(författare)
-
Accelerated inflammatory aging in Alzheimer’s disease and its relation to amyloid, tau, and cognition
- 2021
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- It is unclear how pathological aging of the inflammatory system relates to Alzheimer’s disease (AD). We tested whether age-related inflammatory changes in cerebrospinal fluid (CSF) and plasma exist across different stages of AD, and whether such changes related to AD pathology. Linear regression was first used model chronological age in amyloid-β negative, cognitively unimpaired individuals (Aβ− CU; n = 312) based on a collection of 73 inflammatory proteins measured in both CSF and plasma. Fitted models were then applied on protein levels from Aβ+ individuals with mild cognitive impairment (Aβ+ MCI; n = 150) or Alzheimer’s disease dementia (Aβ+ AD; n = 139) to test whether the age predicted from proteins alone (“inflammatory age”) differed significantly from true chronological age. Aβ− individuals with subjective cognitive decline (Aβ− SCD; n = 125) or MCI (Aβ− MCI; n = 104) were used as an independent contrast group. The difference between inflammatory age and chronological age (InflammAGE score) was then assessed in relation to core AD biomarkers of amyloid, tau, and cognition. Both CSF and plasma inflammatory proteins were significantly associated with age in Aβ− CU individuals, with CSF-based proteins predicting chronological age better than plasma-based counterparts. Meanwhile, the Aβ− SCD and validation Aβ− CU groups were not characterized by significant inflammatory aging, while there was increased inflammatory aging in Aβ− MCI patients for CSF but not plasma inflammatory markers. Both CSF and plasma inflammatory changes were seen in the Aβ+ MCI and Aβ+ AD groups, with varying degrees of change compared to Aβ− CU and Aβ− SCD groups. Finally, CSF inflammatory changes were highly correlated with amyloid, tau, general neurodegeneration, and cognition, while plasma changes were mostly associated with amyloid and cognition. Inflammatory pathways change during aging and are specifically altered in AD, tracking closely with pathological hallmarks. These results have implications for tracking AD progression and for suggesting possible pathways for drug targeting.
|
|
| 4. |
- Hall, Sara, et al.
(författare)
-
Cerebrospinal fluid concentrations of inflammatory markers in Parkinson's disease and atypical parkinsonian disorders
- 2018
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Inflammation has been implicated in the pathogenesis of Parkinson's disease (PD). We here investigate levels of inflammatory biomarkers in cerebrospinal fluid (CSF) in PD and atypical parkinsonian disorders (APD) compared with neurologically healthy controls. We included 131 patients with PD and 27 PD with dementia (PDD), 24 with multiple system atrophy (MSA), 14 with progressive supranuclear palsy (PSP) and 50 controls, all part of the Swedish BioFINDER study. CSF was analyzed for CRP, SAA, IL-6, IL-8, YKL-40 and MCP-1 (CCL2) as well as alpha-synuclein (alpha-syn), tau, tau phosphorylated at Thr181 (P-tau), A beta(42) and NfL. In this exploratory study, we found higher levels of the inflammatory biomarker SAA in PDD and MSA compared with controls and PD and higher levels of CRP in PDD and MSA compared with PD. YKL-40 was lower in PD compared with controls. There were multiple positive correlations between the inflammatory markers, a-syn and markers of neuroaxonal injury (NfL and tau). In PD, higher levels of inflammatory biomarkers correlated with worse motor function and cognitive impairment. Thus, inflammatory biomarkers were increased in PDD and MSA. Furthermore, inflammatory biomarkers correlated with more severe disease regarding motor symptoms and cognitive impairment in PD, indicating an association between inflammation and more aggressive disease course. However, the results need confirmation in follow-up studies.
|
|
| 5. |
- Jalakas, Mattis, et al.
(författare)
-
A quick test of cognitive speed can predict development of dementia in Parkinson’s disease
- 2019
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- Parkinson’s disease (PD) patients frequently develop cognitive impairment. There is a need for brief clinical assessments identifying PD patients at high risk of progressing to dementia. In this study, we look into predicting dementia in PD and underlying structural and functional correlates to cognitive decline in PD. We included 175 patients with PD, 30 with PD dementia, 51 neurologically healthy controls and 121 patients with Alzheimer’s disease (AD) from Skane University Hospital, BIOFINDER cohorts. All underwent cognitive tests, including MMSE, 10-word list delayed recall (ADAS-cog), A Quick Test of cognitive speed (AQT), Letter S fluency, Clock Drawing Test (CDT) and pentagon copying. In non-demented patients with PD, abnormal AQT and CDT results predicted an increased risk of subsequent development of dementia (hazard ratio 2.2 for both). When comparing the cognitive profile between PD and AD, decreased performance on AQT, which measures attention and processing speed, was more typical in PD. Lastly, we investigated the underlying structural and functional correlates for the PD-specific test AQT with magnetic resonance imaging. In PD patients, decreased performance on AQT was associated with i) cortical thinning in temporoparietal regions, ii) changes in diffusion MRI, especially in the cingulum tract, and iii) decreased functional connectivity in posterior brain networks.
|
|
| 6. |
- Janelidze, Shorena, et al.
(författare)
-
Plasma beta-amyloid in Alzheimer's disease and vascular disease
- 2016
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Implementation of amyloid biomarkers in clinical practice would be accelerated if such biomarkers could be measured in blood. We analyzed plasma levels of A beta 42 and A beta 40 in a cohort of 719 individuals (the Swedish BioFINDER study), including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer's disease (AD) dementia and cognitively healthy elderly, using a ultrasensitive immunoassay (Simoa platform). There were weak positive correlations between plasma and cerebrospinal fluid (CSF) levels for both A beta 42 and A beta 40, and negative correlations between plasma A beta 42 and neocortical amyloid deposition (measured with PET). Plasma levels of A beta 42 and A beta 40 were reduced in AD dementia compared with all other diagnostic groups. However, during the preclinical or prodromal AD stages (i.e. in amyloid positive controls, SCD and MCI) plasma concentration of A beta 42 was just moderately decreased whereas A beta 40 levels were unchanged. Higher plasma (but not CSF) levels of A beta were associated with white matter lesions, cerebral microbleeds, hypertension, diabetes and ischemic heart disease. In summary, plasma A beta is overtly decreased during the dementia stage of AD indicating that prominent changes in A beta metabolism occur later in the periphery compared to the brain. Further, increased levels of A beta in plasma are associated with vascular disease.
|
|
| 7. |
- Kumar, Atul, et al.
(författare)
-
Genetic effects on longitudinal cognitive decline during the early stages of Alzheimer’s disease
- 2021
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence, and educational attainment) to predict longitudinal cognitive change (measured by mini-mental state examination (MMSE) [primary outcome] and other cognitive tests) over a mean of 4.2 years. We included 260 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 121 Aβ-positive CU (preclinical AD), 50 Aβ-negative mild cognitive impairment (MCI) patients, and 127 Aβ-positive MCI patients (prodromal AD). Statistical significance was determined at Bonferroni corrected p value < 0.05. The PGS for intelligence (beta = 0.1, p = 2.9e−02) was protective against decline in MMSE in CU and MCI participants regardless of Aβ status. The polygenic risk score for AD (beta = − 0.12, p = 9.4e−03) was correlated with the rate of change in MMSE and was partially mediated by Aβ-pathology (mediation effect 20%). There was no effect of education PGS on cognitive measures. Genetic variants associated with intelligence mitigate cognitive decline independent of Aβ-pathology, while effects of genetic variants associated with AD are partly mediated by Aβ-pathology.
|
|
| 8. |
- Sjostrom, H, et al.
(författare)
-
Mapping of apparent susceptibility yields promising diagnostic separation of progressive supranuclear palsy from other causes of parkinsonism
- 2019
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 6079-
-
Tidskriftsartikel (refereegranskat)abstract
- There is a need for methods that distinguish Parkinson’s disease (PD) from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), which have similar characteristics in the early stages of the disease. In this prospective study, we evaluate mapping of apparent susceptibility based on susceptibility weighted imaging (SWI) for differential diagnosis. We included 134 patients with PD, 11 with PSP, 10 with MSA and 44 healthy controls. SWI data were processed into maps of apparent susceptibility. In PSP, apparent susceptibility was increased in the red nucleus compared to all other groups, and in globus pallidus, putamen, substantia nigra and the dentate nucleus compared to PD and controls. In MSA, putaminal susceptibility was increased compared to PD and controls. Including all studied regions and using discriminant analysis between PSP and PD, 100% sensitivity and 97% specificity was achieved, and 91% sensitivity and 90% specificity in separating PSP from MSA. Correlations between putaminal susceptibility and disease severity in PD could warrant further research into using susceptibility mapping for monitoring disease progression and in clinical trials. Our study indicates that susceptibility in deep nuclei could play a role in the diagnosis of atypical parkinsonism, especially in PSP.
|
|
| 9. |
- Skillbäck, Tobias, et al.
(författare)
-
A novel quantification-driven proteomic strategy identifies an endogenous peptide of pleiotrophin as a new biomarker of Alzheimer's disease
- 2017
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- We present a new, quantification-driven proteomic approach to identifying biomarkers. In contrast to the identification-driven approach, limited in scope to peptides that are identified by database searching in the first step, all MS data are considered to select biomarker candidates. The endopeptidome of cerebrospinal fluid from 40 Alzheimer's disease (AD) patients, 40 subjects with mild cognitive impairment, and 40 controls with subjective cognitive decline was analyzed using multiplex isobaric labeling. Spectral clustering was used to match MS/MS spectra. The top biomarker candidate cluster (215% higher in AD compared to controls, area under ROC curve = 0.96) was identified as a fragment of pleiotrophin located near the protein's C-terminus. Analysis of another cohort (n = 60 over four clinical groups) verified that the biomarker was increased in AD patients while no change in controls, Parkinson's disease or progressive supranuclear palsy was observed. The identification of the novel biomarker pleiotrophin 151-166 demonstrates that our quantification-driven proteomic approach is a promising method for biomarker discovery, which may be universally applicable in clinical proteomics.
|
|
| 10. |
- Smith, Ruben, et al.
(författare)
-
18F-AV-1451 in Parkinson's Disease with and without dementia and in Dementia with Lewy Bodies.
- 2018
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 1-6
-
Tidskriftsartikel (refereegranskat)abstract
- Mixed pathologies of α-synuclein, β-amyloid and tau are relatively common in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). We therefore wanted to study the retention patterns of18F-AV-1451 in PD, PD-dementia (PDD), and DLB. To do this 44 healthy controls, 11 non-demented patients with PD, 18 patients with PDD, and six patients with DLB underwent MRI and18F-AV-1451 PET scanning and cognitive testing. We found that parietal18F-AV-1451 retention was increased in patients with DLB compared to controls and PD patients, while18F-AV-1451 uptake was reduced in the substantia nigra in PDD. Increased parietal18F-AV-1451 PET uptake was associated with impaired performance on verbal fluency tests, and the decreased uptake in the substantia nigra correlated with worse motor function. We found no effect of the monoamine oxidase B inhibitor rasagiline on18F-AV-1451 binding. In conclusion DLB patients have increased parietal18F-AV-1451 uptake. Increased parietal tau is associated with executive impairment in patients with synucleinopathies, while decreased uptake in the substantia nigra is associated with parkinsonism. Further, our data indicate that18F-AV-1451 does not significantly bind to MAO-B in vivo.
|
|
