| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
- Willemse, E. A. J., et al.
(författare)
-
Pre-analytical stability of novel cerebrospinal fluid biomarkers
- 2019
-
Ingår i: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981. ; 497, s. 204-211
-
Tidskriftsartikel (refereegranskat)abstract
- Stability of the cerebrospinal fluid (CSF) composition under different pre-analytical conditions is relevant for the diagnostic potential of biomarkers. Our aim was to examine the pre-analytical stability of promising CSF biomarkers that are currently evaluated for their discriminative use in various neurological diseases. Pooled CSF was aliquoted and experimentally exposed to delayed storage: 0, 1, 2, 4, 24, 72, or 168 h at 4 °C or room temperature (RT), or 1–4 months at −20 °C; or up to 7 freeze/thaw (f/t) cycles, before final storage at −80 °C. Eleven CSF biomarkers were screened using immunoassays, liquid chromatography, or enzymatic methods. Levels of neurogranin (truncP75), chitinase-3-like protein (YKL-40), beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), acetylcholinesterase (AChE) enzymatic activity, theobromine, secreted protein acidic and rich in cysteine-like 1 (SPARCL-1) and homovanillic acid (HVA) levels were not affected by the applied storage conditions. 3-Methoxy-4-hydroxyphenylglycol (MHPG) levels linearly and strongly decreased after 4 h at RT (−10%) or 24 h at 4 °C (−27%), and with 6% after every f/t cycle. 5-Methyltetrahydrofolate (5-MTHF) (−29% after 1 week at RT) and 5-hydroxyindoleacetic acid levels (5-HIAA) (−16% after 1 week at RT) were reduced and 3,4-dihydroxyphenylacetic acid (DOPAC) levels (+22% after 1 week at RT) increased, but only after >24 h at RT. Ten out of eleven potential CSF novel biomarkers showed very limited change under common storage and f/t conditions, suggesting that these CSF biomarkers can be trustfully tested under the pre-analytical conditions present across different cohorts. © 2019 Elsevier B.V.
|
|
| 26. |
|
|
| 27. |
- Gallagher, Michael D., et al.
(författare)
-
TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
- 2014
-
Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:3, s. 407-418
-
Tidskriftsartikel (refereegranskat)abstract
- Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
|
|
| 28. |
- Reus, LM, et al.
(författare)
-
Genome-wide association study of frontotemporal dementia identifies a C9ORF72 haplotype with a median of 12-G4C2 repeats that predisposes to pathological repeat expansions
- 2021
-
Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1, s. 451-
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants. To identify rare and new common variant FTD risk loci and provide more insight into the heritability of C9ORF72-related FTD, we performed a GWAS consisting of 354 FTD patients (including and excluding N = 28 pathological repeat carriers) and 4209 control subjects. The Haplotype Reference Consortium was used as reference panel, allowing for the imputation of rare genetic variants. Two rare genetic variants nearby C9ORF72 were strongly associated with FTD in the discovery (rs147211831: OR = 4.8, P = 9.2 × 10−9, rs117204439: OR = 4.9, P = 6.0 × 10−9) and replication analysis (P < 1.1 × 10−3). These variants also significantly associated with amyotrophic lateral sclerosis in a publicly available dataset. Using haplotype analyses in 1200 individuals, we showed that these variants tag a sub-haplotype of the founder haplotype of the repeat expansion that was previously found to be present in virtually all pathological C9ORF72 G4C2 repeat lengths. This new risk haplotype was 10 times more likely to contain a C9ORF72 pathological repeat length compared to founder haplotypes without one of the two risk variants (~22% versus ~2%; P = 7.70 × 10−58). In haplotypes without a pathologic expansion, the founder risk haplotype had a higher number of repeats (median = 12 repeats) compared to the founder haplotype without the risk variants (median = 8 repeats) (P = 2.05 × 10−260). In conclusion, the identified risk haplotype, which is carried by ~4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 G4C2. These findings strongly indicate that longer C9ORF72 repeats are unstable and more likely to convert to germline pathological C9ORF72 repeat expansions.
|
|
| 29. |
- Toledo, Jon B, et al.
(författare)
-
Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects.
- 2015
-
Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 138:Pt 9, s. 2701-15
-
Tidskriftsartikel (refereegranskat)abstract
- In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.
|
|
| 30. |
- Vanholder, R, et al.
(författare)
-
Uremic toxicity: present state of the art
- 2001
-
Ingår i: The International journal of artificial organs. - : SAGE Publications. - 0391-3988 .- 1724-6040. ; 24:10, s. 695-725
-
Tidskriftsartikel (refereegranskat)abstract
- The uremic syndrome is a complex mixture of organ dysfunctions, which is attributed to the retention of a myriad of compounds that under normal condition are excreted by the healthy kidneys (uremic toxins). In the area of identification and characterization of uremic toxins and in the knowledge of their pathophysiologic importance, major steps forward have been made during recent years. The present article is a review of several of these steps, especially in the area of information about the compounds that could play a role in the development of cardiovascular complications. It is written by those members of the Uremic Toxins Group, which has been created by the European Society for Artificial Organs (ESAO). Each of the 16 authors has written a state of the art in his/her major area of interest.
|
|
