| 1. |
- Andersson, Carl-Henrik, et al.
(författare)
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A Genetic Variant of the Sortilin 1 Gene isAssociated with Reduced Risk ofAlzheimer's Disease
- 2016
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 53:4, s. 1353-1363
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc=0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.
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| 2. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 3. |
- Brinkmalm, Gunnar, et al.
(författare)
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Soluble amyloid precursor protein α and β in CSF in Alzheimer's disease.
- 2013
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Ingår i: Brain research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 1513, s. 117-26
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral accumulation of amyloid β (Aβ) is a pathological hallmark of Alzheimer's disease (AD). Proteolytic processing of amyloid precursor protein (APP) by α- or β-secretase results in two soluble metabolites, sAPPα and sAPPβ, respectively. However, previous data have shown that both α- and β-secretase have multiple cleavage sites. The aim of this study was to characterize the C-termini of sAPPα and sAPPβ in cerebrospinal fluid (CSF) by mass spectrometry (MS) and to evaluate whether different combinations of these fragments better separate between AD patients and controls by comparing two different sAPP immunoassays. Methods: Using immunoprecipitation and high resolution MS, the APP species present in CSF were investigated. CSF levels of sAPPα and sAPPβ from patients with AD (n=43) and from non-demented controls (n=44) were measured using AlphaLISA and MSD immunoassays that employ different antibodies for C-terminal recognition of sAPPα. Results: Four different C-terminal forms of sAPP were identified, sAPPβ-M671, sAPPβ-Y681, sAPPα-Q686, and sAPPα-K687 (APP770 numbering). Neither immunoassay for the sAPP species could separate the two patient groups. The correlation (R(2)) between the two immunoassays was 0.41 for sAPPα and 0.45 for sAPPβ. Conclusion: Using high resolution MS, we show here for the first time that sAPPα in CSF ends at Q686 and K687. The findings also support the conclusion from several previous studies that sAPPα and sAPPβ levels are unaltered in AD.
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| 4. |
- Brinkmalm-Westman, Ann, 1966, et al.
(författare)
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SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease
- 2014
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Synaptic degeneration is an early pathogenic event in Alzheimer's disease, associated with cognitive impairment and disease progression. Cerebrospinal fluid biomarkers reflecting synaptic integrity would be highly valuable tools to monitor synaptic degeneration directly in patients. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, however these assays were not sensitive enough for individual samples. Results: We report a new strategy to study synaptic pathology by using affinity purification and mass spectrometry to measure the levels of the presynaptic protein SNAP-25 in cerebrospinal fluid. By applying this novel affinity mass spectrometry strategy on three separate cohorts of patients, the value of SNAP-25 as a cerebrospinal fluid biomarker for synaptic integrity in Alzheimer's disease was assessed for the first time. We found significantly higher levels of cerebrospinal fluid SNAP-25 fragments in Alzheimer's disease, even in the very early stages, in three separate cohorts. Cerebrospinal fluid SNAP-25 differentiated Alzheimer's disease from controls with area under the curve of 0.901 (P < 0.0001). Conclusions: We developed a sensitive method to analyze SNAP-25 levels in individual CSF samples that to our knowledge was not possible previously. Our results support the notion that synaptic biomarkers may be important tools for early diagnosis, assessment of disease progression, and to monitor drug effects in treatment trials.
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| 5. |
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| 6. |
- Hall, Sara, et al.
(författare)
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CSF biomarkers and clinical progression of Parkinson disease.
- 2015
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Ingår i: Neurology. - 1526-632X. ; 84:1, s. 57-63
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Tidskriftsartikel (refereegranskat)abstract
- To investigate whether certain CSF biomarkers at baseline can predict future progression of motor symptoms and cognitive decline in patients with Parkinson disease (PD).
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| 7. |
- Hall, Sara, et al.
(författare)
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Longitudinal Measurements of Cerebrospinal Fluid Biomarkers in Parkinson's Disease.
- 2016
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Ingår i: Movement disorders : official journal of the Movement Disorder Society. - : Wiley. - 1531-8257 .- 0885-3185. ; 31:6, s. 898-905
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to investigate whether cerebrospinal fluid (CSF) levels of tau, phosphorylated tau, β-amyloid42 , α-synuclein, neurofilament light, and YKL-40 change over time and if changes correlate with motor progression and/or cognitive decline in patients with PD and controls.
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