| 1. |
- Heslegrave, Amanda, et al.
(författare)
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Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer's disease.
- 2016
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Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The discovery that heterozygous missense mutations in the gene encoding triggering receptor expressed on myeloid cells 2 (TREM2) are risk factors for Alzheimer's disease (AD), with only the apolipoprotein E (APOE) ε4 gene allele conferring a higher risk, has led to increased interest in immune biology in the brain. TREM2 is expressed on microglia, the resident immune cells of the brain and has been linked to phagocytotic clearance of amyloid β (Aβ) plaques. Soluble TREM2 (sTREM2) has previously been measured in cerebrospinal fluid (CSF) by ELISA but in our hands commercial kits have proved unreliable, suggesting that other methods may be required. We developed a mass spectrometry method using selected reaction monitoring for the presence of a TREM2 peptide, which can be used to quantify levels of sTREM2 in CSF.
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| 2. |
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| 3. |
- Wallin, Anders, 1950, et al.
(författare)
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Alzheimer's disease-subcortical vascular disease spectrum in a hospital-based setting: overview of results from the Gothenburg MCI and dementia studies.
- 2016
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 36:1, s. 95-113
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Forskningsöversikt (refereegranskat)abstract
- The ability to discriminate between Alzheimer's disease (AD), subcortical vascular disease, and other cognitive disorders is crucial for diagnostic purposes and clinical trial outcomes. Patients with primarily subcortical vascular disease are unlikely to benefit from treatments targeting the AD pathogenic mechanisms and vice versa. The Gothenburg mild cognitive impairment (MCI) and dementia studies are prospective, observational, single-center cohort studies suitable for both cross-sectional and longitudinal analysis that outline the cognitive profiles and biomarker characteristics of patients with AD, subcortical vascular disease, and other cognitive disorders. The studies, the first of which started in 1987, comprise inpatients with manifest dementia and patients seeking care for cognitive disorders at an outpatient memory clinic. This article gives an overview of the major published papers (neuropsychological, imaging/physiology, and neurochemical) of the studies including the ongoing Gothenburg MCI study. The main findings suggest that subcortical vascular disease with or without dementia exhibit a characteristic neuropsychological pattern of mental slowness and executive dysfunction and neurochemical deviations typical of white matter changes and disturbed blood-brain barrier function. Our findings may contribute to better healthcare for this underrecognized group of patients. The Gothenburg MCI study has also published papers on multimodal prediction of dementia, and cognitive reserve.Journal of Cerebral Blood Flow & Metabolism advance online publication, 29 July 2015; doi:10.1038/jcbfm.2015.148.
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| 4. |
- Wallin, Anders, 1950, et al.
(författare)
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The Gothenburg MCI study: design and distribution of Alzheimer's disease and subcortical vascular disease diagnoses from baseline to 6-year follow-up.
- 2016
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 36:1, s. 114-131
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Tidskriftsartikel (refereegranskat)abstract
- There is a need for increased nosological knowledge to enable rational trials in Alzheimer's disease (AD) and related disorders. The ongoing Gothenburg mild cognitive impairment (MCI) study is an attempt to conduct longitudinal in-depth phenotyping of patients with different forms and degrees of cognitive impairment using neuropsychological, neuroimaging, and neurochemical tools. Particular attention is paid to the interplay between AD and subcortical vascular disease, the latter representing a disease entity that may cause or contribute to cognitive impairment with an effect size that may be comparable to AD. Of 664 patients enrolled between 1999 and 2013, 195 were diagnosed with subjective cognitive impairment (SCI), 274 with mild cognitive impairment (MCI), and 195 with dementia, at baseline. Of the 195 (29%) patients with dementia at baseline, 81 (42%) had AD, 27 (14%) SVD, 41 (21%) mixed type dementia (=AD+SVD=MixD), and 46 (23%) other etiologies. After 6 years, 292 SCI/MCI patients were eligible for follow-up. Of these 292, 69 (24%) had converted to dementia (29 (42%) AD, 16 (23%) SVD, 15 (22%) MixD, 9 (13%) other etiologies). The study has shown that it is possible to identify not only AD but also incipient and manifest MixD/SVD in a memory clinic setting. These conditions should be taken into account in clinical trials.Journal of Cerebral Blood Flow & Metabolism advance online publication, 15 July 2015; doi:10.1038/jcbfm.2015.147.
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| 5. |
- Åberg, Daniel, 1973, et al.
(författare)
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Increased Cerebrospinal Fluid Level of Insulin-like Growth Factor-II in Male Patients with Alzheimer's Disease
- 2015
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 48:3, s. 637-646
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Tidskriftsartikel (refereegranskat)abstract
- Background: Insulin-like growth factor-II (IGF-II) is important for brain development. Although IGF-II is abundant also in adult life, little is known of the role of IGF-II in Alzheimer's disease (AD). Objective and methods: This was a cross-sectional study of 60 consecutive patients under primary evaluation of cognitive impairment and 20 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 32), stable MCI (SMCI, n = 13), or other dementias (n = 15). IGF-II, IGF-binding protein-1 (IGFBP-1), and IGFBP-2 were analyzed in serum and cerebrospinal fluid (CSF). Results: Levels of IGF-II, IGFBP-1, and IGFBP-2 were similar in all groups in the total study population. Gender-specific analyses showed that in men (n = 40), CSF IGF-II level was higher in AD compared to SMCI and controls (p < 0.01 and p < 0.05, respectively). Furthermore, CSF IGFBP-2 levelwas increased inADmen versus SMCI men (p < 0.01) and tended to be increased versus control men (p = 0.09). There were no between-group differences in women (n = 40). In the total study population (n = 80) as well as in men (n = 40), CSF levels of IGF-II and IGFBP-2 correlated positively with CSF levels of the AD biomarkers total-tau and phosphorylated tau protein. Conclusion: In men, but not women, in the early stages of AD, CSF IGF-II level was elevated, and CSF IGFBP-2 level tended to be increased, compared to healthy controls.
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| 6. |
- Åberg, Daniel, 1973, et al.
(författare)
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Serum IGFBP-1 Concentration as a Predictor of Outcome after Ischemic Stroke—A Prospective Observational Study
- 2023
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Ingår i: International Journal of Molecular Sciences. - 1422-0067. ; 24:11
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor-binding protein-1 (IGFBP-1) regulates insulin-like growth factor- I (IGF-I) bioactivity, and is a central player in normal growth, metabolism, and stroke recovery. However, the role of serum IGFBP-1 (s-IGFBP-1) after ischemic stroke is unclear. We determined whether s-IGFBP-1 is predictive of poststroke outcome. The study population comprised patients (n = 470) and controls (n = 471) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Functional outcome was evaluated after 3 months, 2, and 7 years using the modified Rankin Scale (mRS). Survival was followed for a minimum of 7 years or until death. S-IGFBP-1 was increased after 3 months (p < 0.01), but not in the acute phase after stroke, compared with the controls. Higher acute s-IGFBP-1 was associated with poor functional outcome (mRS score > 2) after 7 years [fully adjusted odds ratio (OR) per log increase 2.9, 95% confidence interval (CI): 1.4-5.9]. Moreover, higher s-IGFBP-1 after 3 months was associated with a risk of poor functional outcome after 2 and 7 years (fully adjusted: OR 3.4, 95% CI: 1.4–8.5 and OR 5.7, 95% CI: 2.5–12.8, respectively) and with increased mortality risk (fully adjusted: HR 2.0, 95% CI: 1.1–3.7). Thus, high acute s-IGFBP-1 was only associated with poor functional outcome after 7 years, whereas s-IGFBP-1 after 3 months was an independent predictor of poor long-term functional outcome and poststroke mortality.
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| 7. |
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| 8. |
- Axelsson, Elin, et al.
(författare)
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Diagnostic Performance of Cerebrospinal Fluid Neurofilament Light Chain and Soluble Amyloid-β Protein Precursor β in the Subcortical Small Vessel Type of Dementia.
- 2023
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 96:4, s. 1515-1528
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Tidskriftsartikel (refereegranskat)abstract
- The subcortical small vessel type of dementia (SSVD) is a common subtype of vascular dementia, but there is a lack of disease-specific cerebrospinal fluid (CSF) biomarkers.We investigated whether CSF concentrations of neurofilament light chain (NFL), soluble amyloid-β protein precursor α (sAβPPα), sAβPPβ, and CSF/serum albumin ratio could separate SSVD from healthy controls, Alzheimer's disease (AD), and mixed dementia (combined AD and SSVD).This was a mono-center study of patients with SSVD (n = 38), AD (n = 121), mixed dementia (n = 62), and controls (n = 96). The CSF biomarkers were measured using immunoassays, and their independent contribution to the separation between groups were evaluated using the Wald test. Then, the area under the receiver operating characteristics curve (AUROC) and 95% confidence intervals (CIs) were calculated.Elevated neurofilament light chain (NFL) and decreased sAβPPβ independently separated SSVD from controls, and sAβPPβ also distinguished SSVD from AD and mixed dementia. The combination of NFL and sAβPPβ discriminated SSVD from controls with high accuracy (AUROC 0.903, 95% CI: 0.834-0.972). Additionally, sAβPPβ combined with the core AD biomarkers (amyloid-β42, total tau, and phosphorylated tau181) had a high ability to separate SSVD from AD (AUROC 0.886, 95% CI: 0.830-0.942) and mixed dementia (AUROC 0.903, 95% CI: 0.838-0.968).The high accuracy of NFL and sAβPPβ to separate SSVD from controls supports that SSVD is a specific diagnostic entity. Moreover, SSVD was distinguished from AD and mixed dementia using sAβPPβ in combination with the core AD biomarkers.
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| 9. |
- Deming, Y., et al.
(författare)
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The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk
- 2019
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:505
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Tidskriftsartikel (refereegranskat)abstract
- Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 x 10(-15)); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.
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| 10. |
- Funkquist, Anders, 1977-, et al.
(författare)
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Higher CSF/serum free-T4 ratio is associated with improvement of quality of life during treatment with L-thyroxine
- 2023
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Ingår i: Journal of Neuroendocrinology. - : Wiley-Blackwell Publishing Inc.. - 0953-8194 .- 1365-2826. ; 35:5
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Tidskriftsartikel (refereegranskat)abstract
- Up to 20% of individuals with primary hypothyroidism treated with L-thyroxine still suffer from severe symptoms. These are supposedly brain derived and involve both cognitive and emotional domains. Previously, no consistent relationship has been found between thyroid hormones (TH) or TSH levels in blood and quality of life (QoL). Recently, we reported an association between cerebrospinal fluid (CSF)/serum free-thyroxine (f-T4) ratio and QoL, in juvenile hypothyroid patients. Here, we investigated if CSF/serum f-T4 ratio and QoL estimates correlate also during L-thyroxine treatment. Moreover, the CSF biomarker neurogranin (Ng) was used as a biomarker for synaptic function and integrity in clinical research. Ng is partially controlled by TH and therefore we investigated the relationship between QoL parameters and Ng levels. Patients diagnosed with primary hypothyroidism were investigated using vital parameters, serum and CSF analyses of TH, TSH, Ng and QoL questionnaires. Similar procedures were performed after 6 months of treatment. The most marked associations with QoL were found for CSF/serum f-T4 ratio, which was strongly related to several QoL parameters such as the mental subscore of SF-36 (r = 0.83, p < .0005). Ng, which did not differ from that in our healthy controls, was lower in some patients during treatment and higher in others. However, the change in Ng during treatment was significantly correlated with QoL parameters including the mental subscore of SF-36 (r = -0.86, p < .0001). In addition, the CSF/serum f-T4 ratio correlated with the change in Ng (r = -0.75, p = .001). Our results suggest that the ratio between CSF and serum f-T4 is an important biomarker for QoL during treatment of patients with primary hypothyroidism, so far in research, but in the future maybe also in clinical settings. Moreover, this ratio also correlates with the changes in Ng levels during L-thyroxine treatment, further supporting the impact of the TH balance between serum and CSF on QoL.
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