| 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. |
- Borland, Emma, et al.
(författare)
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The Montreal Cognitive Assessment : Normative Data from a Large Swedish Population-Based Cohort
- 2017
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 59:3, s. 893-901
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Montreal Cognitive Assessment (MoCA) has a high sensitivity for detecting cognitive dysfunction. Swedish normative data does not exist and international norms are often derived from populations where cognitive impairment has not been screened for and not been thoroughly assessed to exclude subjects with dementia or mild cognitive impairment. Objective: To establish norms for MoCA and develop a regression-based norm calculator based on a large, well-examined cohort. Methods: MoCA was administered on 860 randomly selected elderly people from a population-based cohort from the EPIC study. Cognitive dysfunction was screened for and further assessed at a memory clinic. After excluding cognitively impaired participants, normative data was derived from 758 people, aged 65-85. Results: MoCA cut-offs (-1 to -2 standard deviations) for cognitive impairment ranged from <25 to <21 for the lowest educated and <26 to <24 for the highest educated, depending on age group. Significant predictors for MoCA score were age, sex and level of education. Conclusion: We present detailed normative MoCA data and cut-offs according to the DSM-5 criteria for cognitive impairment based on a large population-based cohort of elderly individuals, screened and thoroughly investigated to rule out cognitive impairment. Level of education, sex, and age should be taken in account when evaluating MoCA score, which is facilitated by our online regression-based calculator that provide percentile and z-score for a subject's MoCA score.
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| 3. |
- Hertze, Joakim, et al.
(författare)
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Evaluation of CSF Biomarkers as Predictors of Alzheimer's Disease: A Clinical Follow-Up Study of 4.7 Years.
- 2010
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 21, s. 1119-1128
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we determined the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers to predict development of Alzheimer's disease (AD) within five years in patients with mild cognitive impairment (MCI). To do so, the levels of tau, phosphorylated tau, Abeta42, Abeta40, Abeta38, sAbetaPPalpha, and sAbetaPPbeta were analyzed in 327 CSF samples obtained at baseline from patients with AD (n= 94), MCI (n= 166), depressive disorder (n= 29), and cognitively healthy controls (n= 38). In the cohort with MCI at baseline, 33% subsequently developed AD and 16% developed other types of dementia; however, 51% were still cognitively stable after a follow-up of 4.7 years (range 3.0-7.4). Optimal cut-offs for each biomarker or combinations of biomarkers were defined in the AD, control, and depressive disorder groups. Several combinations resulted in sensitivity and specificity levels > 85% for differentiation of AD from controls and depressive disorder. Using the previously established cut-offs, a combination of Abeta42 and tau could predict future development of AD in MCI patients with a sensitivity of 88%, specificity 82%, positive predictive value 71%, and negative predictive value 94%. MCI patients with both low Abeta42 and high tau levels had a substantially increased risk of developing AD (OR 20; 95% CI 6-58), even after adjustment for confounding factors. Ultimately, CSF biomarkers can stratify MCI patients into those with very low or high risk for future development of AD. However, the specificities and positive predictive values are still too low to be able to diagnose AD before the patients fulfill the clinical criteria.
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| 4. |
- Höglund, Kina, 1976, et al.
(författare)
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Longitudinal Stability Evaluation of Biomarkers and Their Correlation in Cerebrospinal Fluid and Plasma from Patients with Alzheimer's Disease
- 2012
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 32:4, s. 939-947
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Tidskriftsartikel (refereegranskat)abstract
- There is an increasing demand for biomarkers in clinical treatment trials to demonstrate target engagement and to support disease modification claims. To be able to detect treatment related effects, a prerequisite is that the levels of the biomarker are stable over time or that the change over time is known. In the present study, the stability of alpha- and beta-cleaved soluble amyloid-beta protein precursor (sA beta PP alpha and sA beta PP beta), A beta(1-40) together with the phosphorylated form of neurofilament heavy/medium (pNfH/M) in cerebrospinal fluid (CSF) was analyzed in a cohort of 51 patients with Alzheimer's disease. In addition, the stability of A beta(1-40), beta(1-42), and sA beta PP beta in plasma was explored. Plasma and CSF was sampled at baseline and after 6-months follow up, and all patients were on stable treatment with acetylcholinesterase inhibitors. During this 6-month longitudinal follow-up, we saw a small, but consistent and statistically significant increase in CSF levels of sA beta PP beta (103% of baseline levels) and a statistically significant decrease in the CSF levels of pNfH/M (91% of baseline levels). The mean level of the CSF biomarkers were very stable between baseline and endpoint, with within-patients coefficients of variation (CVs) of 5.84-17.3%, while the variability was larger for the plasma biomarkers, with CVs of 14.1-42.3%. This stability suggests that these biomarkers may have the potential to detect and monitor biochemical changes induced by disease-modifying drugs.
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| 5. |
- Leoni, Valerio, et al.
(författare)
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Diagnostic Power of 24S-Hydroxycholesterol in Cerebrospinal Fluid: Candidate Marker of Brain Health
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 36:4, s. 739-747
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the diagnostic potential of 24S-hydroxycholesterol (24OHC) in cerebrospinal fluid. At a memory clinic, we investigated subjects with subjective cognitive impairment (SCI, n = 33), mild cognitive impairment (MCI) patients (n = 27), MCI patients with later progression into Alzheimer dementia at follow up (n = 10), and patients with AD (n = 24). We also had a control group of healthy volunteers who did not later develop cognitive problems (n = 13). The fraction of the population with pathological levels of 24OHC was 8% in controls, 34% in SCI, 37% in MCI, 80% in MCI with progression, and 42% in AD. The corresponding fractions for T-tau, P-tau, and A beta(42) were lower in the case of SCI and MCI but higher in the case of controls and AD. In case of MCI with progression, the fraction of pathological levels of 24OHC and A beta(42) were 80% and 63% respectively. We also studied a population of old healthy subjects age 75-99 years (n = 25). The fraction of individuals in this population with pathological levels of 24OHC was 0% whereas the fraction of individuals with pathological level of at least one of the other three biomarkers was 40%. The diagnostic power of 24OHC in cerebrospinal fluid seems to be similar to or lower than that of the established biomarkers T-tau, P-tau, and A beta(42) in the diagnosis of established AD. Our data suggest that 24OHC may be more sensitive than the classical biomarkers in an early phase of the neurodegenerative process and a better marker for "brain health" in old age.
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| 6. |
- Nielsen, Henrietta, et al.
(författare)
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Low levels of soluble NG2 in cerebrospinal fluid from patients with dementia with Lewy bodies
- 2014
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 40:2, s. 343-350
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Tidskriftsartikel (refereegranskat)abstract
- The proteoglycan NG2 plays a major role in proliferation, migration, and differentiation of pericytes and NG2 cells in the brain. We have previously reported decreased soluble NG2 (sNG2) levels in cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) and a relationship between sNG2 and AD biomarkers in these patients. To further investigate whether alterations in sNG2 is specific to AD pathology, we measured levels of sNG2 in CSF from a patient cohort consisting of non-demented controls (n = 51), patients with Parkinson's disease (PD) (n = 61), and patients with dementia with Lewy bodies (DLB) (n = 37), two synucleinopathies whereof the latter disorder frequently coincides with amyloid-β pathology similar to AD. We found decreased sNG2 concentrations in DLB patients, but not in PD patients, compared to controls. Levels of sNG2 in controls and PD patients correlated to T-tau, P-tau, α-synuclein, and neurosin. Only one correlation, between sNG2 and neurosin, was found in DLB patients. Analysis of a second cohort consisting of controls (n = 23) and DLB patients (n = 31) showed that the result was reproducible, as lower levels of sNG2 again were found in DLB patients compared to controls. We conclude that lower levels of sNG2 levels indicate a DLB-related impact on NG2 expressing cells foremost associated with neuropathology linked to accumulation of amyloid-β and not α-synuclein.
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| 7. |
- Nilsson, Erik D., et al.
(författare)
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Copeptin, a Marker of Vasopressin, Predicts Vascular Dementia but not Alzheimer's Disease
- 2016
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 52:3, s. 1047-1053
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Copeptin is a reliable surrogate marker for the neurohypophyseal hormone vasopressin. Elevated plasma level of copeptin has been associated with cardiovascular and metabolic disease risk.OBJECTIVE: To investigate the association between copeptin and risk of dementia.METHODS: In all, 18,240 individuals from Malmö, Sweden, were examined between 2002 and 2006 (mean age 69.3 years, 69.8% men). Incident cases of dementia until 31 December 2009 were identified by linkage with the Swedish National Patient Register. To validate the dementia diagnoses, medical records as well as laboratory and neuroimaging data were carefully reviewed. Baseline level of copeptin was measured in frozen plasma in: (1) all participants who were diagnosed with dementia during follow-up, (2) a random sample of 5100 individuals of the cohort.RESULTS: During a median follow-up of 4.2 years, there were 374 incident dementia cases (age range 60-83 years at baseline): 120 were classified as Alzheimer's disease (AD), 84 as vascular dementia (VaD), and 102 as mixed dementia. In logistic regressions adjusted for cardiovascular risk factors, baseline level of copeptin predicted incident VaD (Odds ratio (OR) 1.30 per 1 SD increase in log copeptin, 95% CI 1.03-1.64). Copeptin did not predict incidence of all-cause dementia (OR 1.05, 95% CI 0.94-1.18), AD (OR 0.97, 95% CI 0.79-1.18), or mixed dementia (OR 0.85, 95% CI 0.68-1.05).CONCLUSION: Elevated plasma level of copeptin is a risk marker for incident VaD, but not for incident AD. This suggests that the vasopressin hormonal system might be involved in the development of VaD.
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| 8. |
- Nägga, Katarina, 1962-, et al.
(författare)
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Increased levels of hyaluronic acid in cerebrospinal fluid in patients with vascular dementia
- 2014
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 42:4, s. 1435-1441
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Tidskriftsartikel (refereegranskat)abstract
- Hyaluronic acid (HA) has been shown to affect angiogenesis and the function of the blood-brain barrier, and a crucial role for HA in atherosclerosis has been described. We have recently demonstrated changes in the levels of HA in cerebrospinal fluid (CSF) in patients with Alzheimer's disease (AD) with documented vascular alterations. To further investigate if the level of HA in CSF can be used as a clinical diagnostic biomarker to identify vascular pathology in dementia, we analyzed the levels of HA in the CSF of patients with vascular dementia (VaD) (n = 46), AD (n = 45), and controls without dementia (n = 26). In line with our previous data, we found significantly increased levels of HA in CSF from patients with VaD compared with controls, whereas the levels of HA in patients with AD were found to be unaltered compared with controls and patients with VaD. We also detected increased levels of HA in individuals with vascular changes determined as significant white matter changes or previous infarction on cranial computed tomography or magnetic resonance imaging, compared with individuals without these findings. Furthermore, we found a significant positive correlation between the levels of HA and the CSF/serum albumin ratio, an indicator of blood-brain barrier integrity, in patients with VaD and AD, supporting the role of HA in vascular changes in the brain. Our results indicate a potential diagnostic value for the detection of vascular brain changes in dementia using CSF levels of HA, but emphasize the importance of further development of more sensitive HA assays.
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| 9. |
- Olsson, Bob, 1969, et al.
(författare)
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Cerebrospinal Fluid Levels of Heart Fatty Acid Binding Protein are Elevated Prodromally in Alzheimer's Disease and Vascular Dementia
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 34:3, s. 673-679
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Tidskriftsartikel (refereegranskat)abstract
- Heart fatty acid binding protein (HFABP) is expressed in the brain and is elevated in cerebrospinal fluid (CSF) from patients with several forms of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease with dementia, Lewy body dementia, vascular dementia (VaD), and Creutzfeldt-Jakob disease. However, whether HFABP in CSF is a stable biomarker or if it can help predict conversion from mild cognitive impairment (MCI) to AD or VaD has not been well studied. To address the role of HFABP in neurodegeneration, we analyzed CSF levels of HFABP in 96 AD patients and 65 controls and also in 170 patients with MCI with an average follow up time of 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six month interval in between. HFABP levels in CSF were very stable over the six month period (r = 0.93, p < 0.001). Furthermore, the CSF levels of HFABP were significantly elevated in AD compared with controls after adjustments for age and gender (p < 0.001). They were also elevated in the patients with MCI that subsequently converted to AD or VaD compared with those that remained stable (p < 0.001 and p < 0.05, respectively). However, ROC curve analysis showed that HFABP had lesser predictive value in determining conversion from MCI to AD and VaD than A beta(42), t-tau, and p-tau. In conclusion, HFABP seems to be a stable CSF biomarker that reflects neuronal cell death in several neurodegenerative disorders, including early stages of AD and VaD.
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| 10. |
- Olsson, Bob, 1969, et al.
(författare)
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Microglial markers are elevated in the prodromal phase of Alzheimer's disease and vascular dementia.
- 2013
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908 .- 1387-2877. ; 33:1, s. 45-53
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Tidskriftsartikel (refereegranskat)abstract
- Microglia manage immunosurveillance and mediate inflammation, both suggested to be important in Alzheimer's disease (AD). The aim of this study was to investigate if microglial markers could differentiate, firstly between AD and controls, and secondly between stable mild cognitive impairment (MCI) and those progressing to AD and vascular dementia (VaD). Furthermore, we investigated if these markers were sufficiently stable to be used in clinical trials. We quantified YKL-40 and sCD14 in cerebrospinal fluid (CSF) from 96 AD patients, 65 healthy controls, and 170 patients with MCI from baseline and over 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six-month interval in between. YKL-40, but not sCD14, was significantly elevated in AD compared with healthy controls (p = 0.003). Furthermore, YKL-40 and sCD14 were increased in MCI patients who converted to VaD (p = 0.029 and p = 0.008), but not to AD according to NINCDS-ADRDA. However, when stratified according to CSF levels of tau and Aβ42, YKL-40 was elevated in those with an AD-indicative profile compared with stable MCI with a normal profile (p = 0.037). In addition, YKL-40 and sCD14 were very stable in AD patients with good correlation between time-points (r = 0.94, p = 3.4 × 10-25; r = 0.77, p = 2.0 × 10-11) and the cortical damage marker T-tau. Thus, microglial markers are stable and may be used as safety markers for monitoring CNS inflammation and microglia activation in clinical trials. Moreover, YKL-40 differentiates between AD and controls and between stable MCI to AD and those that convert to AD and VaD.
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