Authors: Wennström, Malin | Londos, Elisabet | Minthon, Lennart | Nielsen, Henrietta M
Article Type: Research Article
Abstract: Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in …orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-Tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation. Show more
Keywords: Alpha-synuclein, Alzheimer's disease, biomarker, dementia with Lewy bodies, orexin
DOI: 10.3233/JAD-2012-111655
Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 125-132, 2012
Authors: Borland, Emma | Nägga, Katarina | Nilsson, Peter M. | Minthon, Lennart | Nilsson, Erik D. | Palmqvist, Sebastian
Article Type: Research Article
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. Show more
Keywords: Cognitively healthy elderly, excluding cognitively impaired, Montreal Cognitive Assessment, normative, population-based, representative, Swedish
DOI: 10.3233/JAD-170203
Citation: Journal of Alzheimer's Disease, vol. 59, no. 3, pp. 893-901, 2017
Authors: Sjölander, Annica | Minthon, Lennart | Nuytinck, Lieve | Vanmechelen, Eugeen | Blennow, Kaj | Nilsson, Staffan
Article Type: Research Article
Abstract: Mannan-Binding lectin (MBL) is a serum lectin and an important constituent of the innate immune system. Processes linked to the innate immune response have previously been implicated in Alzheimer's disease (AD). MBL is associated with blood vessels in the brain and AD patients demonstrate lower MBL levels in the cerebrospinal fluid compared to controls. We investigated six single nucleotide polymorphisms, linked to MBL deficiency, in the corresponding MBL2 gene in AD patients and controls. Two MBL2 haplotypes, LXP and LYQ, were significantly associated with AD risk (OR = 1.6, p = 0.01 and OR = 1.5, p = 0.02, respectively). …The present study is the first investigating MBL2 genotypes and haplotypes in relation to AD. Our findings support that the MBL2 gene impact the disease risk. Show more
Keywords: Alzheimer's disease, cerebrospinal fluid, gene, immune response, Mannan-Binding lectin, single nucleotide polymorphism
DOI: 10.3233/JAD-122044
Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 121-127, 2013
Authors: Hertze, Joakim | Minthon, Lennart | Zetterberg, Henrik | Vanmechelen, Eugeen | Blennow, Kaj | Hansson, Oskar
Article Type: Research Article
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, Aβ42 , Aβ40 , Aβ38 , sAβPPα, and sAβPPβ 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 3.0–7.2). 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 Aβ42 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 Aβ42 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. Show more
Keywords: Alzheimer's disease, amyloid-β, biomarkers, cerebrospinal fluid, early diagnosis, mild cognitive impairment
DOI: 10.3233/JAD-2010-100207
Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1119-1128, 2010
Authors: Nägga, Katarina | Hansson, Oskar | van Westen, Danielle | Minthon, Lennart | Wennström, Malin
Article Type: Research Article
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. Show more
Keywords: Biomarker, cerebrospinal fluid, glycocalyx, hyaluronic acid, vascular dementia
DOI: 10.3233/JAD-141200
Citation: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1435-1441, 2014
Authors: Nilsson, Erik D. | Melander, Olle | Elmståhl, Sölve | Lethagen, Eva | Minthon, Lennart | Pihlsgård, Mats | Nägga, Katarina
Article Type: Research Article
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. Show more
Keywords: Alzheimer’s disease, copeptin, dementia, vascular dementia
DOI: 10.3233/JAD-151118
Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1047-1053, 2016
Authors: Nielsen, Henrietta M. | Hall, Sara | Surova, Yulia | Nägga, Katarina | Nilsson, Christer | Londos, Elisabet | Minthon, Lennart | Hansson, Oskar | Wennström, Malin
Article Type: Research Article
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. Show more
Keywords: α-synuclein, Alzheimer's disease markers, amyloid-β, biomarker, cerebrospinal fluid, dementia with Lewy bodies, NG2, neurosin, Parkinson's disease, synucleinopathies
DOI: 10.3233/JAD-132246
Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 343-350, 2014
Authors: Leoni, Valerio | Solomon, Alina | Lövgren-Sandblom, Anita | Minthon, Lennart | Blennow, Kaj | Hansson, Oskar | Wahlund, Lars-Olof | Kivipelto, Miia | Björkhem, Ingemar
Article Type: Research Article
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 Aβ42 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 Aβ42 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 Aβ42 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. Show more
Keywords: Aging, ApoE, biomarker, cholesterol, cognitive decline, mass spectrometry, neurodegenerative diseases, oxysterols
DOI: 10.3233/JAD-130035
Citation: Journal of Alzheimer's Disease, vol. 36, no. 4, pp. 739-747, 2013
Authors: Kettunen, Petronella | Larsson, Susanna | Holmgren, Sandra | Olsson, Sandra | Minthon, Lennart | Zetterberg, Henrik | Blennow, Kaj | Nilsson, Staffan | Sjölander, Annica
Article Type: Research Article
Abstract: Background: Glycogen synthase kinase 3 beta (GSK3B) is the major kinase phosphorylating tau protein. Hyperphosphorylated tau is one of the hallmarks of Alzheimer's disease (AD). Despite extensive research, the role of GSK3B in AD pathogenesis is not fully understood. Objective: To evaluate possible associations between gene variants of GSK3B and risk of AD. Methods: Twelve GSK3B tag single-nucleotide polymorphisms (SNPs), together with the previously AD-associated rs334558, were analyzed in 583 AD patients and 673 controls. Analyses on single marker and haplotype levels were done to relate to risk of AD, Mini-Mental State Examination (MMSE) scores, and cerebrospinal fluid (CSF) biomarker …levels of total tau (T-tau), hyperphosphorylated tau (P-tau181 ), and amyloid-β (Aβ42 ). Results: After correction for multiple testing, we found a number of associations of gene variants with CSF biomarker levels and cognitive function in the AD patients. Firstly, rs334558 was associated with elevated T-tau levels (pc = 0.04). Next, rs1154597 showed association with reduced Aβ42 levels (pc = 0.007). Lastly, rs3107669 was associated with lower MMSE scores (pc = 0.03). In addition, one more SNP was nominally significantly associated with reduced Aβ42 levels and another was associated with reduced MMSE. Conclusion: We found GSK3B gene variants associated with cognitive function and CSF biomarkers T-tau and Aβ42 . To our knowledge, this is the first time GSK3B has been associated with cognitive function or CSF biomarkers reflecting neuronal degeneration (T-tau) and brain amyloid load (Aβ42 ). The regulation of GSK3B needs to be investigated further, to fully understand how these GSK3B gene variants are involved in AD pathogenesis. Show more
Keywords: Alzheimer's disease, amyloid-β peptide, association, biomarker, cerebrospinal fluid, gene, glycogen synthase kinase 3 beta, Mini-Mental State Examination, single nucleotide polymorphism, tau
DOI: 10.3233/JAD-142025
Citation: Journal of Alzheimer's Disease, vol. 44, no. 4, pp. 1313-1322, 2015
Authors: Höglund, Kina | Bogstedt, Anna | Fabre, Susanne | Aziz, Ali | Annas, Peter | Basun, Hans | Minthon, Lennart | Lannfelt, Lars | Blennow, Kaj | Andreasen, Niels
Article Type: Research Article
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 α- and β-cleaved soluble amyloid-β protein precursor (sAβPPα and sAβPPβ), Aβ1-40 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 Aβ1-40 , Aβ1-42 …, and sAβPPβ 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 sAβPPβ (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. Show more
Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, longitudinal, plasma, stability
DOI: 10.3233/JAD-2012-120976
Citation: Journal of Alzheimer's Disease, vol. 32, no. 4, pp. 939-947, 2012