Publications (138)582.42 Total impact
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Article: Diagnostic Power of 24S-Hydroxycholesterol in Cerebrospinal Fluid: Candidate Marker of Brain Health.
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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.Journal of Alzheimer's disease: JAD 05/2013; · 3.74 Impact Factor -
Article: NG2 cells, a new trail for Alzheimer's disease mechanisms?
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ABSTRACT: Background: Neuron Glial 2 (NG2) cells are glial cells known to serve as oligodendrocyte progenitors as well as modulators of the neuronal network. Altered NG2 cell morphology and up-regulation as well as increased shedding of the proteoglycan NG2 expressed on the cell surface have been described in rodent models of brain injury. Here we describe alterations in the human NG2 cell population in response to pathological changes characteristic of Alzheimer's disease (AD). Results: Immunohistological stainings of postmortem brain specimens from clinically diagnosed and postmortem verified AD patients and non-demented controls revealed reduced NG2 immunoreactivity as well as large numbers of NG2 positive astrocytes in individuals with high amyloid beta plaque load. Since fibrillar amyloid beta (Aβ)1-42 is the major component of AD-related senile plaques, we exposed human NG2 cells to oligomer-and fibril enriched preparations of Aβ1-42. We found that both oligomeric and fibrillar Aβ1-42 induced changes in NG2 cell morphology. Further, in vitro exposure to fibrillar Aβ1-42 decreased the NG2 concentrations in both cell lysates and supernatants. Interestingly, we also found significantly decreased levels of soluble NG2 in the cerebrospinal fluid (CSF) from clinically diagnosed AD patients compared to non-demented individuals. Additionally, the CSF NG2 levels were found to significantly correlate with the core AD biomarkers Aß1-42, T-tau and P-tau. Conclusion: Our results demonstrate major alterations in the NG2 cell population in relation to AD pathology which highlights the NG2 cell population as a new attractive research target in the search for cellular mechanisms associated with AD pathogenesis.Acta Neuropathologica Communications. 05/2013; 1:7. -
Article: Single-Domain Amnestic Mild Cognitive Impairment Identified by Cluster Analysis Predicts Alzheimer's Disease in the European Prospective DESCRIPA Study.
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ABSTRACT: Background/Aims: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI). Methods: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e.g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE ≥28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. Results: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (Aβ42, t-tau, APOE ε4, and medial temporal atrophy), compared to SCI or naMCI. Conclusion: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings.Dementia and Geriatric Cognitive Disorders 05/2013; 36(1-2):1-19. · 2.14 Impact Factor -
Article: Measurements of medial temporal lobe atrophy for prediction of AD in subjects with MCI
Neurobiology of Aging 03/2013; · 6.19 Impact Factor -
Article: Plasma tau levels in Alzheimer's disease.
Alzheimer's Research and Therapy 03/2013; 5(2):9. -
Article: Soluble Amyloid Precursor Protein α and β in CSF in Alzheimer's Disease.
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ABSTRACT: OBJECTIVE: 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.Brain research 03/2013; · 2.46 Impact Factor -
Article: Measurements of medial temporal lobe atrophy for prediction of Alzheimer's disease in subjects with mild cognitive impairment.
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ABSTRACT: Our aim was to compare the predictive accuracy of 4 different medial temporal lobe measurements for Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Manual hippocampal measurement, automated atlas-based hippocampal measurement, a visual rating scale (MTA-score), and lateral ventricle measurement were compared. Predictive accuracy for AD 2 years after baseline was assessed by receiver operating characteristics analyses with area under the curve as outcome. Annual cognitive decline was assessed by slope analyses up to 5 years after baseline. Correlations with biomarkers in cerebrospinal fluid (CSF) were investigated. Subjects with MCI were selected from the Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) multicenter study (n = 156) and the single-center VU medical center (n = 172). At follow-up, area under the curve was highest for automated atlas-based hippocampal measurement (0.71) and manual hippocampal measurement (0.71), and lower for MTA-score (0.65) and lateral ventricle (0.60). Slope analysis yielded similar results. Hippocampal measurements correlated with CSF total tau and phosphorylated tau, not with beta-amyloid 1-42. MTA-score and lateral ventricle volume correlated with CSF beta-amyloid 1-42. We can conclude that volumetric hippocampal measurements are the best predictors of AD conversion in subjects with MCI.Neurobiology of aging 03/2013; · 5.94 Impact Factor -
Article: A longitudinal study of risk factors for community-based home help services in Alzheimer's disease: the influence of cholinesterase inhibitor therapy
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ABSTRACT: BACKGROUND: To investigate the long-term effects of cholinesterase inhibitor (ChEI) therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS) by patients with Alzheimer's disease (AD). METHODS: This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL), and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used. RESULTS: During the study, 332 patients (38%) used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS. CONCLUSIONS: Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The "silent group" of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization.Clinical Interventions in Aging 03/2013; 8:329-339. · 2.08 Impact Factor -
Article: Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI.
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ABSTRACT: OBJECTIVE: To compare the predictive accuracy of β-amyloid (Aβ)1-42 and total tau in CSF, hippocampal volume (HCV), and APOE genotype for Alzheimer disease (AD)-type dementia in subjects with amnestic mild cognitive impairment (aMCI) and nonamnestic mild cognitive impairment (naMCI). METHODS: We selected 399 subjects with aMCI and 226 subjects with naMCI from a multicenter memory clinic-based cohort. We measured CSF Aβ1-42 and tau by ELISA (n = 231), HCV on MRI (n = 388), and APOE ε4 (n = 523). Follow-up was performed annually up to 5 years. Outcome measures were progression to AD-type dementia and cognitive decline. RESULTS: At least 1 follow-up was available for 538 subjects (86%). One hundred thirty-two subjects with aMCI (38%) and 39 subjects with naMCI (20%) progressed to AD-type dementia after an average follow-up of 2.5 years. CSF Aβ1-42, tau, Aβ1-42/tau ratio, HCV, and APOE ε4 predicted AD-type dementia in each MCI subgroup with the same overall diagnostic accuracy. However, CSF Aβ1-42 concentration was higher and hippocampal atrophy less severe in subjects with naMCI compared with aMCI. This reduced the sensitivity but increased the specificity of these markers for AD-type dementia in subjects with naMCI. CONCLUSIONS: AD biomarkers are useful to predict AD-type dementia in subjects with aMCI and naMCI. However, biomarkers might not be as sensitive for early diagnosis of AD in naMCI compared with aMCI. This may have implications for clinical implementation of the National Institute on Aging and Alzheimer's Association criteria.Neurology 02/2013; · 8.31 Impact Factor -
Dataset: Amyloid beta Oligomers in Cerebrospinal 2012
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Article: The Association Between APOE ε4 and Alzheimer-type Dementia among Memory Clinic Patients is Confined to those with a Higher Education. The DESCRIPA Study.
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ABSTRACT: We assessed the interaction between the APOE ε4 allele and education level in the etiology of Alzheimer's disease (AD) among memory clinic patients from the multicenter DESCRIPA study. Subjects (n = 544) were followed for 1 to 5 years. We used Cox's stratified survival modeling, adjusted for age, gender, and center. APOE ε4 predicted the onset of AD-type dementia in middle (HR 3.45 95% CI 1.79-6.65, n = 222) and high (HR 3.67 95% CI 1.36-9.89, n = 139) but not in low educated subjects (HR 0.81, 95% CI 0.38-1.72, n = 183). This suggests that mechanisms in developing Alzheimer-type dementia may differ between educational groups that raises questions related to Alzheimer-type dementia prevention.Journal of Alzheimer's disease: JAD 02/2013; · 3.74 Impact Factor -
Article: Functional Mannose-Binding Lectin Haplotype Variants are Associated with Alzheimer's Disease.
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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.Journal of Alzheimer's disease: JAD 01/2013; · 3.74 Impact Factor -
Article: Complement Gene Single Nucleotide Polymorphisms and Biomarker Endophenotypes of Alzheimer's Disease.
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ABSTRACT: The complement system has been implicated in both physiological synapse elimination and Alzheimer's disease (AD). Here, we investigated associations between four single nucleotide polymorphisms (SNPs) in complement genes and cerebrospinal fluid (CSF) biomarkers for AD in 452 neurochemically or neuropathologically verified AD cases and 678 cognitively normal controls. None of the SNPs associated with risk of AD but there were potential associations of rs9332739 in the C2 gene and rs4151667 in the complement factor B gene with CSF tau levels (p = 0.023) and Mini-Mental State Examination scores (p = 0.012), both of which may be considered markers of disease intensity/severity.Journal of Alzheimer's disease: JAD 01/2013; · 3.74 Impact Factor -
Article: Low CSF Levels of Both α-Synuclein and the α-Synuclein Cleaving Enzyme Neurosin in Patients with Synucleinopathy.
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ABSTRACT: Neurosin is a protease that in vitro degrades α-synuclein, the main constituent of Lewy bodies found in brains of patients with synucleinopathy including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Several studies have reported reduced cerebrospinal fluid (CSF) levels of α-synuclein in synucleinopathy patients and recent data also proposes a significant role of α-synuclein in the pathophysiology of Alzheimer's disease (AD). To investigate potential links between neurosin and its substrate α-synuclein in vivo we used a commercially available sandwich ELISA and an in-house developed direct ELISA to quantify CSF levels of α-synuclein and neurosin in patients diagnosed with DLB, PD and PD dementia (PDD) versus AD patients and non-demented controls. We found that patients with synucleinopathy displayed lower CSF levels of neurosin and α-synuclein compared to controls and AD patients. In contrast, AD patients demonstrated significantly increased CSF α-synuclein but similar neurosin levels compared to non-demented controls. Further, CSF neurosin and α-synuclein concentrations were positively associated in controls, PD and PDD patients and both proteins were highly correlated to CSF levels of phosphorylated tau in all investigated groups. We observed no effect of gender or presence of the apolipoprotein Eε4 allele on neither neurosin or α-synuclein CSF levels. In concordance with the current literature our study demonstrates decreased CSF levels of α-synuclein in synucleinopathy patients versus AD patients and controls. Importantly, decreased α-synuclein levels in patients with synucleinopathy appear linked to low levels of the α-synuclein cleaving enzyme neurosin. In contrast, elevated levels of α-synuclein in AD patients were not related to any altered CSF neurosin levels. Thus, altered CSF levels of α-synuclein and neurosin in patients with synucleinopathy versus AD may not only mirror disease-specific neuropathological mechanisms but may also serve as fit candidates for future biomarker studies aiming at identifying specific markers of synucleinopathy.PLoS ONE 01/2013; 8(1):e53250. · 4.09 Impact Factor -
Article: Cerebrospinal Fluid Levels of Heart Fatty Acid Binding Protein are Elevated Prodromally in Alzheimer's Disease and Vascular Dementia.
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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 Aβ42, 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.Journal of Alzheimer's disease: JAD 12/2012; · 3.74 Impact Factor -
Article: Functional response to cholinesterase inhibitor therapy in a naturalistic Alzheimer's disease cohort.
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ABSTRACT: BACKGROUND: Activities of daily living (ADL) are an essential part of the diagnostic criteria for Alzheimer's disease (AD). A decline in ADL affects independent living and has a strong negative impact on caregiver burden. Functional response to cholinesterase inhibitor (ChEI) treatment and factors that might influence this response in naturalistic AD patients need investigating. The aim of this study was to identify the socio-demographic and clinical factors that affect the functional response after 6 months of ChEI therapy. METHODS: This prospective, non-randomised, multicentre study in a routine clinical setting included 784AD patients treated with donepezil, rivastigmine or galantamine. At baseline and after 6 months of treatment, patients were assessed using several rating scales, including the Instrumental Activities of Daily Living (IADL) scale, Physical Self-Maintenance Scale (PSMS) and Mini-Mental State Examination (MMSE). Demographic and clinical characteristics were investigated at baseline. The functional response and the relationships of potential predictors were analysed using general linear models. RESULTS: After 6 months of ChEI treatment, 49% and 74% of patients showed improvement/no change in IADL and in PSMS score, respectively. The improved/unchanged patients exhibited better cognitive status at baseline; regarding improved/unchanged PSMS, patients were younger and used fewer anti-depressants. A more positive functional response to ChEI was observed in younger individuals or among those having the interaction effect of better preserved cognition and lower ADL ability. Patients with fewer concomitant medications or those using NSAIDs/acetylsalicylic acid showed a better PSMS response. CONCLUSIONS: Critical characteristics that may influence the functional response to ChEI in AD were identified. Some predictors differed from those previously shown to affect cognitive response, e.g., lower cognitive ability and older age predicted better cognitive but worse functional response.BMC Neurology 11/2012; 12(1):134. · 2.17 Impact Factor -
Article: A Selected Reaction Monitoring (SRM)-Based Method for Absolute Quantification of Aβ38, Aβ40, and Aβ42 in Cerebrospinal Fluid of Alzheimer's Disease Patients and Healthy Controls.
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ABSTRACT: Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are increasingly used in research centers, clinical trials, and clinical settings. However, their broad-scale use is hampered by lack of standardization across analytical platforms and by interference from binding of amyloid-β (Aβ) to matrix proteins as well as self-aggregation. Here, we report on a matrix effect-resistant method for the measurement of the AD-associated 42 amino acid species of Aβ (Aβ42), together with Aβ40 and Aβ38 in human CSF based on mass spectrometric quantification using selected reaction monitoring (SRM). Samples were prepared by solid-phase extraction and quantification was performed using stable-isotope labeled Aβ peptides as internal standards. The diagnostic performance of the method was evaluated on two independent clinical materials with research volunteers who were cognitively normal and AD patients with mild to moderate dementia. Analytical characteristics of the method include a lower limit of quantification of 62.5 pg/mL for Aβ42 and coefficients of variations below 10%. In a pilot study on AD patients and controls, we verified disease-association with decreased levels of Aβ42 similar to that obtained by ELISA and even better separation was obtained using the Aβ42/Aβ40 ratio. The developed assay is sensitive and is not influenced by matrix effects, enabling absolute quantification of Aβ42, Aβ40, and Aβ38 in CSF, while it retains the ability to distinguish AD patients from controls. We suggest this SRM-based method for Aβ peptide quantification in human CSF valuable for clinical research and trials.Journal of Alzheimer's disease: JAD 10/2012; · 3.74 Impact Factor -
Article: Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters.
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ABSTRACT: Chemokines constitute a class of small inflammatory proteins that control the chemotaxis of leukocytes. They are also present in the central nervous system (CNS) and contribute to diverse physiological functions, such as the regulation of cell migration, axonal growth and neuronal survival. It is to date not known whether chemokines in the CNS are affected in psychiatric disorders. In this study, chemokine levels were measured in the cerebrospinal fluid (CSF) of 137 psychiatric patients in conjunction to a suicide attempt, and 43 healthy controls. A subgroup of patients (n=42) was followed up with blood samples 12 years after the initial CSF collection, when they did not show suicidal behavior. The follow-up chemokine levels were compared to those of psychiatric patients (n=17) who had never attempted suicide. Ultra-sensitive chemokine multiplex immunoassay was used to quantify eotaxin-1 (CCL11), interferon gamma-induced protein-10 (IP-10, CXCL10), macrophage inflammatory protein-1β (MIP-1β, CCL4), monocyte chemotactic protein-1 (MCP-1, CCL2), MCP-4 (CCL13) and thymus and activation regulated chemokine (TARC, CCL17). Patients were diagnosed using DSM-III-R/DSM-IV, and assessed using the Comprehensive Psychopathological Rating Scale (CPRS), including subscales, and the Suicidal Intent Scale (SIS). CSF eotaxin-1, MIP-1β, MCP-1, MCP-4 and TARC were significantly lower in suicide attempters than in healthy controls. Low chemokine levels were specifically associated with psychotic symptoms and pain. In the samples collected at follow-up, TARC was significantly lower in suicide attempters compared to psychiatric patients who had never attempted suicide. We also found a positive correlation between blood TARC and brain-derived neurotrophic factor (BDNF) levels. Our study thus provides evidence of reduced chemokine levels in suicide attempters, both in the acute suicidal setting, and at long-term, compared to non-attempters. These results warrant future studies on the detailed neurobiological functions of chemokines in psychiatric patients.Psychoneuroendocrinology 10/2012; · 5.81 Impact Factor -
Article: Injury markers predict time to dementia in subjects with MCI and amyloid pathology.
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ABSTRACT: OBJECTIVES: Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology. METHODS: We pooled subjects from the VU University Medical Center Alzheimer Center and the Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of β-amyloid(1-42) (Aβ(1-42)) in the CSF, and at least one diagnostic follow-up visit. We assessed the effect of APOE genotype, CSF total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) and hippocampal volume on time to AD-type dementia using Cox proportional hazards models and on decline on the Mini-Mental State Examination (MMSE) using linear mixed models. RESULTS: We included 110 subjects with MCI with abnormal CSF Aβ(1-42) and a mean MMSE score of 26.3 ± 2.8. During a mean follow-up of 2.2 ± 1.0 (range 0.4-5.0) years, 63 subjects (57%) progressed to AD-type dementia. Abnormal CSF t-tau (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1-4.6, p = 0.03) and CSF p-tau (HR 3.5, 95% CI 1.3-9.2, p = 0.01) concentration and hippocampal atrophy (HR 2.5, 95% CI 1.1-5.6, p = 0.02) predicted time to dementia. For subjects with both abnormal t-tau concentration and hippocampal atrophy, HR was 7.3 (95% CI 1.0-55.9, p = 0.06). Furthermore, abnormal CSF t-tau and p-tau concentrations and hippocampal atrophy predicted decline in MMSE score. CONCLUSIONS: In subjects with MCI and evidence of amyloid pathology, the injury markers CSF t-tau and p-tau and hippocampal atrophy can predict further cognitive decline.Neurology 09/2012; 79(17):1809-1816. · 8.31 Impact Factor -
Article: Longitudinal Stability Evaluation of Biomarkers and Their Correlation in Cerebrospinal Fluid and Plasma from Patients with Alzheimer's Disease.
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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.Journal of Alzheimer's disease: JAD 08/2012; · 3.74 Impact Factor
Top co-authors
Top Journals
Institutions
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2003–2013
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University of Gothenburg
- • Department of Psychiatry and Neurochemistry
- • Department of Physiology
- • Department of Clinical Neuroscience and Rehabilitation
Göteborg, Vaestra Goetaland, Sweden
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2012
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Martin-Luther-Universität Halle-Wittenberg
- Poliklinik für Herz- und Thoraxchirurgie
Halle, Saxony-Anhalt, Germany
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2009–2012
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Maastricht University
- • MHeNS School for Mental Health and Neuroscience
- • Psychiatrie en Neuropsychologie
Maastricht, Provincie Limburg, Netherlands -
King's College London
- Wolfson Centre for Age-Related Diseases
London, ENG, United Kingdom -
Malmö University
Malmö, Skane, Sweden
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2008–2012
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Skåne University Hospital
Malmö, Skane, Sweden
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1970–2012
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Lund University
- • Department of Clinical Sciences
- • Department of Clinical Physiology
Lund, Skane, Sweden
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2011
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San Francisco VA Medical Center
San Francisco, CA, USA
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2010–2011
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Ludwig-Maximilian-University of Munich
- Department of Psychiatry
München, Bavaria, Germany
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2009–2011
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Stavanger University Hospital
Stavanger, Rogaland Fylke, Norway
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2003–2011
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Sahlgrenska University Hospital
Göteborg, Vaestra Goetaland, Sweden
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2005
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Copenhagen University Hospital Hvidovre
Hvidovre, Capital Region, Denmark
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