Malin Degerman-Gunnarsson

Uppsala University, Uppsala, Uppsala, Sweden

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Publications (15)78.34 Total impact

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    ABSTRACT: N-terminally truncated Aβ peptides starting with pyroglutamate (AβpE3) represent a major fraction of all Aβ peptides in the brain of Alzheimer disease (AD) patients. AβpE3 has a higher aggregation propensity and stability and shows increased toxicity compared with full-length Aβ. In the present work, we generated a novel monoclonal antibody (9D5) that selectively recognizes oligomeric assemblies of AβpE3 and studied the potential involvement of oligomeric AβpE3 in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost nondetectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal and blood vessel staining was observed. Using a novel sandwich ELISA significantly decreased levels of oligomers in plasma samples from patients with AD compared with healthy controls were identified. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall Aβ plaque load and AβpE3 levels, and normalized behavioral deficits. These data indicate that 9D5 is a therapeutically and diagnostically effective monoclonal antibody targeting low molecular weight AβpE3 oligomers.
    Journal of Biological Chemistry 12/2010; 285(53):41517-41524. · 4.65 Impact Factor
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    ABSTRACT: N-terminally truncated Aβ peptides starting with pyroglutamate (AβpE3) represent a major fraction of all Aβ peptides in the brain of Alzheimer disease (AD) patients. AβpE3 has a higher aggregation propensity and stability and shows increased toxicity compared with full-length Aβ. In the present work, we generated a novel monoclonal antibody (9D5) that selectively recognizes oligomeric assemblies of AβpE3 and studied the potential involvement of oligomeric AβpE3 in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost nondetectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal and blood vessel staining was observed. Using a novel sandwich ELISA significantly decreased levels of oligomers in plasma samples from patients with AD compared with healthy controls were identified. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall Aβ plaque load and AβpE3 levels, and normalized behavioral deficits. These data indicate that 9D5 is a therapeutically and diagnostically effective monoclonal antibody targeting low molecular weight AβpE3 oligomers.
    Journal of Biological Chemistry 10/2010; 285(53):41517-24. · 4.65 Impact Factor
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    ABSTRACT: Cathepsin B is suggested to be involved in amyloid-β (Aβ) processing and Alzheimer's disease (AD). Studies of cathepsin B levels in plasma and cerebrospinal fluid (CSF) have not been previously performed. We examined cathepsin B levels in plasma and CSF samples in persons with AD, mild cognitive impairment (MCI), and healthy controls in order to test the hypothesis that cathepsin B levels can discriminate persons with AD or MCI from healthy controls. Cathepsin B, Cystatin C, Aβ1-40 and Aβ1-42, total tau, phosphorylated tau, and albumin levels in plasma and CSF were analyzed by ELISA (Cathepsin B) turbidimetry (cystatin C), xMAP Luminex technology (Aβ1-40 and Aβ1-42 and tau), and Cobas C501 analyzer (albumin) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Plasma cathepsin B levels were higher in persons with AD compared to healthy controls, both in unadjusted models and in multivariable models adjusting for age, gender, APOE genotype, cystatin C, and albumin levels: Odds ratio (OR) for AD per 1 SD of plasma cathepsin B; 2.04, 95% confidence interval (CI); 1.01-4.14, p= 0.05. There was no difference between diagnostic groups in cathepsin B levels in CSF: OR for AD per 1 SD of CSF cathepsin B; 0.93, 95% CI; 0.37-2.30, p= 0.87. Plasma cathepsin B levels were higher in persons with AD compared to healthy controls whereas there was no difference between diagnostic groups in cathepsin B levels in CSF. Further investigation of cathepsin B as a predictor of AD is warranted.
    Journal of Alzheimer's disease: JAD 10/2010; 22(4):1223-30. · 4.17 Impact Factor
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    ABSTRACT: Cystatin C is suggested to be involved in neurodegeneration and the development of Alzheimer's disease (AD) by binding to soluble amyloid-beta (Abeta) peptides. Studies of cystatin C levels in cerebrospinal fluid (CSF) in relation to risk of AD are conflicting and relations between cystatin C, Abeta42, and tau levels in CSF in AD, mild cognitive impairment (MCI), and healthy controls are unknown. The objective of this study was to investigate cystatin C, Abeta42, and tau levels in CSF in AD, MCI, and controls. As a secondary aim, the relationships between cystatin C, Abeta42, and tau levels across disease groups were investigated. Cystatin C, Abeta42, total tau, and phosphorylated tau levels in CSF were analyzed by turbidimetry (cystatin C) and xMAP Luminex technology (Abeta and tau) in persons with AD (n=101), MCI (n=84), and healthy control subjects (n=28). Mean cystatin C levels were similar in cases of AD (5.6 micromol/L +/- 1.7), MCI (5.4 micromol/L +/- 1.48), and controls (5.6 micromol/L +/- 1.6). However, CSF cystatin C levels were strongly and positively correlated with total tau and phosphorylated tau levels (r=0.61-0.81, p< 0.0001) and Abeta42 (r=0.35-0.65, p< 0.001) independent of age, gender, and APOE genotype. Mean CSF cystatin C levels did not differ between patients with AD and MCI and healthy controls. Interestingly, cystatin C levels were positively correlated with both tau and Abeta42 levels in CSF independent of age, gender, and APOE genotype.
    Journal of Alzheimer's disease: JAD 01/2010; 21(2):471-8. · 4.17 Impact Factor
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    ABSTRACT: In the present work, we investigated the level of IgM autoantibodies directed against different Aβ epitopes as potential diagnostic biomarker for Alzheimer's disease (AD). Anti-Aβ autoantibody levels were measured in 75 plasma samples from patients with AD, individuals with mild cognitive impairment (MCI), and healthy age- and sex-matched controls (HC). To validate the presence of anti-Aβ IgMs, pooled plasma samples were subjected to gel-filtration analysis. The mean level of pGluAβ-IgM (N-terminal truncated starting at position three with pyroglutamate) was significantly decreased in AD patients as compared to HC. In the group of MCI patients there was a significant positive correlation between pGluAβ-IgM and cognitive decline analyzed by MMSE (rho = 0.58, d.f. = 13, p = 0.022). These observations indicate that the level of IgM autoantibodies against pGluAβ is a promising plasma biomarker for AD and correlates with the cognitive status of individuals at risk to develop AD.
    Neurobiology of aging 09/2009; 32(8):1379-87. · 5.94 Impact Factor
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    ABSTRACT: Accumulating evidence suggests that diabetes increases the risk of dementia, but few studies have addressed possible mechanisms underlying this relationship. The aim of our study was to investigate the longitudinal association of glucose metabolism, insulin secretion and insulin action with the development of Alzheimer's disease and vascular dementia. The Uppsala Longitudinal Study of Adult Men is an ongoing observational study in Sweden in which 1,125 men aged 71 years and free from dementia underwent an OGTT and a euglycaemic insulin clamp between 1990 and 1995. During a median follow-up of 12 years, 257 persons developed dementia or cognitive impairment, of whom 81 had Alzheimer's disease and 26 vascular dementia. Associations were analysed with the Cox proportional hazards method. Low early insulin response to oral glucose challenge, but not low insulin sensitivity, was associated with a higher risk of Alzheimer's disease (HR for 1 SD decrease 1.32; 95% CI 1.02, 1.69) after adjustment for diabetes, blood pressure, body mass index, cholesterol, smoking and educational level. Low insulin sensitivity was associated with a higher risk of vascular dementia (HR for 1 SD decrease 1.55; 95% CI 1.02, 2.35), but not after multiple adjustments. Diabetes increased the risk of any dementia and cognitive impairment by 63%. In this community-based study, low early insulin response was associated with increased risk of subsequent Alzheimer's disease, whereas low insulin sensitivity was not. Vascular dementia was not related to early insulin response. We suggest that glucometabolic disturbances are linked differentially to the pathogenesis of these two main dementia subtypes.
    Diabetologia 06/2009; 52(8):1504-10. · 6.49 Impact Factor
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    ABSTRACT: Oxidative stress in the brain is suggested to be involved in the pathophysiology of Alzheimer's disease (AD). In this study, serum alpha- and gamma-tocopherol, the two major systemic antioxidants, were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 616 and age 77, n = 761). In addition, urinary F2-isoprostane levels, as markers of systemic oxidative stress, were analyzed at the age of 77 in this cohort (n = 679). Cox regression analyses were used to examine associations between serum alpha-, gamma-tocopherol and urinary F2-isoprostane levels and AD, any type of dementia (all-cause dementia) and non-AD dementia. On follow-up (median, 12.3 years), 40 subjects developed AD and 86 subjects developed all-cause dementia. Serum alpha- and gamma-tocopherol or urinary F2-isoprostane levels were not associated with the future risk of AD or dementia. In conclusion, systemic serum alpha- and gamma-tocopherol and urinary F2-isoprostane levels are not associated with the future risk of AD or dementia and do not seem to be useful predictors of clinical AD or dementia.
    Journal of Alzheimer's disease: JAD 06/2009; 18(1):71-8. · 4.17 Impact Factor
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    ABSTRACT: Inflammation is suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Serum interleukin-6 (IL-6) and high sensitivity serum reactive protein C (hsCRP) as markers of systemic inflammation were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 1062 and age 77, n = 749). In addition, serum amyloid protein A (SAA) and urinary prostaglandin F2alpha (PGF2alpha) metabolite levels were analyzed at age 77 in this cohort. Two serial samples (at ages 70 and 77) were available from 704 individuals. Using Cox regression analyses, associations between serum IL-6, hsCRP, SAA and PGF2alpha metabolite levels and risk of AD, any type of dementia (all-cause dementia) and non-AD dementia were analyzed. On follow-up (median, 11.3 years) in the age 70 cohort, 81 subjects developed AD and 165 subjects developed all-cause dementia. Serum IL-6, hsCRP, SAA, or PGF2alpha levels were not associated with risk of AD. At age 70, high IL-6 levels were associated with an increased risk of non-AD dementia (Hazard ratio 2.21 for above vs. below/at median, 95%confidence interval 1.23-3.95, p-value = 0.008). A longitudinal change in CRP or IL-6 levels was not associated with AD ordementia. In conclusion, Serum IL-6, hsCRP, SAA, and PGF2alpha levels are not associated with the risk of AD. High serum IL-6 levels may be associated with increased risk of non-AD dementia.
    Journal of Alzheimer's disease: JAD 06/2009; 18(1):79-87. · 4.17 Impact Factor
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    ABSTRACT: It has previously been shown that immune complexes (IC) of a given biomarker with class M immunoglobulins (IgM) provide better performances compared to the unbound biomarker in a number of cancer entities. In the present work, we investigated IC of IgM-Abeta as a potential biomarker for Alzheimer's disease (AD). Abeta-IgM concentration has been measured in 75 plasma samples from patients with AD, individuals with mild cognitive impairment (MCI), and healthy age- and sex-matched controls (HC). To characterize the fractions associated with Abeta, pooled plasma samples were subjected to gel-filtration analysis. Size-separated fractions were analyzed for the presence of Abeta using a sandwich ELISA assay. A strong reactivity was observed in the high molecular weight IgM (>500 kDa) and 150 kDa (IgG) fractions indicating that blood Abeta is strongly associated with antibodies. Using an ELISA assay detecting Abeta-IgM complexes, we observed that high levels of Abeta-IgMs were detectable in HC and MCI patients; however, there was no significant difference to the AD group.
    Journal of Neural Transmission 05/2009; 116(7):913-20. · 3.05 Impact Factor
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    ABSTRACT: Genetic factors influencing common complex conditions have proven difficult to identify, and data from numerous investigations have provided incomplete conclusions as to the identity of these genes. Here we aimed to identify susceptibility genes for late-onset Alzheimer's disease (AD). The case-control analysis included samples from 86 AD patients and 404 cognitively healthy controls selected from the Uppsala Longitudinal Study of Adult Men (ULSAM). In the incidence analysis, all 1,088 genotyped ULSAM participants were included. DNA samples from ULSAM participants were analyzed for 2,578 single nucleotide polymorphisms (SNP) within 368 genes. The selection of genes tested for association to AD within this cohort was based on genes previously implicated in conditions with relevance to ULSAM, such as dementia, cardiovascular disease, diabetes and metabolic syndrome, osteoporosis, and cancer. Association analysis revealed 82 genes containing at least 1 significant SNP at p < 0.05 with association to AD. Only 20 genes remained significant after a permutation test to correct for multiple comparisons within individual genes. Using publicly available data from 2 genome-wide association (GWA) studies and linkage disequilibrium data from HapMap, we attempted to replicate the AD association identified in ULSAM. In addition to apolipoprotein E, we were able to replicate 5 other genes in both GWA studies at p < 0.05.
    Dementia and Geriatric Cognitive Disorders 01/2009; 27(1):59-68. · 2.79 Impact Factor
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    ABSTRACT: Multiple lines of research suggest that increased cystatin C activity in the brain protects against the development of Alzheimer disease (AD). Serum cystatin C levels were analyzed at two examinations of the Uppsala Longitudinal Study of Adult Men, a longitudinal, community-based study of elderly men (age 70 years, n = 1,153 and age 77 years, n = 761, a subset of the age 70 examination). Cox regressions were used to examine associations between serum cystatin C and incident AD. AD cases were identified by cognitive screening and comprehensive medical chart review in all subjects. On follow-up (median 11.3 years), 82 subjects developed AD. At age 70 years, lower cystatin C was associated with higher risk of AD independently of age, APOE4 genotype, glomerular filtration rate, diabetes, hypertension, stroke, cholesterol, body mass index, smoking, education level, and plasma amyloid-beta protein 40 and 42 levels (hazard ratio [HR] for lowest [<1.12 micromol/L] vs highest [>1.30 micromol/L] tertile = 2.67, 95% CI 1.22-5.83, p < 0.02). The results were similar at age 77 years (43 participants developed AD during follow-up). Furthermore, a 0.1-mumol/L decrease of cystatin C between ages 70 and 77 years was associated with a 29% higher risk of incident AD (HR 1.29, 95% CI 1.03-1.63, p < 0.03). Low levels of serum cystatin C precede clinically manifest Alzheimer disease (AD) in elderly men free of dementia at baseline and may be a marker of future risk of AD. These findings strengthen the evidence for a role for cystatin C in the development of clinical AD.
    Neurology 10/2008; 71(14):1072-9. · 8.30 Impact Factor
  • Alzheimer's and Dementia 07/2008; 4(4). · 17.47 Impact Factor
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    ABSTRACT: Subjects with diabetes are reported to have an increased risk of dementia and cognitive impairment. However, the underlying causes remain unknown. We investigated the longitudinal associations between midlife insulin secretion, glucose metabolism, and the subsequent development of Alzheimer disease (AD) and dementia. The population-based Uppsala Longitudinal Study of Adult Men started 1970 when the 2,322 participants were 50 years old. Investigation at baseline included determinations of acute insulin response and glucose tolerance using the IV glucose tolerance test and Homeostasis Model Assessment insulin resistance index. During a median follow up of 32 years, 102 participants were diagnosed with AD, 57 with vascular dementia, and 394 with any dementia or cognitive impairment. Associations were analyzed using Cox proportional hazard models. A low insulin response at baseline was associated with a higher cumulative risk of AD (hazard ratio for 1 SD decrease, 1.31; 95% CI, 1.10-1.56) also after adjustment for age, systolic blood pressure, body mass index, serum cholesterol, smoking, education level, and insulin resistance. This association was stronger in subjects without the APOE epsilon4 allele. Impaired glucose tolerance increased the risk of vascular dementia (hazard ratio for 1 SD decrease, 1.45; 95% CI, 1.05-2.00) but not AD. Impaired insulin secretion, glucose intolerance, and estimates of insulin resistance were all associated with higher risk of any dementia and cognitive impairment. In this longitudinal study, impaired acute insulin response at midlife was associated with an increased risk of Alzheimer disease (AD) up to 35 years later suggesting a causal link between insulin metabolism and the pathogenesis of AD.
    Neurology 05/2008; 71(14):1065-71. · 8.30 Impact Factor
  • Article: P1-234
    Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2006; 2(3).
  • Article: P1-230
    Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2006; 2(3).

Publication Stats

244 Citations
78.34 Total Impact Points

Institutions

  • 2010
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 2009
    • Uppsala University Hospital
      Uppsala, Uppsala, Sweden
    • Universitätsmedizin Göttingen
      Göttingen, Lower Saxony, Germany