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  • 1. Andersson, Christin
    et al.
    Blennow, Kaj
    Almkvist, Ove
    Andreasen, Niels
    Engfeldt, Peter
    Johansson, Sven-Erik
    Lindau, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eriksdotter-Jonhagen, Maria
    Increasing CSF phospho-tau levels during cognitive decline and progression to dementia2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 10, p. 1466-1473Article in journal (Refereed)
    Abstract [en]

    Background: Little is known about longitudinal changes of cerebrospinal fluid (CSF) biomarders during cognitive dicline in neurodegenerative disease progression. Objective: To investigate longitudinal changes in CSF biomarkers - total-tau (T-tau), phospho-tau (P-tau) and beta-amyloid (A beta 42) - during cognitive decline. Methods: Forty, memory clinic patients (47.5% females), aged 61.3 +/- 7.6 (S.D.) years, non-demented at baseline, underwent lumbar puncture and neuropsychological testin, Lit two occasions. Baseline mean MMSE-score was 28.3 +/- 1.8. Patient,-, were divided into three groups, based on baseline memory functioning severely impaired (SIM), moderately impaired (MIM) and no impairment (NIM). Results: There was a significant increase in P-tau in the SIM-group during follow-up. while P-tau in MIM and NIM did not change. Eighty-three percent of the SIM-patients converted to dementia (80% AD), while most MIM- and NIM-patients remained non-demented. T-tau- and A beta 42-levels did not change in any of the memory groups during follow-up. Conclusion: Increasing P-tau levels during cognitive decline and conversion to dementia Suggest that P-tau may be useful as a longitudinal marker of the neurodegenerative process.

  • 2.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nordenskjöld, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Burgos, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Le Grevès, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Association between physical activity and brain health in older adults2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 1, p. 83-90Article in journal (Refereed)
    Abstract [en]

    In the present cross-sectional study, we examined physical activity (PA) and its possible association with cognitive skills and brain structure in 331 cognitively healthy elderly. Based on the number of self-reported light and hard activities for at least 30 minutes per week, participants were assigned to 4 groups representing different levels of PA. The cognitive skills were assessed by the Mini Mental State Examination score, a verbal fluency task, and the Trail-making test as a measure of visuospatial orientation ability. Participants also underwent a magnetic resonance imaging of the brain. Multiple regression analysis revealed that greater PA was associated with a shorter time to complete the Trail-making test, and higher levels of verbal fluency. Further, the level of self-reported PA was positively correlated with brain volume, white matter, as well as a parietal lobe gray matter volume, situated bilaterally at the precuneus. These present cross-sectional results indicate that PA is a lifestyle factor that is linked to brain structure and function in late life.

  • 3.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rönnemaa, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schultes, Bernd
    Interdisciplinary Obesity Center, Kantonsspital St. Gallen.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 6, p. 1159.e1-1159.e5Article in journal (Refereed)
    Abstract [en]

    Humans carrying the prevalent rs9939609 A allele of the fat mass and obesity-associated (FTO) gene are more susceptible to developing obesity than noncarries. Recently, polymorphisms in the FTO gene of elderly subjects have also been linked to a reduced volume in the frontal lobe as well as increased risk for incident Alzheimer disease. However, so far there is no evidence directly linking the FTO gene to functional cognitive processes. Here we examined whether the FTO rs9939609 A allele is associated with verbal fluency performance in 355 elderly men at the age of 82 years who have no clinically apparent cognitive impairment. Retrieval of verbal memory is a good surrogate measure reflecting frontal lobe functioning. Here we found that obese and overweight but not normal weight FTO A allele carriers showed a lower performance on verbal fluency than non-carriers (homozygous for rs9939609 T allele). This effect was not observed for a measure of general cognitive performance (i.e., Mini-Mental State Examination score), thereby indicating that the FTO gene primarily affects frontal lobe-dependent cognitive processes in elderly men.

  • 4. Beyer, Anja-Silke
    et al.
    von Einem, Bjoern
    Schwanzar, Daniel
    Keller, Ilona E
    Hellrung, Anke
    Thal, Dietmar R
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Makarova, Alexandra
    Deng, Meihua
    Chhabra, Ekta S
    Pröpper, Christian
    Böckers, Tobias M
    Hyman, Bradley T
    von Arnim, Christine A F
    Engulfment adapter PTB domain containing 1 interacts with and affects processing of the amyloid-beta precursor protein2010In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 4, p. 732-743Article in journal (Refereed)
    Abstract [en]

    Previous studies identified engulfment adapter phosphotyrosine binding (PTB) domain containing 1 (GULP1) as an NPXY-motif interactor of low-density lipoprotein receptor-related protein 1 (LRP1) and suggested a potential relevance in Alzheimer's disease (AD). Since AD associated proteins amyloid-beta A4 precursor protein (APP) and LRP1 were shown to interact with the PTB domain of Fe65 and several other adapters via their intracellular NPXY-motifs, we examined a possible interaction of GULP1 PTB domain with the YENPTY-motif of APP. Here we demonstrate that GULP1 is present in human hippocampal and neocortical neurons. Confocal live cell imaging revealed that coexpressed and endogenous GULP1 colocalizes with APP in the Golgi and endoplasmic reticulum. Analysis of the interacting domains by co-immunoprecipitation of point and deletion mutants revealed that the interaction depends on the PTB domain of GULP1 and the YENPTY-motif of APP. Coexpression of GULP1 affected APP cell surface localization and suppressed generation of Abeta40/42 and sAPPalpha. Taken together, these data identify GULP1 as a novel neuronal APP interacting protein that alters trafficking and processing of APP.

  • 5. Darreh-Shori, T.
    et al.
    Kadir, A.
    Almkvist, O.
    Grut, M.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Blomquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Eriksson, B.
    Långström, B.
    Nordberg, A.
    Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 2, p. 168-184Article in journal (Refereed)
    Abstract [en]

    The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months Galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by C-11-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.

  • 6. Darreh-Shori, Taher
    et al.
    Forsberg, Anton
    Modiri, Negar
    Andreasen, Niels
    Blennow, Kaj
    Kamil, Chelenk
    Ahmed, Hiba
    Almkvist, Ove
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nordberg, Agneta
    Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer's disease in the brain in vivo2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 12, p. 2320.e15-2320.e32Article in journal (Refereed)
    Abstract [en]

    Recently, we reported that 3 of the known risk factors of Alzheimer's disease (AD), i.e., advanced age, apolipoprotein E (ApoE) epsilon 4, and female gender, are associated with differential levels of ApoE proteins and butyrylcholinesterase (BuChE) in the cerebrospinal fluid (CSF) of AD patients. The ApoE epsilon 4 allele and certain BuChE polymorphisms synergistically affect the conversion rate of mild cognitive impairment (MCI) to AD. Here, we investigated interrelationships between ApoE and BuChE levels, and pathological markers of AD in vivo. CSF from patients with probable AD, assessed for cerebral glucose metabolism (CMRglc; n = 50) and Pittsburgh compound B (PIB) retention (beta-amyloid [A beta] load, n = 29) by positron emission tomography (PET), was used for measurement of BuChE, ApoE, A beta, tau, phosphorylated tau (P-tau) and interleukin-1 beta (IL-1 beta) levels. Levels of ApoE and BuChE strongly correlated with CMRglc (fluorodeoxyglucose [FDG]-PET, r = 0.54, p < 0.0001, n = 50), cerebral A beta load (PIB retention, r = 0.73, p < 0.0001, n = 29), and CSF P-tau (r = 0.73, p < 0.0001, n = 33). High ApoE protein was tied to low CMRglc and high PIB retention and P-tau. BuChE levels had opposite relationships. Other CSF covariates were levels of interleukin-1 beta and A beta(42) peptide. The pattern of the patients' cognitive Z-scores strongly supported these observations. High ApoE protein was also linked to changes in 3 of the biodynamic properties of BuChE. In vitro analysis indicated that high ApoE protein levels were related to an increased pool of dormant BuChE molecules with an abnormally high intrinsic catalytic rate in CSF, which was "turned on" by excess A beta peptides. The findings suggest that abnormally high levels of ApoE may play a causative role in the pathological events of AD, particularly those involving the early cholinergic deficit in the AD brain, through modulation of cholinesterases activities, hence disturbing the acetylcholine-dependent activity of neurons and nonexcitable cells such as glial cells.

  • 7. Darreh-Shori, Taher
    et al.
    Vijayaraghavan, Swetha
    Aeinehband, Shahin
    Piehl, Fredrik
    Lindblom, Rickard P F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Almkvist, Ove
    Nordberg, Agneta
    Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 11, p. 2465-2481Article in journal (Refereed)
    Abstract [en]

    Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1 beta, and tumor necrosis factor (TNF)-alpha. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1b and 21%-27% higher TNF-alpha compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low beta-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-alpha and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status.

  • 8. Forsberg, Anton
    et al.
    Engler, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Almkvist, Ove
    Blomquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hagman, Goran
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ringheim, Anna
    Langström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nordberg, Agneta
    PET imaging of amyloid deposition in patients with mild cognitive impairment2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 10, p. 1456-1465Article in journal (Refereed)
    Abstract [en]

    mild cognitive impairment, converters, amyloid, PET, PIB, FDG, CSF biomarkers/k It is of great clinical value to identify Subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3 +/- 7.8 (S.D.) years) Underwent PET Studies with C-11-PIB, and F-18-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, its well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively. were Used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later Lit clinical follow-up converted to AD (8.1 +/- 6.0 (S.D.) months) showed significant higher PI B retention compared to non-converting MCI patients and HC, respcctively (ps < , 0.01). The PIB retention in MCI converters was comparable to AD patients (p > , 0.01). Correlations were observed in the MCI patients between PI B retention and CSF A beta(1-42). total Tau and episodic memory, respectively.

  • 9. Kadir, A.
    et al.
    Darreh-Shori, T.
    Almkvist, O.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Grut, M.
    Strandberg, B.
    Ringheim, A.
    Eriksson, B.
    Blomquist, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Långström, B.
    Nordberg, A.
    PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 8, p. 1204-1217Article in journal (Refereed)
    Abstract [en]

    The effect of galantamine treatment on cortical acetylcholinesterase (AChE) activity and nicotinic receptor binding was investigated by positron emission tomography (PET) in 18 patients with mild Alzheimer's disease (AD) in relation to galantamine concentration and the patients' cognitive performances. The first 3 months of the study was of a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and 6 patients the placebo, and this was followed by 9 months' galantamine treatment in all patients. The patients underwent PET examinations to measure cortical AChE activity (C-11-PMP) and C-11-nicotine binding. Neuropsychological tests were performed throughout the study. Inhibition (30-40%) of cortical AChE activity was observed after 3 weeks to 12 months of galantamine treatment. No significant change in mean cortical C-11-nicotine binding was observed during the study. C-11-Nicotine binding, however, positively correlated with plasma galantamine concentration. Both the changes of AChE activity and C-11-nicotine binding correlated positively with the results of a cognitive test of attention. In conclusion, galantamine caused sustained AChE inhibition for up to 12 months. At the individual level, the in vivo cortical AChE inhibition and C-11-nicotine binding were associated with changes in the attention domain of cognition rather than episodic memory.

  • 10. Kadir, Ahmadul
    et al.
    Almkvist, Ove
    Forsberg, Anton
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Engler, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nordberg, Agneta
    Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 1, p. 198.e1-198.e14Article in journal (Refereed)
    Abstract [en]

    In this study 5 patients with mild cognitive impairment (MCI) and 9 Alzheimer’s disease (AD) patients underwent respectively 3- and 5-year follow-up positron emission tomography (PET) studies with N-methyl [11C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole (11C-PIB) and 18F-fluorodeoxyglucose (18F-FDG) to understand the time courses in AD disease processes. Significant increase in PIB retention as well as decrease in regional cerebral metabolic rate of glucose (rCMRglc) was observed at group level in the MCI patients while no significant change was observed in cognitive function. At group level the AD patients showed unchanged high PIB retention at 5-year follow-up compared with baseline. At the individual level, increased, stable, and decreased PIB retention were observed while disease progression was reflected in significant decrease in rCMRglc and cognition. In conclusion, after a long-term follow-up with PET, we observed an increase in fibrillar amyloid load in MCI patients followed by more stable level in clinical AD patients. The rCMRglc starts to decline in MCI patients and became more pronounced in clinical stage which related to continuous decline in cognition.

  • 11.
    Kovacs, Gabor G.
    et al.
    Med Univ Vienna, Inst Neurol, A-1097 Vienna, Austria.;Semmelweis Univ, Neuropathol & Prion Dis Reference Ctr, H-1085 Budapest, Hungary..
    Horvath, Monika Cs.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
    Majtenyi, Katalin
    Semmelweis Univ, Neuropathol & Prion Dis Reference Ctr, H-1085 Budapest, Hungary..
    Lutz, Mirjam I.
    Med Univ Vienna, Inst Neurol, A-1097 Vienna, Austria..
    Hurd, Yasmin L.
    Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA..
    Keller, Eva
    Semmelweis Univ, Dept Forens & Insurance Med, H-1085 Budapest, Hungary..
    Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions2015In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 36, no 11, p. 3100-3107Article in journal (Refereed)
    Abstract [en]

    The observation of increased hyperphosphorylated tau levels correlating with microglial activation in opiate abusers has been interpreted as predisposition to accelerated Alzheimer diseaseerelated changes. The present study focused on evaluating additional neurodegeneration-related proteins, including a-synuclein and TDP-43, and p62-positive deposits. We performed a systematic mapping of protein deposits in the brains of 27 individuals with documented heroin addiction (age: 19-40 years) and compared with 11 controls (age: 15-40 years). We confirm previous findings that heroin addiction associates with tau hyperphosphorylation in predilection brain areas for aging and Alzheimer disease. Furthermore, we show that this occurs also in areas implicated in the molecular disturbances and in vivo neuronal networks related to heroin abuse. There was, however, no presence of amyloid-beta deposits. We extend previous findings by showing the lack of TDP-43 or alpha-synuclein pathology and emphasize the independent effect of the duration of drug use on the appearance of age-related p62-positive neuritic profiles. These observations provide unique insights about neuropathological alterations in the brains of young heroin addicts and have implications about brain aging and the influences of environmental and toxic factors.

  • 12.
    Lemoine, Laetitia
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nennesmo, Inger
    Karolinska Inst, Stockholm, Sweden..
    Gillberg, Per-Goran
    Karolinska Inst, Stockholm, Sweden..
    Nordberg, Agneta
    Karolinska Inst, Stockholm, Sweden..
    In Vitro Characterization Of Fibrillar Amyloid, Tau Deposits, And Activated Astrocytes In Arctic App And Sporadic Alzheimer's Disease Brain Using, 3H-Pib And 3H-Thk5117 And 3H-Deprenyl In Comparison To Immunostaining2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 39, p. S15-S15Article in journal (Other academic)
  • 13.
    Leão, Richardson N.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Colom, Luis V.
    Borgius, Lotta
    Kiehn, Ole
    Fisahn, Andre
    Medial septal dysfunction by A beta-induced KCNQ channel-block in glutamatergic neurons2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 9, p. 2046-2061Article in journal (Refereed)
    Abstract [en]

    Amyloid beta (A beta) peptides play a central role in the pathophysiology of Alzheimer's disease (AD). The cellular mechanisms underlying A beta toxicity, however, are poorly understood. Here we show that A beta 25-35 and A beta 1-40 acutely and differentially affect the characteristics of 3 classes of medial septum (MS) neurons in mice. In glutamatergic neurons A beta increases firing frequency and blocks the A-and the M-current (I-A and I-M, respectively). While the I-A block is similar in other MS neuron classes, the block of I-M is specific to glutamatergic neurons. I-M block and a simulated A beta block mimic the A beta-induced increase in spontaneous firing in glutamatergic neurons. Calcium imaging shows that under control conditions glutamatergic neurons rarely fire while nonglutamatergic neurons fire coherently at theta frequencies. A beta increases the firing rate of glutamatergic neurons while nonglutamatergic neurons lose theta firing coherence. Our results demonstrate that A beta-induced dysfunction of glutamatergic neurons via I-M decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer's disease.

  • 14. Leão, Richardson N
    et al.
    Colom, Luis V
    Borgius, Lotta
    Kiehn, Ole
    Fisahn, André
    Medial septal dysfunction by Aβ-induced KCNQ channel-block in glutamatergic neurons.2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 9, p. 2046-61Article in journal (Refereed)
    Abstract [en]

    Amyloid β (Aβ) peptides play a central role in the pathophysiology of Alzheimer's disease (AD). The cellular mechanisms underlying Aβ toxicity, however, are poorly understood. Here we show that Aβ(25-35) and Aβ(1-40) acutely and differentially affect the characteristics of 3 classes of medial septum (MS) neurons in mice. In glutamatergic neurons Aβ increases firing frequency and blocks the A- and the M-current (I(A) and I(M), respectively). While the I(A) block is similar in other MS neuron classes, the block of I(M) is specific to glutamatergic neurons. I(M) block and a simulated Aβ block mimic the Aβ-induced increase in spontaneous firing in glutamatergic neurons. Calcium imaging shows that under control conditions glutamatergic neurons rarely fire while nonglutamatergic neurons fire coherently at theta frequencies. Aβ increases the firing rate of glutamatergic neurons while nonglutamatergic neurons lose theta firing coherence. Our results demonstrate that Aβ-induced dysfunction of glutamatergic neurons via I(M) decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer's disease.

  • 15. Lillehaug, Sveinung
    et al.
    Syverstad, Gry H.
    Nilsson, Lars N. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bjaalie, Jan G.
    Leergaard, Trygve B.
    Torp, Reidun
    Brainwide distribution and variance of amyloid-beta deposits in tg-ArcSwe mice2014In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 35, no 3, p. 556-564Article in journal (Refereed)
    Abstract [en]

    Transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid-beta precursor protein (A beta PP) develop amyloid-beta (A beta) deposits in the brain that resemble Alzheimer's disease neuropathology. Earlier studies of this model have documented morphologic features in selected parts of the cerebral cortex and hippocampus, but the spatial distribution within the brain and variance of A beta deposits within a group of tg-ArcSwe mice is unknown. Using immunohistochemistry and brainwide microscopic analysis of 12-month-old tg-ArcSwe mice, we show that A beta x-40 plaque deposits are consistently present in the cerebral cortex, hippocampus, and thalamus and variably present in other regions. Using quantitative image analysis, we demonstrated that the average A beta burden in the cortex and hippocampus is similar across animals, with coefficients of variance of 22% and 25%, respectively. This indicates that interventional studies of tg-ArcSwe mice are feasible using region-of-interest comparisons and that interventional trials require larger group sizes than commonly used. We also present an online atlas providing access to images showing the detailed characteristics and spatial distribution patterns of A beta x-40 labeling. 

  • 16. Liu, Yao
    et al.
    Atkinson, Rachel A. K.
    Fernandez-Martos, Carmen M.
    Kirkcaldie, Matthew T. K.
    Cui, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Vickers, James C.
    King, Anna E.
    Changes in TDP-43 expression in development, aging, and in the neurofilament light protein knockout mouse2015In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 36, no 2, p. 1151-1159Article in journal (Refereed)
    Abstract [en]

    The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament light (NF-L) messenger RNA (mRNA)-binding protein. Abnormally increased levels of TDP-43 are detected in patients with amyotrophic lateral sclerosis and a downregulation of NF-L mRNA. However, links between NF-L and TDP-43 expressions are unclear. In this study, we investigated whether the deficiency of NF-L protein can result in alterations in TDP-43 localization or protein expression and whether this is altered with aging. There was a significant increase in TDP-43 protein levels in the cortex and lumbar spinal cord in 12-month-old NF-L knockout (NF-L KO) mice, compared with wild-type (WT) C57BL/6 mice. However, there was no difference in either the phosphorylation of TDP-43 between WT and NF-L KO mice or the abnormal mislocalization of TDP-43 to the cytoplasm in NF-L KO animals. Our findings suggest that NF-L protein or mRNA may negatively affect the expression of TDP-43 in the central nervous system. However, altered phosphorylation of TDP-43 may be more highly associated with aging than the levels of TDP-43 expression.

  • 17. Marcello, Andrea
    et al.
    Wirths, Oliver
    Schneider-Axmann, Thomas
    Degerman-Gunnarsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bayer, Thomas A
    Reduced levels of IgM autoantibodies against N-truncated pyroglutamate Abeta in plasma of patients with Alzheimer's disease2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 8, p. 1379-1387Article in journal (Refereed)
    Abstract [en]

    In the present work, we investigated the level of IgM autoantibodies directed against different Abeta epitopes as potential diagnostic biomarker for Alzheimer's disease (AD). Anti-Abeta 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-Abeta IgMs, pooled plasma samples were subjected to gel-filtration analysis. The mean level of pGluAbeta-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 pGluAbeta-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 pGluAbeta is a promising plasma biomarker for AD and correlates with the cognitive status of individuals at risk to develop AD.

  • 18. Martiskainen, Henna
    et al.
    Viswanathan, Jayashree
    Nykänen, Niko-Petteri
    Kurki, Mitja
    Helisalmi, Seppo
    Natunen, Teemu
    Sarajärvi, Timo
    Kurkinen, Kaisa M A
    Pursiheimo, Juha-Pekka
    Rauramaa, Tuomas
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jääskeläinen, Juha E
    Leinonen, Ville
    Soininen, Hilkka
    Haapasalo, Annakaisa
    Huttunen, Henri J
    Hiltunen, Mikko
    Transcriptomics and mechanistic elucidation of Alzheimer's disease risk genes in the brain and in vitro models2015In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 36, no 2, p. 1221e15-1221e28Article in journal (Refereed)
    Abstract [en]

    In this study, we have assessed the expression and splicing status of genes involved in the pathogenesis or affecting the risk of Alzheimer's disease (AD) in the postmortem inferior temporal cortex samples obtained from 60 subjects with varying degree of AD-related neurofibrillary pathology. These subjects were grouped based on neurofibrillary pathology into 3 groups: Braak stages 0-II, Braak stages III-IV, and Braak stages V-VI. We also examined the right frontal cortical biopsies obtained during life from 22 patients with idiopathic shunt-responding normal pressure hydrocephalus, a disease that displays similar pathologic alterations as seen in AD. These 22 patients were categorized according to dichotomized amyloid-β positive or negative pathology in the biopsies. We observed that the expression of FRMD4A significantly decreased, and the expression of MS4A6A significantly increased in relation to increasing AD-related neurofibrillary pathology. Moreover, the expression of 2 exons in both CLU and TREM2 significantly increased with increase in AD-related neurofibrillary pathology. However, a similar trend toward increased expression in CLU and TREM2 was observed with most of the studied exons, suggesting a global change in the expression rather than altered splicing. Correlation of gene expression with well-established AD-related factors, such as α-, β-, and γ-secretase activities, brain amyloid-β42 levels, and cerebrospinal fluid biomarkers, revealed a positive correlation between β-secretase activity and the expression of TREM2 and BIN1. In expression quantitative trait loci analysis, we did not detect significant effects of the risk alleles on gene expression or splicing. Analysis of the normal pressure hydrocephalus biopsies revealed no differences in the expression or splicing profiles of the studied genes between amyloid-β positive and negative patients. Using the protein-protein interaction-based in vitro pathway analysis tools, we found that downregulation of FRMD4A associated with increased APP-β-secretase interaction, increased amyloid-β40 secretion, and altered phosphorylation of tau. Taken together, our results suggest that the expression of FRMD4A, MS4A6A, CLU, and TREM2 is altered in relation to increasing AD-related neurofibrillary pathology, and that FRMD4A may play a role in amyloidogenic and tau-related pathways in AD. Therefore, investigation of gene expression changes in the brain and effects of the identified genes on disease-associated pathways in vitro may provide mechanistic insights on how alterations in these genes may contribute to AD pathogenesis.

  • 19. Oberg, Johanna
    et al.
    Spenger, Christian
    Wang, Fu-Hua
    Andersson, Anders
    Westman, Eric
    Skoglund, Peter
    Sunnemark, Dan
    Norinder, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Klason, Tomas
    Wahlund, Lars-Olof
    Lindberg, Mattias
    Age related changes in brain metabolites observed by 1H MRS in APP/PS1 mice2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 9, p. 1423-1433Article in journal (Refereed)
    Abstract [en]

    Translational biomarkers in Alzheimer's disease based on non-invasive in vivo methods are highly warranted. (1)H magnetic resonance spectroscopy (MRS) is non-invasive and applicable in vivo in both humans and experimental animals. In vivo(1)H MRS and 3D MRI were performed on brains of double transgenic (tg) mice expressing a double mutant human beta-amyloid precursor protein APP(K670N,M671L) and human mutated presenilin gene PS1M146L, and wild-type (wt) littermates at 2.5, 6.5 and 9 months of age using a 9.4T magnet. For quantification, LCModel was used, and the data were analyzed using multivariate data analysis (MVDA). MVDA evidenced a significant separation, which became more pronounced with age, between tg and wt mice at all time points. While myo-inositol and guanidoacetate were important for group separation in young mice, N-acetylaspartate, glutamate and macrolipids were important for separation of aged tg and wt mice. Volume segmentation revealed that brain and hippocampus were readily smaller in tg as compared to wt mice at the age of 2.5 months. Amyloid plaques were seen in 6.5 and 9 months, but not in 2.5 months old animals. In conclusion, differences in brain metabolites could be accurately depicted in tg and wt mice in vivo by combining MRS with MVDA. First differences in metabolite content were readily seen at 2.5 months, when volume defects in tg mice were present, but no amyloid plaques.

  • 20. Ojala, Johanna
    et al.
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland.
    Herukka, Sanna-Kaisa
    van Groen, Thomas
    Tanila, Heikki
    Pirttilä, Tuula
    Expression of interleukin-18 is increased in the brains of Alzheimer's disease patients2009In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 30, no 2, p. 198-209Article in journal (Refereed)
    Abstract [en]

    The inflammatory cytokines can initiate nerve cell degeneration and enhance the plaque production typically found in Alzheimer's disease (AD). Interleukin-18 (IL-18) is an inflammatory cytokine, which can induce the expression of interferon-gamma. This interleukin shares similarities with the IL-1 family of proteins. Like IL-1 beta, IL-18 is cleaved by caspase-1 (ICE) to an active secreted form. We examined the expressions of IL-18, -1 beta and ICE in different brain regions from AD patients that were categorized with respect to the Braak stage, and age-matched with non-demented controls. The levels of total-RNA and protein of IL-18 and ICE were increased, especially in the frontal lobe of AD patients and this change was not modified by ApoE genotype. Immunohistochemistry of AD brain samples detected IL-18 in microglia, astrocytes, and surprisingly in neurons, and it is also co-localized not only with amyloid-beta plaques but also with tau. In CSF, elevated IL-18 level was detected only in men and it also correlated with CSF tau in MCI. IL-18 may thus be a potential biomarker for men. Plasma levels of IL-18 showed no correlation with the disease. In conclusion, amyloid-beta may induce the synthesis of IL-18, and IL-18 kinases involved in tau phosphorylation as a part of the amyloid-associated inflammatory reaction.

  • 21.
    Philipson, Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hammarström, Per
    Nilsson, K Peter R
    Portelius, Erik
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hyman, Bradley T
    Blennow, Kaj
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nilsson, Lars N.G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice2009In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 30, no 9, p. 1393-1405Article in journal (Refereed)
    Abstract [en]

    Amyloid-beta (Abeta) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited Abeta is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited Abeta in both tgAPP-ArcSwe and Alzheimer's disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic Abeta was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Abeta plaques displayed a patchy morphology with bundles of Abeta fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma Abeta was observed following acute administration of an Abeta antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Abeta efflux. TgAPP-ArcSwe, with its insoluble state of deposited Abeta, could serve as a complementary model to better predict the outcome of clinical trials.

  • 22.
    Philipson, Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lord, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lalowski, Maciej
    Soliymani, Rabah
    Baumann, Marc
    Thyberg, Johan
    Bogdanovic, Nenad
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tjernberg, Lars O
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kalimo, Hannu
    Nilsson, Lars N G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    The Arctic amyloid-β precursor protein (AβPP) mutation results in distinct plaques and accumulation of N- and C-truncated Aβ2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 5, p. 1010.e1-1010.e13Article in journal (Refereed)
    Abstract [en]

    The Arctic (p. E693G) mutation in the amyloid-β precursor protein (AβPP) facilitates amyloid-β (Aβ) protofibril formation and generates clinical symptoms of Alzheimer's disease (AD). Here, molecular details of Aβ in post mortem brain were investigated with biochemical and morphological techniques. The basic structure of Arctic plaques resembled cotton wool plaques. However, they appeared ring-formed with Aβ42-specific antibodies, but were actually targetoid, since the periphery and center of many parenchymal Aβ deposits stained differently with mid-domain, N- and C-terminal Aβ antibodies. Aβ fibrils were similar in shape, albeit shorter than in sporadic AD brain, when examined by electron microscopy. Aβwild-type and Aβarctic codeposited and parenchymal deposits were highly enriched in both N- and C-terminally truncated Aβ. In contrast, cerebral amyloid angiopathy (CAA) contained a substantial amount of Aβ1-40. The absence of plaques with cores of fibrillary Aβ might be due to the scarcity of full-length Aβ, although other mechanisms could be involved. Our findings are discussed in relation to mechanisms and relevance of amyloid formation and to the clinical features of AD.

  • 23. Reynolds, Chandra A
    et al.
    Zavala, Catalina
    Gatz, Margaret
    Vie, Loryana
    Johansson, Boo
    Malmberg, Bo
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Prince, Jonathan A
    Pedersen, Nancy L
    Sortilin receptor 1 predicts longitudinal cognitive change2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 6, p. 1710.e11-1710.e18Article in journal (Refereed)
    Abstract [en]

    The gene encoding sortilin receptor 1 (SORL1) has been associated with Alzheimer's disease risk. We examined 15 SORL1 variants and single nucleotide polymorphism (SNP) set risk scores in relation to longitudinal verbal, spatial, memory, and perceptual speed performance, testing for age trends and sex-specific effects. Altogether, 1609 individuals from 3 population-based Swedish twin studies were assessed up to 5 times across 16 years. Controlling for apolipoprotein E genotype (APOE), multiple simple and sex-moderated associations were observed for spatial, episodic memory, and verbal trajectories (p = 1.25E-03 to p = 4.83E-02). Five variants (rs11600875, rs753780, rs7105365, rs11820794, rs2070045) were associated across domains. Notably, in those homozygous for the rs2070045 risk allele, men demonstrated initially favorable performance but accelerating declines, and women showed overall lower performance. SNP set risk scores predicted spatial (Card Rotations, p = 5.92E-03) and episodic memory trajectories (Thurstone Picture Memory, p = 3.34E-02), where higher risk scores benefited men's versus women's performance up to age 75 but with accelerating declines. SORL1 is associated with cognitive aging, and might contribute differentially to change in men and women.

  • 24. Rönnback, Annica
    et al.
    Sagelius, Hanna
    Bergstedt, Karin Dillner
    Naslund, Jan
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Winblad, Bengt
    Graff, Caroline
    Amyloid neuropathology in the single Arctic APP transgenic model affects interconnected brain regions2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 4, article id 831.e11Article in journal (Refereed)
    Abstract [en]

    The Arctic APP mutation (E693G) within the amyloid beta (A beta) domain of amyloid precursor protein (APP) leads to dementia with clinical features similar to Alzheimer's disease (AD), which is believed to be mediated via increased formation of protofibrils. We have generated a transgenic mouse model, TgAPParc, with neuron-specific expression of human amyloid precursor protein with the Arctic mutation (hAPParc), showing mild amyloid pathology with a relatively late onset. Here we performed a detailed analysis of the spatiotemporal progression of neuropathology in homozygous TgAPParc, focusing on intracellular A beta and diffuse A beta aggregates rather than amyloid plaques. We show that the neuropathology in homozygous TgAPParc mice starts with intracellular A beta aggregates, which is followed by diffuse extracellular A beta deposits in subiculum that later expands to brain regions receiving neuronal projections from regions already affected. Together this suggests that the pathology in TgAPParc mice affects interconnected brain regions and may represent a valuable tool to study the spread and progression of neuropathology in Alzheimer's disease. 

  • 25. Schöll, Michael
    et al.
    Almkvist, Ove
    Axelman, Karin
    Stefanova, Elka
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Westman, Eric
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Graff, Caroline
    Nordberg, Agneta
    Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 8, p. 1388-1399Article in journal (Refereed)
    Abstract [en]

    Six young related pre-symptomatic carriers of a His163Tyr mutation in the presenilin 1 gene who will develop early onset familial Alzheimer's disease (eoFAD), and a control group of 23 non-carriers underwent (18)F-fluorodeoxyglucose positron emission tomography (FDG PET). The mutation carriers were followed-up after 2 years. Multivariate analysis showed clear separation of carriers from non-carriers on both occasions, with the right thalamus being the region contributing most to group differentiation. Statistical parametric mapping (SPM) revealed in the carriers non-significantly lower thalamic cerebral glucose metabolism (CMRglc) at baseline and significantly decreased CMRglc in the right thalamus at follow-up. One mutation carrier was followed-up with FDG PET 10 years after baseline and showed reductions in cognition and CMRglc in the posterior cingulate and the frontal cortex. This subject was diagnosed with AD 1 year later and assessed with an additional FDG as well as an (11)C-PIB PET scan 12 years after baseline. Global cortical CMRglc and cognition were distinctly decreased. PIB binding was comparable with sporadic AD patterns but showing slightly higher striatal levels.

  • 26. Shepherd, C. E.
    et al.
    Goyette, J.
    Utter, V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Rahimi, F.
    Yang, Z.
    Geczy, C. L.
    Halliday, G. M.
    Inflammatory S100A9 and S100A12 proteins in Alzheimer's disease2006In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 27, no 11, p. 1554-1563Article in journal (Refereed)
    Abstract [en]

    Inflammation, insoluble protein deposition and neuronal cell loss are important features of the Alzheimer's disease (AD) brain. S100B is associated with the neuropathological hallmarks of AD where it is thought to play a role in neuritic pathology. S100A8, S100A9 and S100A12 comprise anew group of inflammation-associated proteins that are constitutively expressed by neutrophils and inducible in numerous inflammatory cells. We investigated expression of S100B, S100A8, S100A9 and S100A12 in brain samples from sporadic and familial (PS-1) AD cases and controls using immunohistochemistry and Western blot analysis. S100B, S100A9 and S100A12, but not S100A8, were consistently associated with the neuropathological hallmarks of AD. Western blot analysis confirmed significant increases in soluble S100A9 in PS-1 AD compared to controls. S100A9 complexes that were resistant to reduction were also evident in brain extracts. A reactive component of a size consistent with hexameric S100A12 was seen in all cases. This study indicates a potential role for pro-inflammatory S100A9 and S100A12 in pathogenesis caused by inflammation and protein complex formation in AD.

  • 27.
    Skillbäck, Tobias
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Neurochem, Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden..
    Delsing, Louise
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Neurochem, Molndal, Sweden.;Univ Skovde, Sch Biosci, Syst Biol Res Ctr, Box 408, S-54128 Skovde, Sweden..
    Synnergren, Jane
    Univ Skovde, Sch Biosci, Syst Biol Res Ctr, Box 408, S-54128 Skovde, Sweden..
    Mattsson, Niklas
    Lund Univ, Dept Clin Sci Malmo, Clin Memory Res Unit, Malmo, Sweden.;Skane Univ Hosp, Dept Neurol, Lund, Sweden..
    Janelidze, Shorena
    Lund Univ, Dept Clin Sci Malmo, Clin Memory Res Unit, Malmo, Sweden..
    Nägga, Katarina
    Lund Univ, Dept Clin Sci Malmo, Clin Memory Res Unit, Malmo, Sweden..
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hicks, Ryan
    AstraZeneca, IMED Biotech Unit, Discovery Sci, Molndal, Sweden..
    Wimo, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc NVS, Div Neurogeriatr, Huddinge, Sweden..
    Winblad, Bengt
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc NVS, Div Neurogeriatr, Huddinge, Sweden.;Karolinska Univ Hosp, Dept Geriatr Med, Huddinge, Sweden..
    Hansson, Oskar
    Lund Univ, Dept Clin Sci Malmo, Clin Memory Res Unit, Malmo, Sweden.;Skane Univ Hosp, Dept Neurol, Lund, Sweden..
    Blennow, Kaj
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Neurochem, Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden..
    Eriksdotter, Maria
    Karolinska Univ Hosp, Dept Geriatr Med, Huddinge, Sweden.;Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc NVS, Div Clin Geriatr, Huddinge, Sweden..
    Zetterberg, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Neurochem, Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden.;UCL Inst Neurol, Dept Mol Neurosci, London, England.;UCL, UK Dementia Res Inst, London, England..
    CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 59, p. 1-9Article in journal (Refereed)
    Abstract [en]

    A connection between dementias and blood-brain barrier (BBB) dysfunction has been suggested, but previous studies have yielded conflicting results. We examined cerebrospinal fluid (CSF)/serum albumin ratio in a large cohort of patients diagnosed with Alzheimer's disease (AD, early onset [EAD, n = 130], late onset AD [LAD, n = 666]), vascular dementia (VaD, n = 255), mixed AD and VaD (MIX, n = 362), Lewy body dementia (DLB, n = 50), frontotemporal dementia (FTD, n = 56), Parkinson's disease dementia (PDD, n = 23), other dementias (other, n = 48), and dementia not otherwise specified (NOS, n = 271). We compared CSF/serum albumin ratio to 2 healthy control groups (n = 292, n = 20), between dementia diagnoses, and tested biomarker associations. Patients in DLB, LAD, VaD, MIX, other, and NOS groups had higher CSF/serum albumin ratio than controls. CSF/serum albumin ratio correlated with CSF neurofilament light in LAD, MIX, VaD, and other groups but not with AD biomarkers. Our data show that BBB leakage is common in dementias. The lack of association between CSF/serum albumin ratio and AD biomarkers suggests that BBB dysfunction is not inherent to AD but might represent concomitant cerebrovascular pathology.

  • 28.
    Thienel, Matthias
    et al.
    Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Otfried Muller Str 25, D-72076 Tubingen, Germany..
    Wilhelm, Ines
    Univ Childrens Hosp Zurich, Child Dev Ctr, Zurich, Switzerland..
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Born, Jan
    Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Otfried Muller Str 25, D-72076 Tubingen, Germany.;German Ctr Diabet Res DZD, Tubingen, Germany.;Univ Tubingen IDM, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany..
    Hallschmid, Manfred
    Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Otfried Muller Str 25, D-72076 Tubingen, Germany.;German Ctr Diabet Res DZD, Tubingen, Germany.;Univ Tubingen IDM, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany..
    Intranasal insulin decreases circulating cortisol concentrations during early sleep in elderly humans2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 54, p. 170-174, article id 170e174Article in journal (Refereed)
    Abstract [en]

    Aging is associated with increases in hypothalamic-pituitary-adrenal (HPA) axis activity that can predispose to metabolic and cognitive impairments. We investigated in elderly and young subjects whether intranasal insulin administration to the human brain reduces early-sleep nadir concentrations of adrenocorticotropin and cortisol, that is, indicators of baseline HPA axis activity. In within-subject comparisons, intranasal insulin (160 IU) or placebo was administered to 14 elderly (mean age 70.0 years) and 30 young (23.6 years) healthy subjects before bedtime. Sleep was polysomno-graphically assessed and blood samples were repeatedly collected. Elderly compared with young participants displayed increased early-sleep cortisol concentrations (p < 0.04) and reductions in slow wave and REM sleep (p < 0.001). Insulin administration reduced cortisol levels between 2300 hours and 0020 hours in the elderly (p = 0.03) but not young participants (p = 0.56; p = 0.003 for interaction). Findings indicate that central nervous insulin acts as an inhibitory signal in basal HPA axis activity regulation and suggest that intranasal insulin may normalize sleep-associated stress axis activity in older age.

  • 29.
    Titova, Olga E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Elmståhl, Solve
    Lund Univ, Skane Univ Hosp, Sweden CRC, Dept Hlth Sci,Div Geriatr Med, Malmo, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Association between shift work history and performance on the trail making test in middle-aged and elderly humans: the EpiHealth study2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 45, p. 23-29Article in journal (Refereed)
    Abstract [en]

    Shift work has been proposed to promote cognitive disturbances in humans; however, conflicting evidence is also present. By using data from 7143 middle-aged and elderly humans (45-75 years) who participated in the Swedish EpiHealth cohort study, the present analysis sought to investigate whether self-reported shift work history would be associated with performance on the trail making test (TMT). The TMT has been proposed to be a useful neuropsychological tool to evaluate humans' executive cognitive function, which is known to decrease with age. After adjustment for potential confounders (e.g., age, education, and sleep duration), it was observed that current and recent former shift workers (worked shifts during the past 5 years) performed worse on the TMT than nonshift workers. In contrast, performance on the TMT did not differ between past shift workers (off from shift work for more than 5 years) and nonshift workers. Collectively, our results indicate that shift work history is linked to poorer performance on the TMT in a cohort of middle-aged and elderly humans.

  • 30.
    Yakovleva, Tatjana
    et al.
    Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden.
    Marinova, Z.
    Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden.
    Kuzmin, A.
    Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden.
    Seidah, N. G.
    Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Que., Canada.
    Haroutunian, V.
    Department of Psychiatry, The Mount Sinai School of Medicine, New York, USA.
    Terenius, L.
    Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden.
    Bakalkin, G.
    Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden.
    Dysregulation of dynorphins in Alzheimer disease2007In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 28, no 11, p. 1700-8Article in journal (Refereed)
    Abstract [en]

    The opioid peptides dynorphins may be involved in pathogenesis of Alzheimer disease (AD) by inducing neurodegeneration or cognitive impairment. To test this hypothesis, the dynorphin system was analyzed in postmortem samples from AD and control subjects, and subjects with Parkinson or cerebro-vascular diseases for comparison. Dynorphin A, dynorphin B and related neuropeptide nociceptin were determined in the Brodmann area 7 by radioimmunoassay. The precursor protein prodynorphin, processing convertase PC2 and the neuroendocrine pro7B2 and 7B2 proteins required for PC2 maturation were analyzed by Western blot. AD subjects displayed robustly elevated levels of dynorphin A and no differences in dynorphin B and nociceptin compared to controls. Subjects with Parkinson or cerebro-vascular diseases did not differ from controls with respect to any of the three peptides. PC2 levels were also increased, whereas, those of prodynorphin and pro7B2/7B2 were not changed in AD. Dynorphin A levels correlated with the neuritic plaque density. These results along with the known non-opioid ability of dynorphin A to induce neurodegeneration suggest a role for this neuropeptide in AD neuropathology.

  • 31.
    Zhang, Linyu
    et al.
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    Dong, Hao
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    Si, Youwen
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    Wu, Nan
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    Cao, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mei, Bing
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    Meng, Bo
    East China Normal Univ, Shanghai Key Lab Brain Funct Genom, Minist Educ, Key Lab Brain Funct Genom, Shanghai, Peoples R China.
    miR-125b promotes tau phosphorylation by targeting the neural cell adhesion molecule in neuropathological progression2019In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 73, p. 41-49Article in journal (Refereed)
    Abstract [en]

    MicroRNAs, small noncoding RNAs, not only regulate gene expression at the post-transcriptional level in a variety of physiological processes but also accompany the initiation and progression of a vast number of diseases, including dementia. While miR-125b has been shown to be aberrantly expressed in some dementia patients, its role in the pathological process remains ambiguous. Presenilin-1/2 conditional double knockout mice exhibit a range of symptoms, including impaired cognition and memory, increased tau phosphorylation, neuroinflammation, and apoptosis, and are therefore regarded as a useful dementia model. In the prefrontal cortices of double knockout mice, miR-125b was found to be abnormally increased in an age-dependent manner. We further verified the neural cell adhesion molecule (NCAM) as an miR-125b target using the dual luciferase reporter assay. The NCAM protein level was decreased when miR-125b was overexpressed (OE) in neuronal growth factor-induced differentiated PC12 cells, which further inhibited the neuronal growth factor-induced phosphorylation of glycogen synthase kinase 3 beta (GSK beta) at the Ser9 site and ultimately increased the GSK3 beta activity and tau phosphorylation. Moreover, on serum deprivation, high GSK3 beta activity in differentiated miR-125b-OE PC12 cells induced increased caspase-3 activation. Finally, adeno-associated virus-mediated miR-125b overexpression in the prefrontal cortexes of wild-type C57B/L6 mice resulted in decreased dendritic spine density. In addition, similar to the in vitro data, elevated GSK3 beta activity and hyperphosphorylation of the tau protein were confirmed. Taken together, our findings reveal a direct regulation of miR-125b on NCAM, which leads to further effects on downstream GSK3 beta activity and tau phosphorylation and may contribute to the generation of neurofibrillary tangles in neuropathological progression. 

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