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  • 1.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rollman Waara, Erik
    BioArctic Neurosci AB, Stockholm, Sweden.
    Möller, Christer
    BioArctic Neurosci AB, Stockholm, Sweden.
    Söderberg, Linda
    BioArctic Neurosci AB, Stockholm, Sweden.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury2018In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, no 4, p. 451-462Article in journal (Refereed)
    Abstract [en]

    Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.

  • 2.
    Almkvist, Ove
    et al.
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Neurobiol, Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden.;Stockholm Univ, Dept Psychol, Stockholm, Sweden..
    Rodriguez-Vieitez, Elena
    Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Neurobiol, Stockholm, Sweden..
    Thordardottir, Steinunn
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden.;Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Stockholm, Sweden..
    Amberla, Kaarina
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden..
    Axelman, Karin
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden..
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kinhult-Stahlbom, Anne
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden.;Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Stockholm, Sweden..
    Lilius, Lena
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden..
    Remes, Anne
    Univ Eastern Finland, Inst Clin Med Neurol, Dept Neurol, Kuopio, Finland..
    Wahlund, Lars-Olof
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden.;Karolinska Inst, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Stockholm, Sweden..
    Viitanen, Matti
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden.;Karolinska Inst, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Stockholm, Sweden.;Turku City Hosp, Dept Geriatr, Turku, Finland.;Univ Turku, Turku, Finland..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Graff, Caroline
    Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden.;Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Stockholm, Sweden..
    Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease2017In: Journal of the International Neuropsychological Society, ISSN 1355-6177, E-ISSN 1469-7661, Vol. 23, no 3, p. 195-203Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to investigate cognitive performance including preclinical and clinical disease course in carriers and non-carriers of autosomal-dominant Alzheimer's disease (adAD) in relation to multiple predictors, that is, linear and non-linear estimates of years to expected clinical onset of disease, years of education and age. Methods: Participants from five families with early-onset autosomal-dominant mutations (Swedish and Arctic APP, PSEN1 M146V, H163Y, and I143T) included 35 carriers (28 without dementia and 7 with) and 44 non-carriers. All participants underwent a comprehensive clinical evaluation, including neuropsychological assessment at the Memory Clinic, Karolinska University Hospital at Huddinge, Stockholm, Sweden. The time span of disease course covered four decades of the preclinical and clinical stages of dementia. Neuropsychological tests were used to assess premorbid and current global cognition, verbal and visuospatial functions, short-term and episodic memory, attention, and executive function. Results: In carriers, the time-related curvilinear trajectory of cognitive function across disease stages was best fitted to a formulae with three predictors: years to expected clinical onset (linear and curvilinear components), and years of education. In non-carriers, the change was minimal and best predicted by two predictors: education and age. The trajectories for carriers and non-carriers began to diverge approximately 10 years before the expected clinical onset in episodic memory, executive function, and visuospatial function. Conclusions: The curvilinear trajectory of cognitive functions across disease stages was mimicked by three predictors in carriers. In episodic memory, executive and visuospatial functions, the point of diverging trajectories occurred approximately 10 years ahead of the clinical onset compared to non-carriers.

  • 3.
    Basun, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Bogdanovic, Nenad
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Almkvist, Ove
    Näslund, Jan
    Axelman, Karin
    Bird, Thomas D
    Nochlin, David
    Schellenberg, Gerard D
    Wahlund, Lars-Olof
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease2008In: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 65, no 4, p. 499-505Article in journal (Refereed)
    Abstract [en]

    Background: A majority of mutations within the beta-amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-beta-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. Objective: To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation. Design, Setting, and Participants: Affected and non-affected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, 1 brain from each family was investigated neuropathologically. Results: The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of Alzheimer disease and similar to the phenotype for other Alzheimer disease APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe as demonstrated by magnetic resonance imaging and single-photon emission computed tomography. One Swedish case and 1 American case with the Arctic APP mutation came to autopsy, and both showed no signs of hemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathological findings, and abundant amyloid plaques. Intriguingly, most plaques from both of these cases had a characteristic ringlike character. Conclusions: Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with Alzheimer disease.

  • 4. Blennow, Kaj
    et al.
    Zetterberg, Henrik
    Minthon, Lennart
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Strid, Stig
    Annas, Peter
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Andreasen, Niels
    Longitudinal stability of CSF biomarkers in Alzheimer's disease2007In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 419, no 1, p. 18-22Article in journal (Refereed)
    Abstract [en]

    Biomarker levels in cerebrospinal fluid (CSF) may serve as surrogate markers for treatment efficacy in clinical trials of disease-modifying drugs against Alzheimer's disease (AD). A prerequisite, however, is that the marker is sufficiently stable over time in individual patients. Here, we tested the stability of the three established CSF biomarkers for AD, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181) and the 42 amino acid isoform of β-amyloid (Aβ42), over 6 months in a cohort of AD patients on stable treatment with acetylcholinesterase (AChE) inhibitors. Fifty-three patients completed the study, 29 men and 24 women, mean age (±S.D.) 76.1 ± 7.9 years. Mean levels of CSF biomarkers were very stable between baseline and endpoint, with coefficients of variation (CVs) of 4.4–6.1%. Intra-individual biomarker levels at baseline and endpoint were also highly correlated with Pearson r-values above 0.95 (p < 0.0001), for all three markers. We conclude that T-tau, P-tau and Aβ42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients. This suggest that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness as surrogate markers in clinical trials with drug candidates with disease-modifying potential, such as secretase inhibitors, Aβ immunotherapy and tau phosphorylation inhibitors.

  • 5.
    Degerman Gunnarsson, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Reduction of Phosphorylated Tau during Memantine Treatment of Alzheimer's Disease2007In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 24, no 4, p. 247-252Article in journal (Refereed)
    Abstract [en]

    Background: Memantine is a moderate affinity N-methyl-D-aspartate receptor antagonist approved for treatment of Alzheimer's disease (AD). In AD, tau is abnormally hyperphosphorylated. However, no significant changes of phosphorylated tau levels in CSF are found at follow-up in studies with AD patients. It has been shown in vitro that memantine reverse induced abnormal hyperphosphorylation of tau in hippocampal neurons of rats. Methods: Eleven AD patients were examined with cognitive tests and interviews of relatives. CSF analyses were performed before starting treatment with memantine as well as after 1 year. Results: A statistically significant reduction of CSF phosphorylated tau at the 1-year follow-up was seen, from median 126 (interquartile range 107-153) to 108 (88-133) ng/l (p = 0.018). No statistically significant differences of total tau or A42 were found. Conclusion: The results may reflect effects of memantine on a key pathological feature in AD in line with previous in vitro findings.

  • 6.
    Degerman Gunnarsson, Malin
    et al.
    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.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Basun, Hans
    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.
    High Tau Levels in Cerebrospinal Fluid Predict Rapid Decline and Increased Dementia Mortality in Alzheimer's Disease2014In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 37, no 3-4, p. 196-206Article in journal (Refereed)
    Abstract [en]

    Objective: Cerebrospinal fluid (CSF) amyloid beta(42) (A beta(42)), total tau (t-tau) and phosphorylated tau (p-tau) are useful as predictors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. However, results are contradictory as to whether these biomarkers reflect the future rate of clinical decline. Methods: This is a retrospective study on 196 patients with AD [mild/moderate AD (n = 72) or AD-MCI (n = 124) at baseline] with a follow-up period of 2-9 years' duration (median 6 years). Lumbar punctures were performed at baseline as a part of the diagnostic procedure. Results: We found an increased risk of rapid cognitive decline defined as a drop in the Mini-Mental State Examination score of = 4 points/year in patients with CSF t-tau concentrations above the median (OR 3.31, 95% CI 1.53-7.16) and CSF p-tau above the median (OR 2.53, 95% CI 1.21-5.26). Patients with CSF t-tau in the highest quartile had a higher risk of dying in severe dementia (HR 4.67, 95% CI 1.16-18.82). Conclusions: In this large AD cohort, we found an association between high levels of CSF t-tau and p-tau and a more aggressive course of the disease, measured as a rapid cognitive decline and a higher risk of dying in severe dementia.

  • 7.
    Degerman Gunnarsson, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindau, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Santillo, A F
    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, H
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Basun, Hans
    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.
    Re-evaluation of clinical dementia diagnoses with pittsburgh compound B positron emission tomography2013In: Dementia and geriatric cognitive disorders extra, ISSN 1664-5464, Vol. 3, no 1, p. 472-481Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    There is an overlap regarding Pittsburgh compound B (PIB) retention in patients clinically diagnosed as Alzheimer's disease (AD) and non-AD dementia. The aim of the present study was to investigate whether there are any differences between PIB-positive and PIB-negative patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with [(18)F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET).

    METHODS:

    Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting.

    RESULTS:

    The PIB-positive patients (7 out of 18) had slower psychomotor speed and more impaired visual episodic memory than the PIB-negative patients; otherwise performance did not differ between the groups. The initial clinical diagnoses were changed in one third of the patients (6 out of 18) during follow-up.

    CONCLUSIONS:

    The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need for amyloid biomarkers and a readiness to re-evaluate the initial diagnosis.

  • 8.
    Eriksdotter, Maria
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Div Clin Geriatr, Huddinge, Sweden.;Karolinska Univ Hosp, Dept Geriatr Med, Huddinge, Sweden..
    Vedin, Inger
    Karolinska Inst, Div Hematol, Dept Med, Huddinge, Sweden..
    Falahati, Farshad
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Div Clin Geriatr, Huddinge, Sweden..
    Freund-Levi, Yvonne
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Div Clin Geriatr, Huddinge, Sweden..
    Hjorth, Erik
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Div Neurodegenerat, Huddinge, Sweden..
    Faxen-Irving, Gerd
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Div Clin Geriatr, Huddinge, Sweden..
    Wahlund, Lars-Olof
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Div Clin Geriatr, Huddinge, Sweden.;Karolinska Univ Hosp, Dept Geriatr Med, Huddinge, Sweden..
    Schultzberg, Marianne
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Div Neurodegenerat, Huddinge, Sweden..
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Palmblad, Jan
    Karolinska Inst, Div Hematol, Dept Med, Huddinge, Sweden..
    Plasma Fatty Acid Profiles in Relation to Cognition and Gender in Alzheimer's Disease Patients During Oral Omega-3 Fatty Acid Supplementation: The OmegAD Study2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 48, no 3, p. 805-812Article in journal (Refereed)
    Abstract [en]

    Background: omega 3 fatty acids (omega 3 FAs) may slow the rate of decline in cognitive performance in mild forms of cognitive impairment and Alzheimer's disease (AD). However, the relationship between changes of plasma omega 3 FA levels and cognitive performance, as well as effects of gender, are poorly known. Objective: To study the effect of 6-month administration of DHA-rich omega 3 FA supplementation on plasma FA profiles in patients with mild to moderate AD in relation to cognitive performance and gender. This investigation is part of the OmegAD Study. Methods: 174 AD patients (74 +/- 9 years) were randomized to a daily intake of 2.3g omega 3 FA or placebo for 6 months; subsequently all received the omega 3 FA preparation for the next 6 months. Baseline as well as changes in plasma levels of the main omega 3 FAs in 165 patients, while receiving omega 3 FA supplementation for 6 months, were analyzed for association to cognitive performance (assessed by ADAS-cog and MMSE scores) as well as to gender. Results: Preservation of cognitive functioning, assessed by ADAS-cog or its sub-items (but not MMSE) scores, was significantly associated to increasing plasma omega 3 FA levels over time. Thus, the higher omega 3 FA plasma levels rose, the lower was the rate of cognitive deterioration. This effect was not related to gender; since although females displayed higher omega 3 FA plasma levels than did males after 6 months of supplementation, this difference disappeared when adjusted for body weight. Conclusions: Since our study suggests dose-response relationships between plasma levels of omega 3 FA and preservation of cognition, future omega 3 FA trials in patients with mild AD should consider exploring graded (and body weight adjusted) doses of omega 3 FA.

  • 9.
    Faxen-Irving, Gerd
    et al.
    Karolinska Inst, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc NVS, Huddinge.
    Falahati, Farshad
    Karolinska Inst, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc NVS, Huddinge.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eriksdotter, Maria
    Karolinska Inst, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc NVS, Huddinge; Karolinska Univ Hosp, Dept Geriatr, Huddinge.
    Vedin, Inger
    Karolinska Inst, Dept NVS, Dept Med, Div Hematol, Huddinge.
    Wahlund, Lars-Olof
    Karolinska Inst, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc NVS, Huddinge; Karolinska Univ Hosp, Dept Geriatr, Huddinge.
    Schultzberg, Marianne
    Karolinska Inst, Div Neurodegenerat, Huddinge.
    Hjorth, Erik
    Karolinska Inst, Div Neurodegenerat, Huddinge.
    Palmblad, Jan
    Karolinska Inst, Dept NVS, Dept Med, Div Hematol, Huddinge.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Akad Sjukhuset, Dept Geriatr Med, Uppsala.
    Freund-Levi, Yvonne
    Karolinska Inst, Div Clin Geriatr, Dept Neurobiol Care Sci & Soc NVS, Huddinge; Karolinska Univ Hosp, Dept Geriatr, Huddinge.
    Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies?2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, no 2, p. 515-519Article in journal (Refereed)
    Abstract [en]

    Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer’s disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.

  • 10. Faxen-Irving, Gerd
    et al.
    Freund-Levi, Yvonne
    Eriksdotter-Jonhagen, Maria
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hjorth, Erik
    Palmblad, Jan
    Vedin, Inger
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Wahlund, Lars-Olof
    Effects on Transthyretin in Plasma and Cerebrospinal Fluid by DHA-Rich n-3 Fatty Acid Supplementation in Patients with Alzheimer's Disease: The OmegAD Study2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 36, no 1, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Transthyretin (TTR) binds amyloid-beta (A beta) and may reduce brain A beta, a pathological feature in Alzheimer's disease (AD). N - 3 fatty acids (FA), docosahexaenoic (DHA), and eicosapentaenoic acid (EPA) may increase TTR transcription in rat hippocampus. We studied effects of n - 3 FA supplementation on TTR-levels in patients with AD. Outpatients were randomized to receive 1.7 g DHA and 0.6 g EPA (n - 3/n - 3 group) or placebo (placebo/n - 3 group) during 6 months. After 6 months, all patients received n - 3 FA for another 6 months. TTR and FA were measured in plasma in all subjects, whereas TTR in cerebrospinal fluid (CSF) was measured in a subgroup. The study was completed by 89 patients in the n- 3/n - 3 group (75 y, 57% w) and 85 in the placebo/n - 3 group (75 y, 46% w). Baseline plasma - TTR was within normal range in both groups. After 6 months, plasma - TTR decreased in the placebo/n - 3 group (p < 0.001 within and p < 0.015 between the groups). No changes were observed in CSF TTR. From 6 to 12 months when both groups were supplemented, plasma - TTR increased significantly in both groups. Repeated measures ANOVA indicated an increase in TTR over time (p = 0.04) in those receiving n - 3 FA for 12 months. By linear regression analyses, n - 3 FA treatment was independently associated with increased plasma - TTR at 6 months (beta = -0.172, p = 0.028). Thus, n - 3 FA treatment appeared to increase plasma-TTR in patients with AD. Since TTR may influence A beta deposition in the brain, the results warrant further exploration.

  • 11. Faxén-Irving, G
    et al.
    Andrén-Olsson, B
    af Geijerstam, A
    Basun, H
    Cederholm, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    The effect of nutritional intervention in elderly subjects residing in group-living for the demented.2002In: Eur J Clin Nutr, ISSN 0954-3007, Vol. 56, no 3, p. 221-7Article in journal (Other scientific)
  • 12. Faxén-Irving, G
    et al.
    Andrén-Olsson, B
    Geijerstam, A
    Basun, H
    Cederholm, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Nutrition education for care staff and possible effects on nutritional status in residents of sheltered accommodation.2005In: Eur J Clin Nutr, ISSN 0954-3007, Vol. 59, no 8, p. 947-54Article in journal (Refereed)
  • 13. Faxén-Irving, Gerd
    et al.
    Basun, Hans
    Cederholm, Tommy
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Nutritional and cognitive relationships and long-term mortality in patients with various dementia disorders.2005In: Age Ageing, ISSN 0002-0729, Vol. 34, no 2, p. 136-41Article in journal (Refereed)
  • 14. Freund Levi, Y
    et al.
    Vedin, I
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Faxén Irving, G
    Eriksdotter, M
    Hjorth, E
    Schultzberg, M
    Vessby, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Wahlund, L-O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Salem, N
    Palmblad, J
    Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 4, p. 428-436Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Little is known about the transfer of essential fatty acids (FAs) across the human blood-brain barrier (BBB) in adulthood. In this study, we investigated whether oral supplementation with omega-3 (n-3) FAs would change the FA profile of the cerebrospinal fluid (CSF).

    METHODS: A total of 33 patients (18 receiving the n-3 FA supplement and 15 receiving placebo) were included in the study. These patients were participants in the double-blind, placebo-controlled randomized OmegAD study in which 204 patients with mild Alzheimer's disease (AD) received 2.3 g n-3 FA [high in docosahexaenoic acid (DHA)] or placebo daily for 6 months. CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation.

    RESULTS: At 6 months, the n-3 FA supplement group displayed significant increases in CSF (and plasma) eicosapentaenoic acid (EPA), DHA and total n-3 FA levels (P < 0.01), whereas no changes were observed in the placebo group. Changes in CSF and plasma levels of EPA and n-3 docosapentaenoic acid were strongly correlated, in contrast to those of DHA. Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau, and directly correlated with soluble interleukin-1 receptor type II. Thus, the more DHA increased in CSF, the greater the change in CSF AD/inflammatory biomarkers.

    CONCLUSIONS: Oral supplementation with n-3 FAs conferred changes in the n-3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults.

  • 15. Freund-Levi, Yvonne
    et al.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Faxén-Irving, Gerd
    Garlind, Anita
    Grut, Mikaela
    Vedin, Inger
    Palmblad, Jan
    Wahlund, Lars-Olof
    Eriksdotter-Jönhagen, Maria
    Omega-3 supplementation in mild to moderate Alzheimer's disease: effects on neuropsychiatric symptoms2008In: International Journal of Geriatric Psychiatry, ISSN 0885-6230, E-ISSN 1099-1166, Vol. 23, no 2, p. 161-169Article in journal (Refereed)
    Abstract [en]

    Background: Epidemiological and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids (ω3), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may have effects in psychiatric and behavioral symptoms in Alzheimer's disease (AD). An association with APOEω4 carriers and neuropsychiatric symptoms in AD has also been suggested. Objective: To determine effects of dietary ω3 supplementation to AD patients with mild to moderate disease on psychiatric and behavioral symptoms, daily functions and a possible relation to APOEgenotype. Methods: Randomized, double-blind, placebo-controlled clinical trial where 204 AD patients (74 ± 9 years) with acetylcholine esterase inhibitor treatment and a MMSE >15 points were randomized to daily intake of 1.7 g DHA and 0.6 g EPA (ω3 group) or placebo for 6 months. Then, all received the ω3 supplementation for 6 more months. Neuropsychiatric symptoms were measured with Neuropsychiatric Inventory (NPI) and Montgomery Åsberg Depression Scale (MADRS). Caregivers burden and activities of daily living (Disability Assessment for Dementia, DAD) were also assessed. Results: One hundred and seventy-four patients fulfilled the trial. 72% were APOEω4 carriers. No significant overall treatment effects on neuropsychiatric symptoms, on activities of daily living or on caregiver's burden were found. However, significant positive treatment effects on the scores in the NPI agitation domain in APOEω4 carriers (p = 0.006) and in MADRS scores in non-APOEω4 carriers (p = 0.005) were found. Conclusions: Supplementation with ω3 in patients with mild to moderate AD did not result in marked effects on neuropsychiatric symptoms except for possible positive effects on depressive symptoms (assessed by MADRS) in non-APOEω4 carriers and agitation symptoms (assessed by NPI) in APOEω4 carriers. ClinicalTrials.gov identifier: NCT00211159.

  • 16. Freund-Levi, Yvonne
    et al.
    Eriksdotter-Jonhagen, Maria
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Faxén-Irving, Gerd
    Garlind, Anita
    Vedin, Inger
    Vessby, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Wahlund, Lars-Olof
    Palmblad, Jan
    Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study - A randomized double-blind trial2006In: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 63, no 10, p. 1402-1408Article in journal (Refereed)
    Abstract [en]

    Background: Epidemiologic and animal studies have suggested that dietary fish or fish oil rich in omega-3 fatty acids, for example, docosahexaenoic acid and eicosapentaenoic acid, may prevent Alzheimer disease (AD).

    Objective: To determine effects of dietary omega-3 fatty acid supplementation on cognitive functions in patients with mild to moderate AD.

    Design: Randomized, double-blind, placebo-controlled clinical trial.

    Participants: Two hundred four patients with AD (age range [mean +/- SD], 74 +/- 9 years) whose conditions were stable while receiving acetylcholine esterase inhibitor treatment and who had a Mini-Mental State Examination (MMSE) score of 15 points or more were randomized to daily intake of 1.7 g of docosahexaenoic acid and 0.6 g of eicosapentaenoic acid (omega-3 fatty acid-treated group) or placebo for 6 months, after which all received omega-3 fatty acid supplementation for 6 months more.

    Main Outcome Measures: The primary outcome was cognition measured with the MMSE and the cognitive portion of the Alzheimer Disease Assessment Scale. The secondary outcome was global function as assessed with the Clinical Dementia Rating Scale; safety and tolerability of omega-3 fatty acid supplementation; and blood pressure determinations.

    Results: One hundred seventy-four patients fulfilled the trial. At baseline, mean values for the Clinical Dementia Rating Scale, MMSE, and cognitive portion of the Alzheimer Disease Assessment Scale in the 2 randomized groups were similar. At 6 months, the decline in cognitive functions as assessed by the latter 2 scales did not differ between the groups. However, in a subgroup (n=32) with very mild cognitive dysfunction (MMSE > 27 points), a significant (P <.05) reduction in MMSE decline rate was observed in the omega-3 fatty acid-treated group compared with the placebo group. A similar arrest in decline rate was observed between 6 and 12 months in this placebo subgroup when receiving omega-3 fatty acid supplementation. The omega-3 fatty acid treatment was safe and well tolerated.

    Conclusions: Administration of omega-3 fatty acid in patients with mild to moderate AD did not delay the rate of cognitive decline according to the MMSE or the cognitive portion of the Alzheimer Disease Assessment Scale. However, positive effects were observed in a small group of patients with very mild AD (MMSE > 27 points).

  • 17. Freund-Levi, Yvonne
    et al.
    Vedin, Inger
    Hjorth, Erik
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Irving, Gerd Faxen
    Schultzberg, Marianne
    Eriksdotter, Maria
    Palmblad, Jan
    Vessby, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Wahlund, Lars-Olof
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Effects of Supplementation with Omega-3 Fatty Acids on Oxidative Stress and Inflammation in Patients with Alzheimer's Disease: The OmegAD Study2014In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 42, no 3, p. 823-831Article in journal (Refereed)
    Abstract [en]

    Background: Oxidative stress and inflammation are two key mechanisms suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Omega-3 fatty acids (omega-3 FAs) found in fish and fish oil have several biological properties that may be beneficial in AD. However, they may also auto-oxidize and induce in vivo lipid peroxidation. Objective: The objective of this study was to evaluate systemic oxidative stress and inflammatory biomarkers following oral supplementation of dietary omega-3 FA. Methods: Forty patients with moderate AD were randomized to receive 1.7 g DHA (22:6) and 0.6 g EPA (20:5) or placebo for 6 months. Urinary samples were collected before and after supplementation. The levels of the major F-2-isoprostane, 8-iso-PGF(2 alpha) a consistent in vivo biomarker of oxidative stress, and 15-keto-dihydro-PGF(2 alpha), a major metabolite of PGF(2 alpha) and biomarker of inflammatory response, were measured. Results: F-2-isoprostane in urine increased in the placebo group after 6 months, but therewas no clear difference in treatment effect between supplemented and non-supplemented patients on the urinary levels of F-2-isoprostanes and 15-keto-dihydro-PGF(2 alpha). At baseline, the levels of 15-keto-dihydro-PGF(2 alpha) showed negative correlative relationships to omega-3 FAs, and a positive correlation to linoleic acid. 8-iso-PGF(2 alpha) correlated negatively to the omega-6 FA arachidonic acid. Conclusion: The findings indicate that supplementation of omega-3 FAs to patients with AD for 6 months does not have a clear effect on free radical-mediated formation of F-2-isoprostane or cyclooxygenase-mediated formation of prostaglandin F-2 alpha. The correlative relationships to FAs indicate a potential role of FAs in immunoregulation.

  • 18.
    Froelich-Fabre, Susanne
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Skoglund, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ostojic, Jovanka
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Kilander, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lindau, Maria
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Glaser, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Basun, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lannfelt, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Clinical and molecular aspects of frontotemporal dementia.2004In: Neurodegener Dis, ISSN 1660-2854, Vol. 1, no 4-5, p. 218-24Article in journal (Refereed)
  • 19.
    Gunnarsson, Malin Degerman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Blennow, Kaj
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Neurosci & Physiol, Clin Neurochem Lab, SE-43180 Molndal, Sweden..
    Basun, Hans
    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.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease2016In: Alzheimer's Research & Therapy, E-ISSN 1758-9193, Vol. 8, article id 22Article in journal (Refereed)
    Abstract [en]

    Background: Increased concentrations of cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau, as well as decreased amyloid-beta 42 peptide, are biomarkers of Alzheimer's disease (AD) pathology, but few studies have shown an association with AD progression rate. We hypothesized that high CSF tau, as a marker of ongoing neurodegeneration, would predict a more aggressive course of AD, using time to nursing home placement (NHP) as the main outcome. Methods: Our sample inlcuded 234 patients with mild cognitive impairment (MCI) due to AD (n = 134) or mild to moderate AD (n = 100) who underwent lumbar puncture at a memory clinic and were followed for 2-11 years (median 4.9 years). Results: Individuals with CSF t-tau in the highest quartile (>= 900 ng/L) had a higher ratio of NHP, both in the total cohort and in patients with MCI only (adjusted HR 2.17 [95 % CI 1.24-3.80]; HR 2.37 [95 % CI 1.10-5.09], respectively), than the lowest quartile. The association between high t-tau levels and future steep deterioration was confirmed in analyses with conversion to moderate dementia (HR 1.66; 95 % CI 1.08-2.56), rapid decline in Mini Mental State Examination score (>= 4-point drop/12 months), and dying in severe dementia as outcomes. Conclusions: To our knowledge, this is the first study to show that high CSF t-tau levels predict early NHP and conversion to moderate dementia in an AD cohort. Selecting patients with high CSF t-tau, indicating more aggressive neurodegeneration and steeper decline, for AD immunotherapy trials might increase the possibility of showing contrast between active treatment and placebo.

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  • 20. Hjorth, Erik
    et al.
    Zhu, Mingqin
    Toro, Veronica Cortes
    Vedin, Inger
    Palmblad, Jan
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Freund-Levi, Yvonne
    Faxen-Irving, Gerd
    Wahlund, Lars-Olof
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eriksdotter, Maria
    Schultzberg, Marianne
    Omega-3 Fatty Acids Enhance Phagocytosis of Alzheimer's Disease-Related Amyloid-beta(42) by Human Microglia and Decrease Inflammatory Markers2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 35, no 4, p. 697-713Article in journal (Refereed)
    Abstract [en]

    The use of supplements withomega-3 (omega 3) fatty acids (FAs) such as docosahexaenoic acid(DHA) and eicosapentaenoic acid (EPA) is widespread due to proposed beneficial effects on the nervous and cardiovascular systems. Many effects of omega 3 FAs are believed to be caused by down-regulation and resolution of inflammation. Alzheimer's disease (AD) is associated with inflammation mediated by microglia and astrocytes, and omega 3 FAs have been proposed as potential treatments for AD. The focus of the present study is on the effects of DHA and EPA on microglial phagocytosis of the AD pathogen amyloid-beta(A beta), on secreted and cellular markers of immune activity, and on production of brain-derived neurotrophic factor (BDNF). Human CHME3 microglial cells were exposed to DHA or EPA, with or without the presence of A beta(42). Phagocytosis of A beta(42) was analyzed by flow cytometry in conjunction with immunocytochemistry using antibodies to cellular proteins. Secreted proteins were analyzed by ELISA. Both DHA and EPA were found to stimulate microglial phagocytosis of A beta(42). Phagocytosis of A beta(42) was performed by microglia with a predominance of M2 markers. EPA increased the levels of BDNF in the culture medium. The levels of TNF-alpha were decreased by DHA. Both DHA and EPA decreased the pro-inflammatory M1 markers CD40 and CD86, and DHA had a stimulatory effect on the anti-inflammatory M2 marker CD206. DHA and EPA can be beneficial in AD by enhancing removal of A beta(42), increasing neurotrophin production, decreasing pro-inflammatory cytokine production, and by inducing a shift in phenotype away from pro-inflammatory M1 activation.

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  • 21. Höglund, Kina
    et al.
    Bogstedt, Anna
    Fabre, Susanne
    Aziz, Ali
    Annas, Peter
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Minthon, Lennart
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Blennow, Kaj
    Andreasen, Niels
    Longitudinal Stability Evaluation of Biomarkers and Their Correlation in Cerebrospinal Fluid and Plasma from Patients with Alzheimer's Disease2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 32, no 4, p. 939-947Article in journal (Refereed)
    Abstract [en]

    There is an increasing demand for biomarkers in clinical treatment trials to demonstrate target engagement and to support disease modification claims. To be able to detect treatment related effects, a prerequisite is that the levels of the biomarker are stable over time or that the change over time is known. In the present study, the stability of alpha- and beta-cleaved soluble amyloid-beta protein precursor (sA beta PP alpha and sA beta PP beta), A beta(1-40) together with the phosphorylated form of neurofilament heavy/medium (pNfH/M) in cerebrospinal fluid (CSF) was analyzed in a cohort of 51 patients with Alzheimer's disease. In addition, the stability of A beta(1-40), beta(1-42), and sA beta PP beta in plasma was explored. Plasma and CSF was sampled at baseline and after 6-months follow up, and all patients were on stable treatment with acetylcholinesterase inhibitors. During this 6-month longitudinal follow-up, we saw a small, but consistent and statistically significant increase in CSF levels of sA beta PP beta (103% of baseline levels) and a statistically significant decrease in the CSF levels of pNfH/M (91% of baseline levels). The mean level of the CSF biomarkers were very stable between baseline and endpoint, with within-patients coefficients of variation (CVs) of 5.84-17.3%, while the variability was larger for the plasma biomarkers, with CVs of 14.1-42.3%. This stability suggests that these biomarkers may have the potential to detect and monitor biochemical changes induced by disease-modifying drugs.

  • 22.
    Ingelsson, Martin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Nilsson, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Basun, Hans
    Aquilonius, Sten-Magnus
    Department of Neuroscience. neurologi.
    Lannfelt, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Konformationsförändrade proteiner orsakar neurodegenerativa sjukdomar2005In: Läkartidningen, Vol. 102, no 47, p. 3542-3551Article in journal (Other (popular scientific, debate etc.))
  • 23.