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  • 1.
    Adlerz, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Beckman, Marie
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Holback, Sofia
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Tehranian, Roya
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Cortés Toro, Veronica
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Accumulation of the amyloid precursor-like protein APLP2 and reduction of APLP1 in retinoic acid-differentiated human neuroblastoma cells upon curcumin-induced neurite retraction2003In: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 119, no 1, p. 62-72Article in journal (Refereed)
    Abstract [en]

    Amyloid precursor protein (APP) belongs to a conserved gene family, also including the amyloid precursor-like proteins, APLP1 and APLP2. The function of these three proteins is not yet fully understood. One of the proposed roles of APP is to promote neurite outgrowth. The aim of this study was to investigate the regulation of the expression levels of APP family members during neurite outgrowth. We observed that retinoic acid (RA)-induced neuronal differentiation of human SH-SY5Y cells resulted in increased expression of APP, APLP1 and APLP2. We also examined the effect of the NFκB, AP-1 and c-Jun N-terminal kinase inhibitor curcumin (diferuloylmethane) on the RA-induced expression levels of these proteins. We found that treatment with curcumin counteracted the RA-induced mRNA expression of all APP family members. In addition, we observed that curcumin treatment resulted in neurite retraction without any effect on cell viability. Surprisingly, curcumin had differential effects on the APLP protein levels in RA-differentiated cells. RA-induced APLP1 protein expression was blocked by curcumin, while the APLP2 protein levels were further increased. APP protein levels were not affected by curcumin treatment. We propose that the sustained levels of APP and the elevated levels of APLP2, in spite of the reduced mRNA expression, are due to altered proteolytic processing of these proteins. Furthermore, our results suggest that APLP1 does not undergo the same type of regulated processing as APP and APLP2.

  • 2.
    Adlerz, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Soomets, Ursel
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology. University of Tartu, Estonia.
    Holmlund, Linda
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Virland, Saade
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Iverfeldt, Kerstin
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Down-regulation of amyloid precursor protein by peptide nucleic acid oligomer in cultured rat primary neurons and astrocytes2003In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 336, no 1, p. 55-59Article in journal (Refereed)
    Abstract [en]

    The amyloid precursor protein (APP) and its proteolytic cleavage products, the amyloid P peptides, have been implicated as a cause of Alzheimer's disease. Peptide nucleic acids (PNA), the DNA mimics, have been shown to block the expression of specific proteins at both transcriptional and translational levels. Generally, the cellular uptake of PNA is low. However, recent studies have indicated that the effect of unmodified antisense PNA uptake is more pronounced in nervous tissue. In this study we have shown that biotinylated PNA directed to the initiator codon region of the APP mRNA (-4 - +11) was taken up into the cytoplasm of primary rat cerebellar granule cells and cortical astrocytes, using fluorescence and confocal microscopy studies. Uptake of PNA was faster in neurons than in astrocytes. Western blotting analysis showed that APP was strongly down-regulated in both neurons and astrocytes. Thus, unmodified PNA can be used for studies on the function of APP in neurons and astrocytes.

  • 3.
    Ahrén-Moonga, Jennie
    et al.
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    von Blixten, Nils
    Rönnelid, Johan
    Holmgren, Sven
    af Klinteberg, Britt
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Levels of tumour necrosis factor-alpha and interleukin-6 in severely ill patients with eating disorders2011In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 63, no 1, p. 8-14Article in journal (Refereed)
    Abstract [en]

    Background: The underlying pathophysiology of eating disorders (ED) is dependent on complex interactions between psychological, biological and social factors. The purpose of the present study was to examine a possible increase in cytokines indicating inflammation, as measured by tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in ED patients, and to explore possible relationships between cytokines and self-reported personality traits. Methods: Female patients with severe ED (n = 26) were recruited consecutively from an inpatient clinic and were compared to age-matched healthy females (n = 12). Commercial ELISA tests developed for the measurement of serum levels of TNF-α and IL-6 were employed. Personality traits were measured using Karolinska Scales of Personality. Results: The patient group displayed increased levels of the cytokine TNF-α and a tendency towards increased IL-6 levels. Spearman's rank correlation coefficient was used to examine possible relationships between levels of cytokines and personality traits. The results showed that IL-6 levels were positively related to both somatic and psychic anxiety and to aggression scales, such as irritability and suspicion. Increased levels of TNF-α, in turn, were significantly correlated with high scores on the depression-related anxiety scale Inhibition of Aggression. However, increased levels of cytokines in the ED group did not seem to be mainly associated with symptoms of depression. Conclusion: We cannot rule out the possibility that comorbid conditions in the group contribute to the higher cytokine values. Further studies need to explore the possible influence of cytokines on the severity of ED and whether this might be mediated or moderated by specific personality traits.

  • 4. Albrecht, Daniel S.
    et al.
    Forsberg, Anton
    Sandstrom, Angelica
    Bergan, Courtney
    Kadetoff, Diana
    Protsenko, Ekaterina
    Lampa, Jon
    Lee, Yvonne C.
    Hoglund, Caroline Olgart
    Catana, Ciprian
    Cervenka, Simon
    Akeju, Oluwaseun
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden.
    Cohen, George
    Halldin, Christer
    Taylor, Norman
    Kim, Minhae
    Hooker, Jacob M.
    Edwards, Robert R.
    Napadow, Vitaly
    Kosek, Eva
    Loggia, Marco L.
    Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation2019In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 75, p. 72-83Article in journal (Refereed)
    Abstract [en]

    Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C-11]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C-11]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C-11]PBR28 PET. 11 FM patients and 11 HC were scanned using [C-11]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V-T) were computed from the [C-11]PBR28 data. [C-11]-L-deprenyl-D2 was quantified using lambda k(3). PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C-11]PBR28 ITT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C-11]-L-deprenyl-Ds signal, including those demonstrating elevated [C-11] PBR28 signal in patients (p's >= 0.53, uncorrected). The elevations in [C-11]PBR28 V-T and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C-11] PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C-11]PBR28 signal were not also accompanied by increased [C-11]-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C-11]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.

  • 5.
    Andreasson, Anna N.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Schiller, Helena
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Contemplate your symptoms and re-evaluate your health2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, p. e38-e39Article in journal (Refereed)
    Abstract [en]

    Bodily signals and how these are interpreted affect self-ratings of health. It is thus reasonable that appraisals of health are affected by imminent exposures and disease primes. We aimed to investigate whether self-ratings of health are affected by a symptom rating and if changes are substantiated in persons who report more symptoms. We used data from 813 persons who completed a questionnaire daily for 21 consecutive days. The questionnaire included a one-item self-rating of health (“pre-SRH”; 1 = excellent, 7 = very poor), a subsequent 26-item rating of physical and mental symptoms and thereafter a second (identical) self-rating of health (“post-SRH”). Paired t-tests were used to test for differences between pre-SRH and post-SRH. Mixed effect regression models were used to calculate the interaction effect of pre-SRH and symptom score on post-SRH adjusted for gender, age and if the person had been working that day (13545 observations). SRH worsened significantly (p  <<.0001) after the symptom rating, from 2.72 pre-SRH (95%CI:−2.70–2.74) to 2.77 post-SRH (95%CI:2.75–2.79). There was a significant interaction between pre-SRH and symptoms on post-SRH so that persons who reported more symptoms changed their post-SRH rating to a higher degree than those who reported fewer symptoms, irrespective of their subjective health status. The results support the notion that subjective health perception is affected by focus of attention, and that the effect depends on level of symptoms.

  • 6.
    Bellander, Martin
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Berggren, Rasmus
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Mårtensson, Johan
    Brehmer, Yvonne
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Wenger, Elisabeth
    Li, Tie-Qiang
    Bodammer, Nils C.
    Shing, Yee-Lee
    Werkle-Bergner, Markus
    Lövdén, Martin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Behavioral correlates of changes in hippocampal gray matter structure during acquisition of foreign vocabulary2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 131, p. 205-213Article in journal (Refereed)
    Abstract [en]

    Experience can affect human gray matter volume. The behavioral correlates of individual differences in such brain changes are not well understood. In a group of Swedish individuals studying Italian as a foreign language, we investigated associations among time spent studying, acquired vocabulary, baseline performance on memory tasks, and gray matter changes. As a way of studying episodic memory training, the language learning focused on acquiring foreign vocabulary and lasted for 10 weeks. T-1-weighted structural magnetic resonance imaging and cognitive testing were performed before and after the studies. Learning behavior was monitored via participants' use of a smartphone application dedicated to the study of vocabulary. A whole-brain analysis showed larger changes in gray matter structure of the right hippocampus in the experimental group (N = 33) compared to an active control group (N = 23). A first path analyses revealed that time spent studying rather than acquired knowledge significantly predicted change in gray matter structure. However, this association was not significant when adding performance on baseline memory measures into the model, instead only the participants' performance on a short-term memory task with highly similar distractors predicted the change. This measure may tap similar individual difference factors as those involved in gray matter plasticity of the hippocampus.

  • 7. Bergendal, G.
    et al.
    Martola, J.
    Stawiarz, L.
    Kristoffersen-Wiberg, M.
    Fredrikson, S.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Callosal atrophy in multiple sclerosis is related to cognitive speed2013In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 127, no 4, p. 281-289Article in journal (Refereed)
    Abstract [en]

    Bergendal G, Martola J, Stawiarz L, Kristoffersen-Wiberg M, Fredrikson S, Almkvist O. Callosal atrophy in multiple sclerosis is related to cognitive speed. Acta Neurol Scand: 2013: 127: 281-289. (C) 2012 John Wiley & Sons A/S. Background Long-term changes regarding corpus callosum area (CCA) and information processing speed in cognitive and sensory-motor tasks have rarely been studied in multiple sclerosis (MS). Objective and methods Information processing speed in cognitive (Symbol Digit Modalities Test, SDMT), sensory (visual and auditory reaction time) and motor (finger-tapping speed, FT; right and left hand) tasks as well as auditory inter-hemispheric transfer (verbal dichotic listening, VDL) was related to CCA, measured by MRI at baseline and at follow-up after nine years in 22 patients with MS. Possible confounding by demographic (age, gender and education), clinical (symptom onset, duration, severity of disease) and relative brain volume (RBV) as well as T2 lesion load was taken into account. Results The smaller the CCA at baseline, the slower was SDMT performance at baseline. In a similar way, CCA at follow-up was associated with poor SDMT result at follow-up. Furthermore, the higher the annual rate of change in CCA, the poorer was performance in VDL on the left ear and the more pronounced was the right ear advantage. A positive relationship between performance in VDL right ear and annual rate of change in RBV was also seen. Sensory-motor tests were not significantly associated with CCA. T2 lesion load at baseline was associated with FT performance at baseline. Demographic, clinical and radiological (RBV and T2 lesion load) characteristics did not confound the significant relation between CCA and SDMT. Conclusions CCA unlike RBV and T2 lesion load was associated with SDMT, which indicated a marked cognitive rather than perceptual-motor component.

  • 8.
    Berglund, Birgitta
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Höglund, Anders
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Esfandabad, Hassan Shams
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    A bisensory method for odor and irritation detection of formaldehyde and pyridine2012In: CHEMOSENS PERCEPT, ISSN 1936-5802, Vol. 5, no 2, p. 146-157Article in journal (Refereed)
    Abstract [en]

    A bisensory method was developed for determining the psychometric functions and absolute thresholds for odor and sensory irritation of two odorous irritants. Individual and group thresholds for formaldehyde or pyridine were measured for 31 age-matched subjects (18-35 years old). P (50) absolute thresholds were for formaldehyde odor 110 ppb (range 23-505), for pyridine odor 77 ppb (range 20-613), and for pyridine irritation 620 ppb (range 90-3,656); too few subjects' formaldehyde irritation thresholds were possible to determine (human exposures limited to 1 ppm). In spite of large interindividual differences, all thresholds for irritation were higher than for odor. The average slopes of the 62 psychometric functions for odor and the 32 possible for sensory irritation were highest for formaldehyde odor (83% per log ppb) and equal for pyridine odor and irritation (68% per log ppb). The bisensory method for measuring odor and sensory irritation jointly produced detection functions and absolute thresholds compatible with those earlier published; however, a steeper slope for sensory irritation than odor was expected for pyridine. The bisensory method is intended for measuring odor and sensory irritation to broadband mixtures and dynamic exposures, like indoor air.

  • 9. Besga, A.
    et al.
    Cedazo-Minguez, A.
    Kåreholt, I.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Solomon, A.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Björkhem, I.
    Winblad, B.
    Leoni, V.
    Hooshmand, B.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Spulber, G.
    Gonzalez-Pinto, A.
    Kivipelto, M.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wahlund, L. O.
    Differences in brain cholesterol metabolism and insulin in two subgroups of patients with different CSF biomarkers but similar white matter lesions suggest different pathogenic mechanisms2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 510, no 2, p. 121-126Article in journal (Refereed)
    Abstract [en]

    Investigate possible associations of white matter hyperintensities (WMHs) with the metabolism of cholesterol and insulin in two subgroups of patients with memory complaints and different CSF A beta 42 and CSF tau levels. 59 patients from the memory clinic at Karolinska Hospital were included. Degree of WMHs was rated using the ARWMC scale and the following biomarkers were measured in CSF and plasma: insulin, cholesterol, lanosterol, lathosterol, and oxidized cholesterol metabolites. The WMHs in CSF control-like group correlated with increased brain cholesterol synthesis and reduced efflux of oxysterols and insulin in CSF. In the CSF AD-like group, the WMHs correlated with increased peripheral cholesterol metabolism. Despite having similar appearance on FLAIR images, the pathogenic mechanisms of WMHS are likely to be different in the two groups investigated.

  • 10. Blix, Eva
    et al.
    Perski, Aleksander
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Berglund, Hans
    Savic, Ivanka
    Long-Term Occupational Stress Is Associated with Regional Reductions in Brain Tissue Volumes2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, article id e64065Article in journal (Refereed)
    Abstract [en]

    There are increasing reports of cognitive and psychological declines related to occupational stress in subjects without psychiatric premorbidity or major life trauma. The underlying neurobiology is unknown, and many question the notion that the described disabilities represent a medical condition. Using PET we recently found that persons suffering from chronic occupational stress had limbic reductions in the 5-HT1A receptor binding potential. Here we examine whether chronic work-related stress is also associated with changes in brain structure. We performed MRI-based voxel-based morphometry and structural volumetry in stressed subjects and unstressed controls focusing on gray (GM) and white matter (WM) volumes, and the volumes of hippocampus, caudate, and putamen - structures known to be susceptible to neurotoxic changes. Stressed subjects exhibited significant reductions in the GM volumes of the anterior cingulate cortex and the dorsolateral prefrontal cortex. Furthermore, their caudate and putamen volumes were reduced, and the volumes correlated inversely to the degree of perceived stress. Our results add to previous data on chronic psychosocial stress, and indicate a morphological involvement of the frontostriatal circuits. The present findings of morphological changes in these regions confirm our previous conclusion that symptoms from occupational stress merit careful investigations and targeted treatment.

  • 11. Boraxbekk, Carl-Johan
    et al.
    Lundquist, Anders
    Nordin, Annelie
    Nyberg, Lars
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Adolfsson, Rolf
    Free Recall Episodic Memory Performance Predicts Dementia Ten Years prior to Clinical Diagnosis: Findings from the Betula Longitudinal Study2015In: Dementia and geriatric cognitive disorders extra, E-ISSN 1664-5464, Vol. 5, no 2, p. 191-202Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Early dementia diagnosis is a considerable challenge. The present study examined the predictive value of cognitive performance for a future clinical diagnosis of late-onset Alzheimer's disease or vascular dementia in a random population sample. Methods: Cognitive performance was retrospectively compared between three groups of participants from the Betula longitudinal cohort. Group 1 developed dementia 11-22 years after baseline testing (n = 111) and group 2 after 1-10 years (n = 280); group 3 showed no deterioration towards dementia during the study period (n = 2,855). Multinomial logistic regression analysis was used to investigate the predictive value of tests reflecting episodic memory performance, semantic memory performance, visuospatial ability, and prospective memory performance. Results: Age-and education-corrected performance on two free recall episodic memory tests significantly predicted dementia 10 years prior to clinical diagnosis. Free recall performance also predicted dementia 11-22 years prior to diagnosis when controlling for education, but not when age was added to the model. Conclusion: The present results support the suggestion that two free recall-based tests of episodic memory function may be useful for detecting individuals at risk of developing dementia 10 years prior to clinical diagnosis.

  • 12.
    Brehmer, Yvonne
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Shing, Yee Lee
    Heekeren, Hauke R.
    Lindenberger, Ulman
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Training-induced changes in subsequent-memory effects: No major differences among children, younger adults, and older adults2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 131, p. 214-225Article in journal (Refereed)
    Abstract [en]

    The neural correlates of encoding mode, or the state of forming new memory episodes, have been found to change with age and mnemonic training. However, it is unclear whether neural correlates of encoding success, termed subsequent-memory (SM) effects, also differ by age and mnemonic skill. In a multi-session training study, we investigated whether SM effects are altered by instruction and training in a mnemonic skill, and whether such alterations differ among children, younger adults, and older adults. Before and after strategy training, fMRI data were collected while participants were memorizing word pairs. In all age groups, participants receiving training showed greater performance gains than control group participants. Analysis of task-relevant regions showed training-induced reductions in SM effects in left frontal regions. Reductions in SM effects largely generalized across age and primarily reflected greater training-induced activation increases for omissions than for remembered items, indicating that training resulted in more consistent use of the mnemonic strategy. The present results reveal no major age differences in SM effects in children, younger adults, and older adults.

  • 13.
    Carlbring, Per
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Hägglund, Malin
    Umeå universitet.
    Luthström, Anne
    Umeå universitet.
    Dahlin, Mats
    Kadowaki, Åsa
    Vernmark, Kristofer
    Andersson, Gerhard
    Linköpings universitet/Karolinska Institutet.
    Internet-based behavioral activation and acceptance-based treatment for depression: a randomized controlled trial2013In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 148, no 2-3, p. 331-337Article in journal (Refereed)
    Abstract [en]

    Background

    Internet-based cognitive behavior therapy for depression has been tested in several trials but there are no internet studies on behavioral activation (BA), and no studies on BA over the internet including components of acceptance and commitment therapy (ACT). The aim of this study was to develop and test the effects of internet-delivered BA combined with ACT against a waiting list control condition as a first test of the effects of treatment.

    Methods

    Selection took place with a computerized screening interview and a subsequent semi-structured telephone interview. A total of 80 individuals from the general public were randomized to one of two conditions. The treatment lasted for 8 weeks after which both groups were assessed. We also included a 3 month follow-up. The treatment included interactive elements online and a CD-ROM for mindfulness and acceptance exercises. In addition, written support and feedback was given by a therapist every week.

    Results

    Results at posttreatment showed a large between group effect size on the Beck Depression inventory IId=0.98 (95%CI=0.51–1.44). In the treated group 25% (10/40) reached remission defined as a BDI score≤10 vs. 5% (2/40) in the control group. Results on secondary measures were smaller. While few dropped out from the study (N=2) at posttreatment, the average number of completed modules was M=5.1 out of the seven modules.

    Limitations

    The study only included a waiting-list comparison and it is not possible to determine which treatment components were the most effective.

    Conclusions

    We conclude that there is initial evidence that BA with components of ACT can be effective in reducing symptoms of depression.

  • 14. Carter, Stephen F.
    et al.
    Schöll, Michael
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Wall, Anders
    Engler, Henry
    Långström, Bengt
    Nordberg, Agneta
    Evidence for Astrocytosis in Prodromal Alzheimer Disease Provided by C-11-Deuterium-L-Deprenyl: A Multitracer PET Paradigm Combining C-11-Pittsburgh Compound B and F-18-FDG2012In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 53, no 1, p. 37-46Article in journal (Refereed)
    Abstract [en]

    Astrocytes colocalize with fibrillar amyloid-beta (A beta) plaques in postmortem Alzheimer disease (AD) brain tissue. It is therefore of great interest to develop a PET tracer for visualizing astrocytes in vivo, enabling the study of the regional distribution of both astrocytes and fibrillar A beta. A multitracer PET investigation was conducted for patients with mild cognitive impairment (MCI), patients with mild AD, and healthy controls using C-11-deuterium-L-deprenyl (C-11-DED) to measure monoamine oxidase B located in astrocytes. Along with C-11-DED PET, C-11-Pittsburgh compound B (C-11-PIB; fibrillar A beta deposition), F-18-FDG (glucose metabolism), T1 MRI, cerebrospinal fluid, and neuropsychologic data were acquired from the patients. Methods: C-11-DED PET was performed in MCI patients (n = 8; mean age 6 SD, 62.6 +/- 7.5 y; mean Mini Mental State Examination, 27.5 +/- 2.1), AD patients (n = 7; mean age, 65.1 +/- 6.3 y; mean Mini Mental State Examination, 24.4 +/- 5.7), and healthy age-matched controls (n = 14; mean age, 64.7 +/- 3.6 y). A modified reference Patlak model, with cerebellar gray matter as a reference, was chosen for kinetic analysis of the C-11-DED data. C-11-DED data from 20 to 60 min were analyzed using a digital brain atlas. Mean regional F-18-FDG uptake and C-11-PIB retention were calculated for each patient, with cerebellar gray matter as a reference. Results: ANOVA analysis of the regional C-11-DED binding data revealed a significant group effect in the bilateral frontal and bilateral parietal cortices related to increased binding in the MCI patients. All patients, except 3 with MCI, showed high C-11-PIB retention. Increased C-11-DED binding in most cortical and subcortical regions was observed in MCI C-11-PIB+ patients relative to controls, MCI C-11-PIB (negative) patients, and AD patients. No regional correlations were found between the 3 PET tracers. Conclusion: Increased C-11-DED binding throughout the brain of the MCI C-11-PIB+ patients potentially suggests that astrocytosis is an early phenomenon in AD development.

  • 15.
    Caster, Ola
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre (UMC), Sweden.
    Edwards, I. Ralph
    Quantitative benefit-risk assessment of methylprednisolone in multiple sclerosis relapses2015In: BMC Neurology, ISSN 1471-2377, E-ISSN 1471-2377, Vol. 15, article id 206Article in journal (Refereed)
    Abstract [en]

    Background: High-dose short-term methylprednisolone is the recommended treatment in the management of multiple sclerosis relapses, although it has been suggested that lower doses may be equally effective. Also, glucocorticoids are associated with multiple and often dose-dependent adverse effects. This quantitative benefit-risk assessment compares high-and low-dose methylprednisolone (at least 2000 mg and less than 1000 mg, respectively, during at most 31 days) and a no treatment alternative, with the aim of determining which regimen, if any, is preferable in multiple sclerosis relapses. Methods: An overall framework of probabilistic decision analysis was applied, combining data from different sources. Effectiveness as well as risk of non-serious adverse effects were estimated from published clinical trials. However, as these trials recorded very few serious adverse effects, risk intervals for the latter were derived from individual case reports together with a range of plausible distributions. Probabilistic modelling driven by logically implied or clinically well motivated qualitative relations was used to derive utility distributions. Results: Low-dose methylprednisolone was not a supported option in this assessment; there was, however, only limited data available for this treatment alternative. High-dose methylprednisolone and the no treatment alternative interchanged as most preferred, contingent on the risk distributions applied for serious adverse effects, the assumed level of risk aversiveness in the patient population, and the relapse severity. Conclusions: The data presently available do not support a change of current treatment recommendations. There are strong incentives for further clinical research to reduce the uncertainty surrounding the effectiveness and the risks associated with methylprednisolone in multiple sclerosis relapses; this would enable better informed and more precise treatment recommendations in the future.

  • 16. Cermakova, Pavla
    et al.
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Garcia-Ptacek, Sara
    Lund, Lars H.
    Winblad, Bengt
    Eriksdotter, Maria
    Religa, Dorota
    Cardiovascular Diseases in similar to 30,000 Patients in the Swedish Dementia Registry2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 48, no 4, p. 949-958Article in journal (Refereed)
    Abstract [en]

    Background: Cardiovascular diseases are leading causes of death and patients with dementia are often affected by them. Objective: Investigate associations of cardiovascular diseases with different dementia disorders and determine their impact on mortality. Methods: This study included 29,630 patients from the Swedish Dementia Registry (mean age 79 years, 59% women) diagnosed with Alzheimer's disease (AD), mixed dementia, vascular dementia, dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), frontotemporal dementia (FTD), or unspecified dementia. Records of cardiovascular diseases come from the Swedish National Patient Register. Multinomial logistic regression and cox proportional hazard models were applied. Results: Compared to AD, we found a higher burden of all cardiovascular diseases in mixed and vascular dementia. Cerebrovascular diseases were more associated with DLB than with AD. Diabetes mellitus was less associated with PDD and DLB than with AD. Ischemic heart disease was less associated with PDD and FTD than AD. All cardiovascular diseases predicted death in patients with AD, mixed, and vascular dementia. Only ischemic heart disease significantly predicted death in DLB patients (HR = 1.72; 95% CI = 1.16-2.55). In PDD patients, heart failure and diabetes mellitus were associated with a higher risk of death (HR = 3.06; 95% CI = 1.74-5.41 and HR = 3.44; 95% CI = 1.31-9.03). In FTD patients, ischemic heart disease and atrial fibrillation or flutter significantly predicted death (HR = 2.11; 95% CI = 1.08-4.14 and HR= 3.15; 95% CI = 1.60-6.22, respectively). Conclusion: Our study highlights differences in the occurrence and prognostic significance of cardiovascular diseases in several dementia disorders. This has implications for the care and treatment of the different dementia disorders.

  • 17. Ceynowa, Dylan J.
    et al.
    Wickström, Ronny
    Olsson, Monica
    Ek, Ulla
    Stockholm University, Faculty of Social Sciences, Department of Special Education.
    Eriksson, Urban
    Kristoffersen Wiberg, Maria
    Tear Fahnehjelm, Kristina
    Morning Glory Disc Anomaly in childhood - a population-based study2015In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 93, no 7, p. 626-634Article in journal (Refereed)
    Abstract [en]

    Purpose: To report prevalence, ocular characteristics and coexisting neurological, behavioural, somatic and neuroradiological abnormalities in children and adolescents with morning glory disc anomaly (MGDA).

    Methods: In a cross-sectional population-based study, 12 patients with MGDA, aged 2-20years, were identified. All 12 agreed to ophthalmological assessments including visual functions, refraction, fundus photography, optical coherence tomography (OCT) and ocular motor score (OMS). Neurological examinations and behavioural/developmental screening were carried out. Data from previous or new neuroradiological investigations were collected.

    Results: The prevalence of MGDA was 2.6/100000. MGDA was unilateral in 11/12 patients with a best-corrected visual acuity (BCVA) in the MGDA eye ranging from hand motion to 0.65 (median 0.06). Severe microphthalmus prevented unilaterality to be determined in one adolescent. All patients had a binocular BCVA of 0.5. OMS showed abnormalities in pupil response, vestibulo-ocular reflex, stereo visual acuity, strabismus and convergence. OCT revealed peripapillary or macular oedema in 5/8 patients and foveal aplasia in 3/8 patients. Three patients had extensive capillary hemangiomas, of which one had PHACES syndrome and one had additional cerebrovascular anomalies and corpus callosum agenesis. Neuroradiology showed craniovascular anomalies in two patients. Neurology was mostly normal. Behavioural/developmental screening showed attention deficit hyperactivity disorder in one patient.

    Conclusions: The prevalence data, previously not reported, of morning glory disc anomaly was 2.6/100 000. Coexisting retinal peripapillary or macular oedema was common, as were cerebral abnormalities and/or cutaneous vascular malformations. The associated findings may not be discovered through routine ophthalmological examination why OCT and neuroimaging are called for.

  • 18. Chan, S-P
    et al.
    Yong, P. Z.
    Sun, Y.
    Mahendran, R.
    Wong, J. C. M.
    Qiu, C.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Ng, T-P
    Kua, E-H
    Feng, L.
    Associations of Long-Term Tea Consumption with Depressive and Anxiety Symptoms in Community-Living Elderly: Findings from the Diet and Healthy Aging Study2018In: The Journal of prevention of Alzheimer's disease, ISSN 2274-5807, Vol. 5, no 1, p. 21-25Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine the association between long-term tea consumption and depressive and anxiety symptoms in community-living elderly. DESTGN: Community based cross-sectional study. SETTING: The Diet and Healthy Aging Study (DaHA), a prospective cohort study in Singapore. PARTICIPANTS: 614 elderly aged 60 years and above, who were free of dementia and cognitive impairment. MEASUREMENTS: Information on tea consumption was obtained through interviewer-administered questionnaire. Long-term tea drinking was defined as regular consumption for at least 15 years. Depressive and anxiety symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15) and the 20-item Geriatric Anxiety Inventory (GAI), respectively. A generalized structural equation model (gSEM) was applied to ascertain the association between long-term tea consumption and depressive and anxiety symptoms. RESULTS: About 59% of the subjects had consumed tea for over 15 years. Long term tea consumption was significantly associated with a reduced odds of having depressive and anxiety symptoms, after adjusting for demographics (i.e., age, gender, education and ethnicity), comorbid conditions (i.e., heart disease, diabetes, stroke, hypertension and hyperlipidaemia) and long-term coffee consumption. CONCLUSION: There was evidence suggesting that long-term tea consumption was associated with reduced depressive and anxiety symptoms among community-living elderly. This suggests that it is worthwhile to further investigate the role of tea's bioactive compounds in promoting mental health in aging.

  • 19. Chiotis, K.
    et al.
    Saint-Aubert, L.
    Rodriguez-Vieitez, E.
    Leuzy, A.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Cognitive psychology. Karolinska Institutet, Sweden; Karolinska University Hospital Huddinge, Sweden.
    Savitcheva, I.
    Jonasson, M.
    Lubberink, M.
    Wall, A.
    Antoni, G.
    Nordberg, A.
    Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, no 7, p. 1666-1673Article in journal (Refereed)
    Abstract [en]

    The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [F-18]THK5317 (tau deposition) and [F-18]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [C-11]PIB (amyloid-beta deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [F-18]THK5317 retention over time, in contrast to significant decreases in [F-18]FDG uptake in temporoparietal areas. The pattern of changes in [F-18]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [F-18]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [F-18]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [C-11]PIB scan, high [F-18]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [F-18]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.

  • 20. Chiotis, Konstantinos
    et al.
    Saint-Aubert, Laure
    Savitcheva, Irina
    Jelic, Vesna
    Andersen, Pia
    Jonasson, My
    Eriksson, Jonas
    Lubberink, Mark
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden.
    Wall, Anders
    Antoni, Gunnar
    Nordberg, Agneta
    Imaging in-vivo tau pathology in Alzheimer's disease with THK5317 PET in a multimodal paradigm2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, no 9, p. 1686-1699Article in journal (Refereed)
    Abstract [en]

    Purpose The aim of this study was to explore the cerebral distribution of the tau-specific PET tracer [F-18]THK5317 (also known as (S)-[F-18]THK5117) retention in different stages of Alzheimer's disease; and study any associations with markers of hypometabolism and amyloid-beta deposition. Methods Thirty-three individuals were enrolled, including nine patients with Alzheimer's disease dementia, thirteen with mild cognitive impairment (MCI), two with non-Alzheimer's disease dementia, and nine healthy controls (five young and four elderly). In a multi-tracer PET design [F-18]THK5317, [C-11] Pittsburgh compound B ([C-11]PIB), and [F-18]FDG were used to assess tau pathology, amyloid-beta deposition and cerebral glucose metabolism, respectively. The MCI patients were further divided into MCI [C-11]PIB-positive (n=11) and MCI [C-11]PIB-negative (n=2) groups. Results Test-retest variability for [F-18]THK5317-PET was very low (1.17-3.81 %), as shown by retesting five patients. The patients with prodromal (MCI [C-11]PIB-positive) and dementia-stage Alzheimer's disease had significantly higher [F-18]THK5317 retention than healthy controls (p=0.002 and p=0.001, respectively) in areas exceeding limbic regions, and their discrimination from this control group (using the area under the curve) was >98 %. Focal negative correlations between [F-18]THK5317 retention and [F-18]FDG uptake were observed mainly in the frontal cortex, and focal positive correlations were found between [F-18]THK5317 and [C-11] PIB retentions isocortically. One patient with corticobasal degeneration syndrome and one with progressive supranuclear palsy showed no [C-11]PIB but high [F-18]THK5317 retentions with a different regional distribution from that in Alzheimer's disease patients. Conclusions The tau-specific PET tracer [F-18]THK5317 images in vivo the expected regional distribution of tau pathology. This distribution contrasts with the different patterns of hypometabolism and amyloid-beta deposition.

  • 21. Chiotis, Konstantinos
    et al.
    Stenkrona, Per
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Cognitive psychology. Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden.
    Stepanov, Vladimir
    Ferreira, Daniel
    Arakawa, Ryosuke
    Takano, Akihiro
    Westman, Eric
    Varrone, Andrea
    Okamura, Nobuyuki
    Shimada, Hitoshi
    Higuchi, Makoto
    Halldin, Christer
    Nordberg, Agneta
    Dual tracer tau PET imaging reveals different molecular targets for C-11-THK5351 and C-11-PBB3 in the Alzheimer brain2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no 9, p. 1605-1617Article in journal (Refereed)
    Abstract [en]

    Several tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (C-11-THK5351 and C-11-PBB3) in a head-to-head, in vivo, multimodal design. Nine patients with a diagnosis of mild cognitive impairment or probable Alzheimer's disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer's disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers C-11-THK5351 and C-11-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer C-11-AZD2184, a T1-MRI sequence, and neuropsychological assessment. The load and regional distribution of binding differed between C-11-THK5351 and C-11-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of C-11-PBB3, but not that of C-11-THK5351, in the temporal lobe resembled that of C-11-AZD2184, with strong correlations detected between C-11-PBB3 and C-11-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with C-11-THK5351 than with C-11-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with C-11-THK5351 than with C-11-PBB3 binding. This research suggests different molecular targets for these tracers; while C-11-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of C-11-THK5351 fitted the expected distribution of tau pathology in Alzheimer's disease better and was more closely related to downstream disease markers.

  • 22. Chowdhury, Rumana
    et al.
    Guitart-Masip, Marc
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University College London, UK.
    Lambert, Christian
    Dayan, Peter
    Huys, Quentin
    Duezel, Emrah
    Dolan, Raymond J.
    Dopamine restores reward prediction errors in old age2013In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 16, no 5, p. 648-653Article in journal (Refereed)
    Abstract [en]

    Senescence affects the ability to utilize information about the likelihood of rewards for optimal decision-making. Using functional magnetic resonance imaging in humans, we found that healthy older adults had an abnormal signature of expected value, resulting in an incomplete reward prediction error (RPE) signal in the nucleus accumbens, a brain region that receives rich input projections from substantia nigra/ventral tegmental area (SN/VTA) dopaminergic neurons. Structural connectivity between SN/VTA and striatum, measured by diffusion tensor imaging, was tightly coupled to inter-individual differences in the expression of this expected reward value signal. The dopamine precursor levodopa (L-DOPA) increased the task-based learning rate and task performance in some older adults to the level of young adults. This drug effect was linked to restoration of a canonical neural RPE. Our results identify a neurochemical signature underlying abnormal reward processing in older adults and indicate that this can be modulated by L-DOPA.

  • 23. Dahl, Sara
    et al.
    Wickström, Ronny
    Ek, Ulla
    Stockholm University, Faculty of Social Sciences, Department of Special Education.
    Fahnehjelm, Kristina Tear
    Children with optic nerve hypoplasia face a high risk of neurodevelopmental disorders2018In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 107, no 3, p. 484-489Article in journal (Refereed)
    Abstract [en]

    Aim: Optic nerve hypoplasia (ONH) is a congenital ocular malformation that has been associated with neurodevelopmental disorders, but the prevalence in unilateral disease and less severe visual impairment is unknown. We studied intellectual disability and autism spectrum disorders (ASDs) in patients with ONH.

    Methods: This was a population-based cross-sectional cohort study of 65 patients (33 female) with ONH below 20 years of age, living in Stockholm in December 2009, with data analysed in January 2016. Of these 35 were bilateral and 30 were unilateral. Neurodevelopmental disorders were diagnosed or confirmed by neurological assessments, the Five to Fifteen parent questionnaire and reviewing previous neuropsychological investigations or conducting neuropsychological tests.

    Results: Bilateral ONH patients had lower mean full scale intelligence quotient scores than unilateral patients (84.4 and 99.4, respectively, p = 0.049). We assessed intellectual disability in 55 eligible patients, and it was more common in patients with bilateral ONH (18 of 32, 56%) than unilateral ONH (two of 23, 9%, p < 0.001). ASDs were diagnosed in seven of 42 (17%) patients.

    Conclusion: Children with bilateral ONH had a high risk of neurodevelopmental disorders, especially intellectual disability. The risk was lower in unilateral ONH, but the levels of neurodevelopmental disorders warrant screening of both groups.

  • 24. Damian, M.
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Single-Domain Amnestic Mild Cognitive Impairment Identified by Cluster Analysis Predicts Alzheimer's Disease in the European Prospective DESCRIPA Study2013In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 36, no 1-2, p. 1-19Article in journal (Refereed)
    Abstract [en]

    Background/Aims: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI).Methods: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e.g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE ≥28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. Results: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (Aβ42, t-tau, APOE ε4, and medial temporal atrophy), compared to SCI or naMCI. Conclusion: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings.

  • 25.
    Dehvari, Nodi
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Mahmud, Tapan
    Persson, Johanna
    Bengtsson, Tore
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Graff, Caroline
    Winblad, Bengt
    Ronnback, Annica
    Behbahani, Homira
    Amyloid precursor protein accumulates in aggresomes in response to proteasome inhibitor2012In: Neurochemistry International, ISSN 0197-0186, E-ISSN 1872-9754, Vol. 60, no 5, p. 533-542Article in journal (Refereed)
    Abstract [en]

    Aggresomes are cytoplasmic inclusions which are localized at the microtubule organizing center (MTOC) as a result of induced proteasome inhibition, stress or over-expression of certain proteins. Aggresomes are linked to the pathogenesis of many neurodegenerative diseases. Here we studied whether amyloid precursor protein (APP), a type-I transmembrane glycoprotein, is localized in aggresomes after exposure to stress condition. Using confocal microscopy we found that APP is located in aggresomes and co-localized with vimentin, gamma-tubulin, 20S and ubiquitin at the MTOC in response to proteasome dysfunction. An interaction between vimentin and APP was found after proteasome inhibition suggesting that APP is an additional protein constituent of aggresomes. Suppression of the proteasome system in APP-HEK293 cells overexpressing APP or transfected with APP Swedish mutation caused an accumulation of stable, detergent-insoluble forms of APP containing poly-ubiquitinated proteins. In addition, brain homogenates from transgenic mice expressing human APP with the Arctic mutation demonstrated an interaction between APP and the aggresomal-marker vimentin. These data suggest that malfunctioning of the proteasome system caused by mutation or overexpression of pathological or non-pathological proteins may lead to the accumulation of stable aggresomes, perhaps contributing to the neurodegeneration.

  • 26.
    Dekhtyar, Serhiy
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Marseglia, Anna
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Darin-Mattsson, Alexander
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Hui-Xin
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Genetic risk of dementia mitigated by cognitive reserve: A cohort study2019In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 86, no 1, p. 68-78Article in journal (Refereed)
    Abstract [en]

    Objective We investigated whether cognitive reserve modifies the risk of dementia attributable to apolipoprotein epsilon 4 (APOE-epsilon 4), a well-known genetic risk factor for dementia. Methods We followed 2,556 cognitively intact participants aged >= 60 years from the ongoing prospective community-based Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Dementia was ascertained through clinical and neuropsychological assessments and diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria. Structural equation modeling was used to generate a cognitive reserve indicator from 4 previously validated contributors: early life education, midlife substantive work complexity, late life leisure activities, and late life social networks. Cox proportional hazard models estimated dementia risk in relation to cognitive reserve indicator. The interaction between the cognitive reserve indicator and APOE-epsilon 4 was assessed on multiplicative and additive scales. Results After an average of 6.3 years (range = 2.1-10.7) of follow-up, 232 dementia cases were ascertained. Relative to individuals in the lowest tertile of cognitive reserve indicator, those with moderate and high reserve were at a reduced risk of dementia. There was no multiplicative interaction between APOE-epsilon 4 status and cognitive reserve indicator (p = 0.113). Additive interaction was statistically significant. Relative to APOE-epsilon 4 carriers with low cognitive reserve, epsilon 4 carriers with high reserve had a reduced risk of dementia (hazard ratio [HR] = 0.28, 95% confidence interval [CI] = 0.13-0.59). The magnitude of risk reduction was similar in epsilon 4 noncarriers with a high cognitive reserve indicator (HR = 0.24, 95% CI = 0.15-0.40). Interpretation Lifelong engagement in reserve-enhancing activities attenuates the risk of dementia attributable to APOE-epsilon 4. Promoting cognitive reserve might be especially effective in subpopulations with high genetic risk of dementia. ANN NEUROL 2019

  • 27.
    Dintica, Christina S.
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Marseglia, Anna
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Rui
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Seubert, Janina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Arfanakis, Konstantinos
    Bennett, David A.
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Impaired olfaction is associated with cognitive decline and neurodegeneration in the brain2019In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 92, no 7, p. e700-e709Article in journal (Refereed)
    Abstract [en]

    Objective

    We aimed to examine whether impaired olfaction is associated with cognitive decline and indicators of neurodegeneration in the brain of dementia-free older adults.

    Methods

    Within the Rush Memory and Aging Project, 380 dementia-free participants (mean age = 78 years) were followed for up to 15 years, and underwent MRI scans. Olfactory function was assessed using the Brief Smell Identification Test (B-SIT) at baseline, and categorized as anosmia (B-SIT <6), hyposmia (B-SIT 6-10 in men and 6-10.25 in women), and normal (B-SIT 10.25-12 in men and 10.5-12 in women). Cognitive function was annually assessed with a battery of 21 tests, from which composite scores were derived. Structural total and regional brain volumes were estimated. Data were analyzed using linear regression and mixed-effects models.

    Results

    At study entry, 138 (36.3%) had normal olfactory function, 213 (56.1%) had hyposmia, and 29 (7.6%) had anosmia. In multiadjusted mixed-effects models, hyposmia (beta = -0.03, 95% confidence interval [CI] -0.05 to -0.02) and anosmia (beta = -0.13, 95% CI -0.16 to -0.09) were associated with faster rate of cognitive decline compared to normal olfaction. On MRI, impaired olfaction (hyposmia or anosmia) was related to smaller volumes of the hippocampus (beta = -0.19, 95% CI -0.33 to -0.05), and in the entorhinal (beta = -0.16, 95% CI -0.24 to -0.08), fusiform (beta = -0.45, 95% CI -0.78 to -0.14), and middle temporal (beta = -0.38, 95% CI -0.72 to -0.01) cortices.

    Conclusion

    Impaired olfaction predicts faster cognitive decline and might indicate neurodegeneration in the brain among dementia-free older adults.

  • 28. Economides, Marcos
    et al.
    Guitart-Masip, Marc
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University College London, England.
    Kurth-Nelson, Zeb
    Dolan, Raymond J.
    Anterior Cingulate Cortex Instigates Adaptive Switches in Choice by Integrating Immediate and Delayed Components of Value in Ventromedial Prefrontal Cortex2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 9, p. 3340-3349Article in journal (Refereed)
    Abstract [en]

    Actions can lead to an immediate reward or punishment and a complex set of delayed outcomes. Adaptive choice necessitates the brain track and integrate both of these potential consequences. Here, we designed a sequential task whereby the decision to exploit or forego an available offer was contingent on comparing immediate value and a state-dependent future cost of expending a limited resource. Crucially, the dynamics of the task demanded frequent switches in policy based on an online computation of changing delayed consequences. We found that human subjects choose on the basis of a near-optimal integration of immediate reward and delayed consequences, with the latter computed in a prefrontal network. Within this network, anterior cingulate cortex (ACC) was dynamically coupled to ventromedial prefrontal cortex (vmPFC) when adaptive switches in choice were required. Our results suggest a choice architecture whereby interactions between ACC and vmPFC underpin an integration of immediate and delayed components of value to support flexible policy switching that accommodates the potential delayed consequences of an action.

  • 29.
    Ek, Ulla
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Special Education.
    Westerlund, Joakim
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Fernell, Elisabeth
    General versus executive cognitive ability in pupils with ADHD and with milder attention problems2013In: Neuropsychiatric Disease and Treatment, ISSN 1176-6328, E-ISSN 1178-2021, Vol. 9, p. 163-168Article in journal (Refereed)
    Abstract [en]

    Background: The aim of this study was to analyze two main types of cognitive domains in school children with different types and severities of attention-related problems. The cognitive domains examined were general cognitive ability and executive abilities. Methods: Three different clinical samples of pupils with school problems were analyzed to assess their cognitive Wechsler Intelligence Scale for Children profiles. In particular, the general cognitive ability index and the executive markers (ie, verbal memory index and processing speed index) were of interest. Of the total sample (n = 198), two main groups were contrasted; one met the full criteria for attention deficit hyperactivity disorder (ADHD)/subthreshold ADHD, and one was comprised of those with milder attention problems, insufficient to meet the criteria for ADHD/subthreshold ADHD. Results: It could be demonstrated that both groups had a significantly higher score on the general cognitive ability index than on measures of working memory and processing speed. This difference was more pronounced for boys. Conclusion: These types of cognitive differences need to be considered in children with different kinds of learning, behavior, and attention problems; this is also true for children presenting with an average general intelligence quotient and with milder attention problems. Current educational expectations are demanding for children with mild difficulties, and such cognitive information will add to the understanding of the child's learning problems, hopefully leading to a better adapted education than that conventionally available.

  • 30. Ferrari, Camilla
    et al.
    Lombardi, Gemma
    Polito, Cristina
    Lucidi, Giulia
    Bagnoli, Silvia
    Piaceri, Irene
    Nacmias, Benedetta
    Berti, Valentina
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Centrum, Sweden.
    Sorbi, Sandro
    Alzheimer's Disease Progression: Factors Influencing Cognitive Decline2018In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, no 2, p. 785-791Article in journal (Refereed)
    Abstract [en]

    Background:

    Alzheimer's disease (AD) patients present high variability in the rate of cognitive decline. Despite the wide knowledge on factors influencing dementia risk, little is known on what accounts for AD progression. Previous studies on this topic have mainly analyzed each factor separately without taking into account the interaction between genetic and non-genetic factors.

    Objective:

    The aim of the present study is to evaluate the role of demographic, clinical, therapeutic, and genetic factors and their interaction on cognitive decline among newly diagnosed AD patients.

    Methods:

    We retrospectively selected 160 AD patients diagnosed at the Neurology Unit of Careggi University Hospital of Florence. We evaluated the occurrence of rapid cognitive changes defined as the worsening of more than four points at the Mini-Mental State Examination after 2-year follow up period.

    Results:

    Among the 160 AD patients, 50% presented rapid disease progression. Extrapyramidal signs at disease onset were predictors of worse outcome (OR 2.2), especially among Apolipoprotein E (APOE) epsilon 4 allele carriers, while the presence of family history for dementia decreased the risk of rapid progression by about 50%. Higher educated epsilon 4-carriers showed a slower AD progression. We identified the chronic use of aspirin as potential secondary preventative strategy for the non epsilon 4-carriers.

    Conclusion:

    At dementia onset, some clinical and demographic data can be predictors of future progression. The outcomes of the present study support the already hypothesized interaction between genetic and non-genetic factors during disease course and suggest genetic-based approaches.

  • 31. Ferreira, Daniel
    et al.
    Hansson, Oskar
    Barroso, Jose
    Molina, Yaiza
    Machado, Alejandra
    Andres Hernandez-Cabrera, Juan
    Muehlboeck, J-Sebastian
    Stomrud, Erik
    Nagga, Katarina
    Lindberg, Olof
    Ames, David
    Kalpouzos, Grégoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Centre, Sweden.
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Centre, Sweden.
    Graff, Caroline
    Mecocci, Patrizia
    Vellas, Bruno
    Tsolaki, Magda
    Kloszewska, Iwona
    Soininen, Hilkka
    Lovestone, Simon
    Ahlström, Håkan
    Lind, Lars
    Larsson, Elna-Marie
    Wahlund, Lars-Olof
    Simmons, Andrew
    Westman, Eric
    The interactive effect of demographic and clinical factors on hippocampal volume: A multicohort study on 1958 cognitively normal individuals2017In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 27, no 6, p. 653-667Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is characterized by hippocampal atrophy. Other factors also influence the hippocampal volume, but their interactive effect has not been investigated before in cognitively healthy individuals. The aim of this study is to evaluate the interactive effect of key demographic and clinical factors on hippocampal volume, in contrast to previous studies frequently investigating these factors in a separate manner. Also, to investigate how comparable the control groups from ADNI, AIBL, and AddNeuroMed are with five population-based cohorts. In this study, 1958 participants were included (100 AddNeuroMed, 226 ADNI, 155 AIBL, 59 BRC, 295 GENIC, 279 BioFiNDER, 398 PIVUS, and 446 SNAC-K). ANOVA and random forest were used for testing between-cohort differences in demographic-clinical variables. Multiple regression was used to study the influence of demographic-clinical variables on hippocampal volume. ANCOVA was used to analyze whether between-cohort differences in demographic-clinical variables explained between-cohort differences in hippocampal volume. Age and global brain atrophy were the most important variables in explaining variability in hippocampal volume. These variables were not only important themselves but also in interaction with gender, education, MMSE, and total intracranial volume. AddNeuroMed, ADNI, and AIBL differed from the population-based cohorts in several demographic-clinical variables that had a significant effect on hippocampal volume. Variability in hippocampal volume in individuals with normal cognition is high. Differences that previously tended to be related to disease mechanisms could also be partly explained by demographic and clinical factors independent from the disease. Furthermore, cognitively normal individuals especially from ADNI and AIBL are not representative of the general population. These findings may have important implications for future research and clinical trials, translating imaging biomarkers to the general population, and validating current diagnostic criteria for Alzheimer's disease and predementia stages.

  • 32. Filtness, Ashleigh J.
    et al.
    Anund, Anna
    Fors, Carina
    Ahlström, Christer
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Radboud University Nijmegen, Netherlands.
    Sleep-related eye symptoms and their potential for identifying driver sleepiness2014In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 23, no 5, p. 568-575Article in journal (Refereed)
    Abstract [en]

    The majority of individuals appear to have insight into their own sleepiness, but there is some evidence that this does not hold true for all, for example treated patients with obstructive sleep apnoea. Identification of sleep-related symptoms may help drivers determine their sleepiness, eye symptoms in particular show promise. Sixteen participants completed four motorway drives on two separate occasions. Drives were completed during daytime and night-time in both a driving simulator and on the real road. Ten eye symptoms were rated at the end of each drive, and compared with driving performance and subjective and objective sleep metrics recorded during driving. 'Eye strain', 'difficulty focusing', 'heavy eyelids' and 'difficulty keeping the eyes open' were identified as the four key sleep-related eye symptoms. Drives resulting in these eye symptoms were more likely to have high subjective sleepiness and more line crossings than drives where similar eye discomfort was not reported. Furthermore, drivers having unintentional line crossings were likely to have 'heavy eyelids' and 'difficulty keeping the eyes open'. Results suggest that drivers struggling to identify sleepiness could be assisted with the advice 'stop driving if you feel sleepy and/or have heavy eyelids or difficulty keeping your eyes open'.

  • 33. Forsberg, A.
    et al.
    Lampa, J.
    Estelius, J.
    Cervenka, S.
    Farde, L.
    Halldin, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Höglund, Olgart C.
    Kosek, E.
    Disease activity in rheumatoid arthritis is inversely related to cerebral TSPO binding assessed by [C-11]PBR28 positron emission tomography2019In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 334, article id UNSP 577000Article in journal (Refereed)
    Abstract [en]

    Reumatoid Arthritis (RA) is an autoimmune disorder characterized by peripheral joint inflammation. Recently, an engagement of the brain immune system has been proposed. The aim with the current investigation was to study the glial cell activation marker translocator protein (TSPO) in a well characterized cohort of RA patients and to relate it to disease activity, peripheral markers of inflammation and autonomic activity. Fifteen RA patients and fifteen healthy controls matched for age, sex and TSPO genotype (rs6971) were included in the study. TSPO was measured using Positron emission tomography (PET) and the radioligand [C-11] PBR28. The outcome measure was total distribution volume (V-T) estimated using Logan graphical analysis, with grey matter (GM) as the primary region of interest. Additional regions of interest analyses as well as voxel-wise analyses were also performed. Clinical evaluation of disease activity, symptom assessments, serum analyses of cytokines and heart rate variability (HRV) analysis of 24 h ambulatory ECG were performed in all subjects. There were no statistically significant group differences in TSPO binding, either when using the primary outcome V-T or when normalizing V-T to the lateral occipital cortex (p > 0.05). RA patients had numerically lower V-T values than healthy controls (Cohen's D for GM = -0.21). In the RA group, there was a strong negative correlation between [C-11]PBR28 V-T in GM and disease activity (DAS28)(r = -0.745, p = 0.002, corrected for rs6971 genotype). Higher serum levels of IFN gamma and TNF-alpha were found in RA patients compared to controls (p < 0.05) and several measures of autonomic activity showed significant differences between RA and controls (p < 0.05). However, no associations between markers of systemic inflammation or autonomic activity and cerebral TSPO binding were found. In conclusion, no statistically significant group differences in TSPO binding as measured with [C-11]PBR28 PET were detected. Within the RA group, lower cerebral TSPO binding was associated with higher disease activity, suggesting that cerebral TSPO expression may be related to disease modifying mechanisms in RA. In light of the earlier confirmed neuro-immune features of RA, these results warrant further investigations regarding neuro-immune joint-to-CNS signalling to open up for potentially new treatment strategies.

  • 34. Franke, Andreas G.
    et al.
    Gränsmark, Patrik
    Stockholm University, Faculty of Social Sciences, The Swedish Institute for Social Research (SOFI).
    Agricola, Alexandra
    Schühle, Kai
    Ronnmel, Thilo
    Sebastian, Alexandra
    Balló, Harald E.
    Gorbulev, Stanislav
    Gerdes, Christer
    Stockholm University, Faculty of Social Sciences, The Swedish Institute for Social Research (SOFI).
    Frank, Björn
    Ruckes, Christian
    Tüscher, Oliver
    Lieb, Klaus
    Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, no 3, p. 248-260Article in journal (Refereed)
    Abstract [en]

    Stimulants and caffeine have been proposed for cognitive enhancement by healthy subjects. This study investigated whether performance in chess - a competitive mind game requiring highly complex cognitive skills - can be enhanced by methylphenidate, modafinil or caffeine. In a phase IV, randomized, double-blind, placebo-controlled trial, 39 male chess players received 2 x 200 mg modafinil, 2 x 20 mg methylphenidate, and 2 x 200 mg caffeine or placebo in a 4 x 4 crossover design. They played twenty 15-minute games during two sessions against a chess program (Fritz 12; adapted to players' strength) and completed several neuropsychological tests. Marked substance effects were observed since all three substances significantly increased average reflection time per game compared to placebo resulting in a significantly increased number of games lost on time with all three treatments. Treatment effects on chess performance were not seen if all games (n=3059) were analysed. Only when controlling for game duration as well as when excluding those games lost on time, both modafinil and methylphenidate enhanced chess performance as demonstrated by significantly higher scores in the remaining 2876 games compared to placebo. In conjunction with results from neuropsychological testing we conclude that modifying effects of stimulants on complex cognitive tasks may in particular result from more reflective decision making processes. When not under time pressure, such effects may result in enhanced performance. Yet, under time constraints more reflective decision making may not improve or even have detrimental effects on complex task performance.

  • 35. Garcia-Ptacek, S.
    et al.
    Eriksdotter, M.
    Jelic, V.
    Porta-Etessam, J.
    Kåreholt, Ingemar
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Jönköping University, Sweden.
    Manzano Palomo, S.
    Subjective cognitive impairment: Towards early identification of Alzheimer disease2016In: Neurología, ISSN 0213-4853, E-ISSN 1578-1968, Vol. 31, no 8, p. 562-571Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Neurodegeneration in Alzheimer disease (AD) begins decades before dementia and patients with mild cognitive impairment (MCI) already demonstrate significant lesion loads. Lack of information about the early pathophysiology in AD complicates the search for therapeutic strategies. Subjective cognitive impairment is the description given to subjects who have memory-related complaints without pathological results on neuropsychological tests. There is no consensus regarding this heterogeneous syndrome, but at least some of these patients may represent the earliest stage in AD. Method: We reviewed available literature in order to summarise current knowledge on subjective cognitive impairment. Results: Although they may not present detectable signs of disease, SCI patients as a group score tower on neuropsychological tests than the general population does, and they also have a higher incidence of future cognitive decline. Depression and psychiatric co-morbidity play a role but cannot account for all cognitive complaints. Magnetic resonance imaging studies in these patients reveal a pattern of hippocampal atrophy similar to that of amnestic mild cognitive impairment and functional MRI shows increased activation during cognitive tasks which might indicate compensation for loss of function. Prevalence of an AD-like pattern of beta-amyloid (A beta 42) and tau proteins in cerebrospinal fluid is higher in SCI patients than in the general population. Conclusions: Memory complaints are relevant symptoms and may predict AD. Interpatient variability and methodological differences between clinical studies make it difficult to assign a definition to this syndrome. In the future, having a standard definition and longitudinal studies with sufficient follow-up times and an emphasis on quantifiable variables may clarify aspects of early AD.

  • 36. Gisselgard, Jens
    et al.
    Lebedev, Alexander
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kurz, Kathinka Daehli
    Joa, Inge
    Johannessen, Jan Olav
    Bronnick, Kolbjorn
    Structural and functional alterations in the brain during working memory in medication-naive patients at clinical high-risk for psychosis2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 5, article id e0196289Article in journal (Refereed)
    Abstract [en]

    Several previous studies suggest that clinical high risk for psychosis (CHR) is associated with prefrontal functional abnormalities and more widespread reduced grey matter in prefrontal, temporal and parietal areas. We investigated neural correlates to CHR in medication-naive patients. 41 CHR patients and 37 healthy controls were examined with 1.5 Tesla MRI, yielding functional scans while performing an N-back task and structural T1-weighted brain images. Functional and structural data underwent automated preprocessing steps in SPM and Freesurfer, correspondingly. The groups were compared employing mass-univariate strategy within the generalized linear modelling framework. CHR demonstrated reduced suppression of the medial temporal lobe (MTL) regions during n-back task. We also found that, consistent with previous findings, CHR subjects demonstrated thinning in prefrontal, cingulate, insular and inferior temporal areas, as well as reduced hippocampal volumes. The present findings add to the growing evidence of specific structural and functional abnormalities in the brain as potential neuroimaging markers of psychosis vulnerability.

  • 37. Golkar, Armita
    et al.
    Johansson, Emilia
    Kasahara, Maki
    Osika, Walter
    Perski, Aleksander
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Savic, Ivanka
    The Influence of Work-Related Chronic Stress on the Regulation of Emotion and on Functional Connectivity in the Brain2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e104550-Article in journal (Refereed)
    Abstract [en]

    Despite mounting reports about the negative effects of chronic occupational stress on cognitive and emotional functions, the underlying mechanisms are unknown. Recent findings from structural MRI raise the question whether this condition could be associated with a functional uncoupling of the limbic networks and an impaired modulation of emotional stress. To address this, 40 subjects suffering from burnout symptoms attributed to chronic occupational stress and 70 controls were investigated using resting state functional MRI. The participants' ability to up-regulate, down-regulate, and maintain emotion was evaluated by recording their acoustic startle response while viewing neutral and negatively loaded images. Functional connectivity was calculated from amygdala seed regions, using explorative linear correlation analysis. Stressed subjects were less capable of down-regulating negative emotion, but had normal acoustic startle responses when asked to up-regulate or maintain emotion and when no regulation was required. The functional connectivity between the amygdala and the anterior cingulate cortex correlated with the ability to down-regulate negative emotion. This connectivity was significantly weaker in the burnout group, as was the amygdala connectivity with the dorsolateral prefrontal cortex and the motor cortex, whereas connectivity from the amygdala to the cerebellum and the insular cortex were stronger. In subjects suffering from chronic occupational stress, the functional couplings within the emotion-and stress-processing limbic networks seem to be altered, and associated with a reduced ability to down-regulate the response to emotional stress, providing a biological substrate for a further facilitation of the stress condition.

  • 38.
    Grande, G.
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Milan, Italy.
    Tramacere, I.
    Vetrano, D. L.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Catholic University of Rome, Italy.
    Clerici, F.
    Pomati, S.
    Mariani, C.
    Filippini, G.
    Role of anticholinergic burden in primary care patients with first cognitive complaints2017In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 24, no 7, p. 950-955Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Drugs with anticholinergic properties might have a negative impact on cognition, but findings are still conflicting. The association was evaluated between anticholinergic drugs and cognitive performance in primary care patients with first cognitive complaints. Methods: From April 2013 to March 2014, 353 general practitioners administered the Mini-Mental State Examination (MMSE) to patients presenting with first cognitive complaints. Drug history was collected and the anticholinergic cognitive burden (ACB) was scored and categorized as ACB 0, ACB 1 and ACB 2+. A mixed effect linear regression model was used to assess the association between ACB and MMSE score. Results: Of 4249 subjects entering the study (mean age 77 +/- 8.2 years, 66.4% women and mean years of schooling 8.9 +/- 4.5), 25.8% received at least one drug with anticholinergic action. According to multivariate analysis, and after adjustment for several confounders, subjects with ACB 2+ had a statistically significant lower MMSE score compared with those with ACB 0 (beta -0.63; 95% confidence interval -1.19; -0.07). Subjects with ACB 1 had a non-statistically significant lower MMSE score than those with ACB 0 (beta -0.11; 95% confidence interval -0.37; 0.15). Conclusions: Anticholinergic medication might affect cognitive function in people with first cognitive complaints. Alternatives should be taken into account when possible, balancing the benefits and harms of these medications.

  • 39.
    Guitart-Masip, Marc
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University College London, England.
    Economides, Marcos
    Huys, Quentin J. M.
    Frank, Michael J.
    Chowdhury, Rumana
    Duzel, Emrah
    Dayan, Peter
    Dolan, Raymond J.
    Differential, but not opponent, effects of L-DOPA and citalopram on action learning with reward and punishment2014In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 231, no 5, p. 955-966Article in journal (Refereed)
    Abstract [en]

    Decision-making involves two fundamental axes of control namely valence, spanning reward and punishment, and action, spanning invigoration and inhibition. We recently exploited a go/no-go task whose contingencies explicitly decouple valence and action to show that these axes are inextricably coupled during learning. This results in a disadvantage in learning to go to avoid punishment and in learning to no-go to obtain a reward. The neuromodulators dopamine and serotonin are likely to play a role in these asymmetries: Dopamine signals anticipation of future rewards and is also involved in an invigoration of motor responses leading to reward, but it also arbitrates between different forms of control. Conversely, serotonin is implicated in motor inhibition and punishment processing. To investigate the role of dopamine and serotonin in the interaction between action and valence during learning. We combined computational modeling with pharmacological manipulation in 90 healthy human volunteers, using levodopa and citalopram to affect dopamine and serotonin, respectively. We found that, after administration of levodopa, action learning was less affected by outcome valence when compared with the placebo and citalopram groups. This highlights in this context a predominant effect of levodopa in controlling the balance between different forms of control. Citalopram had distinct effects, increasing participants' tendency to perform active responses independent of outcome valence, consistent with a role in decreasing motor inhibition. Our findings highlight the rich complexities of the roles played by dopamine and serotonin during instrumental learning.

  • 40.
    Guitart-Masip, Marc
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University College London, UK.
    Salami, Alireza
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Umeå Center for Functional Brain Imaging, Sweden.
    Garrett, Douglas
    Rieckmann, Anna
    Lindenberger, Ulman
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    BOLD Variability is Related to Dopaminergic Neurotransmission and Cognitive Aging2016In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 26, no 5, p. 2074-2083Article in journal (Refereed)
    Abstract [en]

    Dopamine (DA) losses are associated with various aging-related cognitive deficits. Typically, higher moment-to-moment brain signal variability in large-scale patterns of voxels in neocortical regions is linked to better cognitive performance and younger adult age, yet the physiological mechanisms regulating brain signal variability are unknown. We explored the relationship among adult age, DA availability, and blood oxygen level-dependent (BOLD) signal variability, while younger and older participants performed a spatial working memory (SWM) task. We quantified striatal and extrastriatal DA D1 receptor density with [C-11]SCH23390 and positron emission tomography in all participants. We found that BOLD variability in a neocortical region was negatively related to age and positively related to SWM performance. In contrast, BOLD variability in subcortical regions and bilateral hippocampus was positively related to age and slower responses, and negatively related to D1 density in caudate and dorsolateral prefrontal cortex. Furthermore, BOLD variability in neocortical regions was positively associated with task-related disengagement of the default-mode network, a network whose activation needs to be suppressed for efficient SWM processing. Our results show that age-related DA losses contribute to changes in brain signal variability in subcortical regions and suggest a potential mechanism, by which neocortical BOLD variability supports cognitive performance.

  • 41.
    Haasum, Ylva
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fastbom, Johan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Use of antidepressants in Parkinson's disease: A Swedish register-based study of over 1.5 million older people2016In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 27, p. 85-88Article in journal (Refereed)
    Abstract [en]

    Introduction: It has been suggested that depression in Parkinson's Disease (PD) is often unrecognized and undertreated. However, few previous studies have studied the use of antidepressants in a large sample of both home-dwelling and institutionalized elderly persons with PD. We aimed to study the use of antidepressants in older persons using anti-parkinson drugs (APD, used as a proxy for PD), stratified by residential setting. Methods: We analyzed individual data on age, sex, residential setting and drug use in over 1.5 million older persons in the Swedish Prescribed Drug Register on 31th of December 2013. Results: Twenty-two percent of the home-dwellers and 50% of the institutionalized elderly persons with APD used antidepressants. Persons with APD had a higher probability of use of any antidepressant compared to persons without APD. A selective serotonin reuptake inhibitor (SSRI) was the most commonly used antidepressants in both settings followed by mirtazapin. Conclusions: The high use of antidepressants among older persons with APD warrants further studies on the quality of treatment of depression in PD.

  • 42.
    Haasum, Ylva
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Use of antiepileptic drugs and risk of falls in old age: A systematic review2017In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 138, p. 98-104Article, review/survey (Refereed)
    Abstract [en]

    Objective: The aim of this study is to systematically review the scientific literature to investigate if use of antiepileptic drugs (AEDs) is associated with falls and/or recurrent falls in old age. Method: We searched the literature for relevant articles in PubMed and Embase published up until 3rd December 2015. Studies on people aged 60 years and over with an observational design assessing the risk of fall in people exposed to AEDs compared to people not exposed to AED were included. Results: We found 744 studies by searching Medline and Embase and an additional 9 studies by reviewing relevant reference lists. Of these studies, 13 fulfilled our predefined criteria. The articles were of various study design, sizes and follow-up times, and presented the results in different ways. Also, confounder adjustment varied considerably between the studies. Ten studies presented results for the association between use of any AED and any fall/injurious fall. Of these studies, 6 presented adjusted estimates, of which all but one showed statistically significant associations between use of any AED and any fall/injurious fall. Six studies investigated the association between use of any AED and recurrent falls. Of these, only 3 studies presented adjusted effect estimates of which 2 reached statistical significance for the association between use of AEDs and recurrent falls in elderly people. Conclusion: Our results indicate an association between use of AEDs and risk of falls and recurrent falls in older people. This finding may be clinically important given that a substantial amount of older people use these drugs. However, further research is needed to increase the knowledge about the actual risk of falls when using these drugs in old age.

  • 43. Handels, Ron L. H.
    et al.
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Caracciolo, Barbara
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Wang, Rui
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Verhey, Frans R. J.
    Severens, Johan L.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Joore, Manuela A.
    Wimo, Anders
    Natural Progression Model of Cognition and Physical Functioning among People with Mild Cognitive Impairment and Alzheimer's Disease2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 37, no 2, p. 357-365Article in journal (Refereed)
    Abstract [en]

    Background: Empirical models of the natural history of Alzheimer's disease (AD) may help to evaluate new interventions for AD. Objective: We aimed to estimate AD-free survival time in people with mild cognitive impairment (MCI) and decline of cognitive and physical function in AD cases. Methods: Within the Kungsholmen project, 153 incident MCI and 323 incident AD cases (international criteria) were identified during 9 years of follow-up in a cognitively healthy cohort of elderly people aged >= 75 at baseline (n = 1,082). Global cognitive function was assessed with the Mini-Mental State Examination (MMSE), and daily life function was evaluated with the Katz index of activities of daily living (ADL) at each follow-up examination. Data were analyzed using parametric survival analysis and mixed effect models. Results: Median AD-free survival time of 153 participants with incident MCI was 3.5 years. Among 323 incident AD cases, the cognitive decline was 1.84 MMSE points per year, which was significantly associated with age. Physical functioning declined by 0.38 ADL points per year and was significantly associated with age, education, and MMSE, but not with gender. Conclusion: Elderly people with MCI may develop AD in approximately 3.5 years. Both cognitive and physical function may decline gradually after AD onset. The empirical models can be used to evaluate long-term disease progression of new interventions for AD.

  • 44. Hedström, Anna Karin
    et al.
    Hössjer, Ola
    Stockholm University, Faculty of Science, Department of Mathematics.
    Katsoulis, Michail
    Kockum, Ingrid
    Olsson, Tomas
    Alfredsson, Lars
    Organic solvents and MS susceptibility Interaction with MS risk HLA genes2018In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 91, no 5, p. E455-E462Article in journal (Refereed)
    Abstract [en]

    Objective We hypothesize that different sources of lung irritation may contribute to elicit an immune reaction in the lungs and subsequently lead to multiple sclerosis (MS) in people with a genetic susceptibility to the disease. We aimed to investigate the influence of exposure to organic solvents on MS risk, and a potential interaction between organic solvents and MS risk human leukocyte antigen (HLA) genes. Methods Using a Swedish population-based case-control study (2,042 incident cases of MS and 2,947 controls), participants with different genotypes, smoking habits, and exposures to organic solvents were compared regarding occurrence of MS, by calculating odds ratios with 95% confidence intervals using logistic regression. A potential interaction between exposure to organic solvents and MS risk HLA genes was evaluated by calculating the attributable proportion due to interaction. Results Overall, exposure to organic solvents increased the risk of MS (odds ratio 1.5, 95% confidence interval 1.2-1.8, p = 0.0004). Among both ever and never smokers, an interaction between organic solvents, carriage of HLA-DRB1*15, and absence of HLA-A*02 was observed with regard to MS risk, similar to the previously reported gene-environment interaction involving the same MS risk HLA genes and smoke exposure. Conclusion The mechanism linking both smoking and exposure to organic solvents to MS risk may involve lung inflammation with a proinflammatory profile. Their interaction with MS risk HLA genes argues for an action of these environmental factors on adaptive immunity, perhaps through activation of autoaggressive cells resident in the lungs subsequently attacking the CNS.

  • 45.
    Helmfors, Henrik
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Recent developments in applications of cell penetrating peptides uptake mechanisms and oligonucleotide delivery2012In: Chimica oggi, ISSN 0392-839X, E-ISSN 1973-8250, Vol. 30, no 2, p. 10-12Article in journal (Refereed)
    Abstract [en]

    Here we report on recent developments in cell-penetrating peptide mediated delivery of siRNA and other oligonucleotides. We also report on the latest discoveries regarding the debated uptake mechanism of cell-penetrating peptides. For the first time evidence of a cell surface receptor involvement in the uptake of cell-penetrating peptide/oligonucleotide complexes has been described, indicating that properties of the cargo are likely crucial for which pathway is responsible for uptake.

  • 46. Henje Blom, Eva
    et al.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Ingvar, Martin
    Åsberg, Marie
    Mobarrez, Fariborz
    Serlachius, Eva
    Pro-inflammatory cytokines are elevated in adolescent females with emotional disorders not treated with SSRIs2012In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 136, no 3, p. 716-23Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Adults with major depressive disorder (MDD) show elevated levels of IL-6 and TNF-alpha. Studies of adolescents with MDD or anxiety disorders (AD) are few and present conflicting results.

    METHODS: We studied plasma cytokines in a clinical sample of adolescent females with MDD and/or clinical AD (n=60, mean age 16.8 years), compared to healthy controls (n=44; mean age 16.5 years).

    RESULTS: The clinical sample showed significantly higher values of IL-2 (Z=-4.09, p>0.0001), IL1-beta (Z=-2.40, p<0.05) and IL-10 (Z=-2.38, p<0.05) as compared to controls. The subgroup of the clinical sample not treated with SSRIs had a significant difference of IL-6 (Z=-2.26, p<0.05) in addition to the difference of IL-2 and IL1-beta, but showed no difference of IL-10 as compared to the controls. SSRI treatment was related to IL-6, explaining 26% of the variance in the clinical sample after controlling for BMI and symptom severity. In the clinical sample, levels of IL-6 and IFN-gamma were positively correlated with self-assessed symptoms of anxiety and/or depression (corr.coeff 0.35 resp 0.40 at p<0.05).

    LIMITATIONS: The cross-sectional design does not allow for conclusions on causality. The sample sizes were relatively small and a large drop-out in the clinical sample may have influenced the representativity.

    DISCUSSION: The study suggests that pro-inflammatory cytokines are part of the pathophysiology of emotional disorders in adolescent females and that SSRIs have anti-inflammatory properties. The findings prompt further studies on the specific mechanisms involved and may contribute to the development of more effective treatment and prevention.

  • 47. Huenchuguala, Sandro
    et al.
    Sjödin, Birgitta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Segura-Aguilar, Juan
    Novel Alpha-Synuclein Oligomers Formed with the Aminochrome-Glutathione Conjugate Are Not Neurotoxic2019In: Neurotoxicity research, ISSN 1029-8428, E-ISSN 1476-3524, Vol. 35, no 2, p. 432-440Article in journal (Refereed)
    Abstract [en]

    Aminochrome induces neurotoxic alpha-synuclein oligomer formation relevant to the etiology of Parkinson's disease. Oxidative stress produces aminochrome from dopamine, but conjugation with glutathione catalyzed by glutathione transferase M2-2 significantly decreases aminochrome-induced toxicity and alpha-synuclein oligomer formation. Notably, in the presence of the aminochrome-glutathione conjugate, previously unknown species of alpha-synuclein oligomers are formed. These aminochrome-glutathione oligomers of alpha-synuclein differ from formerly characterized oligomers and (i) have high molecular weight, and are stable and SDS-resistant, as determined by the Western blot method, (ii) show positive NBT-quinone-protein staining, which indicates the formation of alpha-synuclein adducts containing aminochrome. Furthermore, aminochrome-glutathione alpha-synuclein oligomers (iii) have distinctive shape and size, as determined by transmission electron microscopy, and (iv) are not toxic in U373MG cells. In conclusion, glutathione conjugated with aminochrome induces a new type of alpha-synuclein oligomers of a different size and shape, which have no demonstrable toxicity.

  • 48. Iaccarino, Leonardo
    et al.
    Chiotis, Konstantinos
    Alongi, Pierpaolo
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden; Karolinska University Hospital Huddinge, Sweden.
    Wall, Anders
    Cerami, Chiara
    Bettinardi, Valentino
    Gianolli, Luigi
    Nordbereg, Agneta
    Perani, Daniela
    A Cross-Validation of FDG- and Amyloid-PET Biomarkers in Mild Cognitive Impairment for the Risk Prediction to Dementia due to Alzheimer's Disease in a Clinical Setting2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 59, no 2, p. 603-614Article in journal (Refereed)
    Abstract [en]

    Assessments of brain glucose metabolism (F-18-FDG-PET) and cerebral amyloid burden (C-11-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of F-18-FDGPET and C-11-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for F-18-FDG-PET and of standardized uptake value ratio semiquantification for C-11-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57 +/- 7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, F-18-FDG-PET and C-11-PiB-PET. F-18-FDG-PET, compared to C-11-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both F-18-FDG-PET and C-11-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.

  • 49. Ibáñez, Clara
    et al.
    Simó, Carolina
    Martín-Álvarez, Pedro J.
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Cedazo-Mínguez, Angel
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Cifuentes, Alejandro
    Toward a predictive model of Alzheimer's disease progression using capillary electrophoresis-mass spectrometry metabolomics2012In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 84, no 20, p. 8532-8540Article in journal (Refereed)
    Abstract [en]

    Alzheimer’s disease (AD) is the most prevalent form of dementia with an estimated worldwide prevalence of over 30 million people, and its incidence is expected to increase dramatically with an increasing elderly population. Up until now, cerebrospinal fluid (CSF) has been the preferred sample to investigate central nervous system (CNS) disorders since its composition is directly related to metabolite production in the brain. In this work, a nontargeted metabolomic approach based on capillary electrophoresis–mass spectrometry (CE–MS) is developed to examine metabolic differences in CSF samples from subjects with different cognitive status related to AD progression. To do this, CSF samples from 85 subjects were obtained from patients with (i) subjective cognitive impairment (SCI, i.e. control group), (ii) mild cognitive impairment (MCI) which remained stable after a follow-up period of 2 years, (iii) MCI which progressed to AD within a 2-year time after the initial MCI diagnostic and, (iv) diagnosed AD. A prediction model for AD progression using multivariate statistical analysis based on CE–MS metabolomics of CSF samples was obtained using 73 CSF samples. Using our model, we were able to correctly classify 97–100% of the samples in the diagnostic groups. The prediction power was confirmed in a blind small test set of 12 CSF samples, reaching a 83% of diagnostic accuracy. The obtained predictive values were higher than those reported with classical CSF AD biomarkers (Aβ42 and tau) but need to be confirmed in larger samples cohorts. Choline, dimethylarginine, arginine, valine, proline, serine, histidine, creatine, carnitine, and suberylglycine were identified as possible disease progression biomarkers. Our results suggest that CE–MS metabolomics of CSF samples can be a useful tool to predict AD progression.

  • 50. Imtiaz, Bushra
    et al.
    Tolppanen, Anna Maija
    Solomon, Alina
    Soininen, Hilkka
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Eastern Finland, Finland; National Institute for Health and Welfare, Finland .
    Estradiol and Cognition in the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Cohort Study2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 56, no 2, p. 453-458Article in journal (Refereed)
    Abstract [en]

    Cardiovascular Risk factors, Aging and Dementia (CAIDE) is a Finnish population-based study. 731 cognitively normal women had self-reported hormone therapy (HT) data in 1998 as: no use, use <= 5 years, and >5 years. Information on type of HT was only available from 1995-1998 (Prescription Register). Cognition was assessed in 1998 and 2005-2008. Longterm (>5 years) HT use, especially use of estradiol alone among women having hysterectomy with bilateral oophorectomy, was associated with better episodic memory in 1998, but not in 2005-2008. Although a strong evidence for protective effect of estradiol on cognition was not observed in our study, improved global cognition among long-term users suggests that long-term postmenopausal HT may be beneficial for some cognitive domains.

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