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  • 1.
    Allard, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Marcusson, J O
    Age-correlated loss of dopamine uptake sites labeled with [3H]GBR-12935 in human putamen.1989In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 10, no 6, p. 661-4Article in journal (Refereed)
    Abstract [en]

    The effects of age (19-100 years) upon dopamine uptake sites labeled with [3H]GBR-12935 in human postmortem putamen from 20 individuals were studied. There was a 70% decrease in binding density (Bmax) over the adult age range. No significant changes in binding affinity (Kd) were detected, the mean Kd being 1.0 +/- 0.2 nM (mean +/- S.E.M.). Nor were there any changes in binding related to the postmortem delay. Based on the findings that [3H]GBR-12935 labels the uptake site for dopamine, it is suggested that the age-related loss of [3H]GBR-12935 binding in human putamen reflects a degeneration of dopamine neurites.

  • 2. Andersson, A
    et al.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Eriksson, K
    Marcusson, J
    Platelet [3H]paroxetine binding to 5-HT uptake sites in Alzheimer's disease.1991In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 12, no 5, p. 531-4Article in journal (Refereed)
    Abstract [en]

    Platelet serotonin (5-hydroxytryptamine, 5-HT) uptake sites were studied in a control group (n = 30) and an Alzheimer group (n = 40) using [3H]paroxetine as radioligand. The maximum number of binding sites (Bmax) for control (1250 +/- 60 fmol/mg protein) was not different from the Alzheimer group (1280 +/- 40 fmol/mg protein). There were no differences in apparent binding affinity (Kd): 0.046 (0.024-0.062) nM for control and 0.040 (0.027-0.061) nM for Alzheimer. Thus even though several previous studies have demonstrated marked atrophy of 5-HT containing neurites and 5-HT uptake sites in Alzheimer's disease, these findings are not found in the periphery on platelets. The platelet 5-HT uptake site cannot be used as a peripheral marker of Alzheimer's disease.

  • 3. Bogaert, Elke
    et al.
    Goris, An
    Van Damme, Philip
    Geelen, Veerle
    Lemmens, Robin
    van Es, Michael A
    van den Berg, Leonard H
    Sleegers, Kristel
    Verpoorten, Nathalie
    Timmerman, Vincent
    Jonghe, Peter De
    Van Broeckhoven, Christine
    Traynor, Bryan J
    Landers, John E
    Brown, Robert H
    Glass, Jonathan D
    Al-Chalabi, Ammar
    Shaw, Christopher E
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Slowik, Agnieszka
    Tomik, Barbara
    Melki, Judith
    Robberecht, Wim
    Van Den Bosch, Ludo
    Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 2, p. 418-420Article in journal (Refereed)
    Abstract [en]

    Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated through the Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors and Ca(2+) permeability is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no nonsynonymous coding variants were observed but 24 polymorphisms were identified, 9 of which were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication set of 3157 cases and 5397 controls from 6 additional populations no association with susceptibility, age at onset, or disease duration was observed. We conclude that polymorphisms in the GluR2 gene (GRIA2) are not a major contributory factor in the pathogenesis of ALS.

  • 4.
    Bäckman, Lars
    et al.
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden.
    Karlsson, Sari
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden.
    Fischer, Håkan
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden.
    Karlsson, Per
    Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden.
    Brehmer, Yvonne
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden.
    Rieckmann, Anna
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden.
    Macdonald, Stuart WS
    Aging Research Center, Karolinska Institutet, Gävlegatan 16, SE-113 30 Stockholm, Sweden; Department of Psychology, University of Victoria, Canada .
    Farde, Lars
    Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Dopamine D(1) receptors and age differences in brain activation during working memory2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 10, p. 1849-1856Article in journal (Refereed)
    Abstract [en]

    In an fMRI study, 20 younger and 20 healthy older adults were scanned while performing a spatial working-memory task under two levels of load. On a separate occasion, the same subjects underwent PET measurements using the radioligand [(11)C] SCH23390 to determine dopamine D(1) receptor binding potential (BP) in caudate nucleus and dorsolateral prefrontal cortex (DLPFC). The fMRI study revealed a significant load modulation of brain activity (higher load>lower load) in frontal and parietal regions for younger, but not older, adults. The PET measurements showed marked age-related reductions of D(1) BP in caudate and DLPFC. Statistical control of caudate and DLPFC D(1) binding eliminated the age-related reduction in load-dependent BOLD signal in left frontal cortex, and attenuated greatly the reduction in right frontal and left parietal cortex. These findings suggest that age-related alterations in dopaminergic neurotransmission may contribute to underrecruitment of task-relevant brain regions during working-memory performance in old age.

  • 5. Canosa, Antonio
    et al.
    De Marco, Giovanni
    Lomartire, Annarosa
    Rinaudo, Maria Teresa
    Di Cunto, Ferdinando
    Turco, Emilia
    Barberis, Marco
    Brunetti, Maura
    Casale, Federico
    Moglia, Cristina
    Calvo, Andrea
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Mora, Gabriele
    Chio, Adriano
    A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms2018In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 72Article in journal (Refereed)
    Abstract [en]

    We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RTPCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate. 

  • 6.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Wennstedt, Sigrid
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Maintained memory in aging is associated with young epigenetic age2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 55, p. 167-171Article in journal (Refereed)
    Abstract [en]

    Epigenetic alterations during aging have been proposed to contribute to decline in physical and cognitive functions, and accelerated epigenetic aging has been associated with disease and all-cause mortality later in life. In this study, we estimated epigenetic age dynamics in groups with different memory trajectories (maintained high performance, average decline, and accelerated decline) over a 15-year period. Epigenetic (DNA-methylation [DNAm]) age was assessed, and delta age (DNAm age - chronological age) was calculated in blood samples at baseline (age: 55-65 years) and 15 years later in 52 age- and gender-matched individuals from the Betula study in Sweden. A lower delta DNAm age was observed for those with maintained memory functions compared with those with average (p = 0.035) or accelerated decline (p = 0.037). Moreover, separate analyses revealed that DNAm age at follow-up, but not chronologic age, was a significant predictor of dementia (p = 0.019). Our findings suggest that young epigenetic age contributes to maintained memory in aging.

  • 7. Diekstra, Frank P.
    et al.
    van Vught, Paul W. J.
    van Rheenen, Wouter
    Koppers, Max
    Pasterkamp, R. Jeroen
    van Es, Michael A.
    Schelhaas, Helenius J.
    de Visser, Marianne
    Robberecht, Wim
    van Damme, Philip
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    van den Berg, Leonard H.
    Veldink, Jan H.
    UNC13A is a modifier of survival in amyotrophic lateral sclerosis2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 3, p. 630.e3-630.e8Article in journal (Refereed)
    Abstract [en]

    A large genome-wide screen in patients with sporadic amyotrophic lateral sclerosis (ALS) showed that the common variant rs12608932 in gene UNC13A was associated with disease susceptibility. UNC13A regulates the release of neurotransmitters, including glutamate. Genetic risk factors that, in addition, modify survival, provide promising therapeutic targets in ALS, a disease whose etiology remains largely elusive. We examined whether UNC13A was associated with survival of ALS patients in a cohort of 450 sporadic ALS patients and 524 unaffected controls from a population-based study of ALS in The Netherlands. Additionally, survival data were collected from individuals of Dutch, Belgian, or Swedish descent (1767 cases, 1817 controls) who had participated in a previously published genome-wide association study of ALS. We related survival to rs12608932 genotype. In both cohorts, the minor allele of rs12608932 in UNC13A was not only associated with susceptibility but also with shorter survival of ALS patients. Our results further corroborate the role of UNC13A in ALS pathogenesis. (C) 2012 Elsevier Inc. All rights reserved.

  • 8. Glasø de Lange, Ann-Marie
    et al.
    Sjøli Bråthen, Anne Cecilie
    Grydeland, Håkon
    Sexton, Claire
    Johansen-Berg, Heidi
    Andersson, Jesper L. R.
    Rohani, Darius A.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Fjell, Anders M.
    Walhovd, Kristine B.
    White matter integrity as a marker for cognitive plasticity in aging2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 47, p. 74-82Article in journal (Refereed)
    Abstract [en]

    Age-related differences in white matter (WM) integrity are substantial, but it is unknown whether between subject variability in WM integrity influences the capacity for cognitive improvement. We investigated the effects of memory training related to active and passive control conditions in older adults and tested whether WM integrity at baseline was predictive of training benefits. We hypothesized that (1) memory improvement would be restricted to the training group, (2) widespread areas would show greater mean diffusivity (MD) and lower fractional anisotropy in older adults relative to young adults, and (3) within these areas, variability in WM microstructure in the older group would be predictive of training gains. The results showed that only the group receiving training improved their memory. Significant age differences in MD and fractional anisotropy were found in widespread areas. Within these areas, voxelwise analyses showed a negative relationship between MD and memory improvement in 3 clusters, indicating that WM integrity could serve as a marker for the ability to adapt in response to cognitive challenges in aging. 

  • 9.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Longitudinal association between hippocampus atrophy and episodic-memory decline2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 51, p. 167-176Article in journal (Refereed)
    Abstract [en]

    There is marked variability in both onset and rate of episodic-memory decline in aging. Structural magnetic resonance imaging studies have revealed that the extent of age-related brain changes varies markedly across individuals. Past studies of whether regional atrophy accounts for episodic-memory decline in aging have yielded inconclusive findings. Here we related 15-year changes in episodic memory to 4-year changes in cortical and subcortical gray matter volume and in white-matter connectivity and lesions. In addition, changes in word fluency, fluid IQ (Block Design), and processing speed were estimated and related to structural brain changes. Significant negative change over time was observed for all cognitive and brain measures. A robust brain-cognition change-change association was observed for episodic-memory decline and atrophy in the hippocampus. This association was significant for older (65-80 years) but not middle-aged (55-60 years) participants and not sensitive to the assumption of ignorable attrition. Thus, these longitudinal findings highlight medial-temporal lobe system integrity as particularly crucial for maintaining episodic-memory functioning in older age. 

  • 10.
    Gromicho, Marta
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Pinto, Susana
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Instituto de Medicina Molecular and Institute of Physiology, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, Lisbon, Portugal.
    Gisca, Eugeniu
    Pronto-Laborinho, Ana Catarina
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    de Carvalho, Mamede
    Frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese patients with amyotrophic lateral sclerosis2018In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 70, article id 325.e7Article in journal (Refereed)
    Abstract [en]

    Mutation frequency of the 2 main amyotrophic lateral sclerosis (ALS) erelated genes, C9orf72 and SOD1, varies considerably across the world. We analyzed those genes in a large population of Portuguese ALS patients (n = 371) and recorded demographic and clinical features. Familial ALS (FALS) was disclosed in 11.6% of patients. Mutations in either SOD1 or C9orf72 were found in 9.2% of patients and accounted for 40% of FALS and 5.2% of sporadic ALS. SOD1 mutations were rare (0.83%), but a novel and probably disease-causing mutation was identified: p. Ala152Pro (c. 457G>C). The C9orf72 hexanucleotide repeat expansion was the commonest abnormality, accounting for 4.6% of sporadic ALS and 37.5% of FALS; in these patients, Frontotemporal Dementia was prevalent. This first report on the frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese ALS patients reiterate that the genetic architecture of ALS varies among different geographic regions. The mutations incidence in ALS patients (w10%) and associated phenotypes suggest that genetic tests should be offered to more patients, and other genes should be investigated in our population. 

  • 11.
    Ingre, Caroline
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Department of Neurology, The Karolinske University Hospital Huddinge, Stockholm, Sweden.
    Landers, John E.
    Rizik, Naji
    Volk, Alexander E.
    Akimoto, Chizuru
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hubers, Annemarie
    Keagle, Pamela J.
    Piotrowska, Katarzyna
    Press, Rayomand
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Neurology, Ulm University, Ulm, Germany.
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 6, article id 1708.e1Article in journal (Refereed)
    Abstract [en]

    Profilin 1 is a central regulator of actin dynamics. Mutations in the gene profilin 1 (PFN1) have veryrecently been shown to be the cause of a subgroup of amyotrophic lateral sclerosis (ALS). Here, weperformed a large screen of US, Nordic, and German familial and sporadic ALS and frontotemporaldementia (FTLD) patients for PFN1 mutations to get further insight into the spectrum and pathogenicrelevance of this gene for the complete ALS/FTLD continuum. Four hundred twelve familial and 260sporadic ALS cases and 16 ALS/FTLD cases from Germany, the Nordic countries, and the United Stateswere screened for PFN1 mutations. Phenotypes of patients carrying PFN1 mutations were studied. Ina German ALS family we identified the novel heterozygous PFN1 mutation p.Thr109Met, which wasabsent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. The recentlydescribed p.Gln117Gly sequence variant was found in another familial ALS patient from the United States.The ALS patients with mutations in PFN1 displayed spinal onset motor neuron disease without overtcognitive involvement. PFN1 mutations were absent in patients with motor neuron disease anddementia, and in patients with only FTLD. We provide further evidence that PFN1 mutations can causeALS as a Mendelian dominant trait. Patients carrying PFN1 mutations reported so far represent the“classic” ALS end of the ALS-FTLD spectrum. The novel p.Thr109Met mutation provides additional proofof-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motorneuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization byphosphorylation of profilin 1 might be necessary for motor neuron survival.

  • 12. Janovjak, Harald
    et al.
    Kedrov, Alexej
    Cisneros, David A.
    Center of Biotechnology, University of Technology and Max-Planck-Institute of Molecular Cell Biology and Genetics, Tatzberg 49, D-01307 Dresden, Germany.
    Sapra, K Tanuj
    Struckmeier, Jens
    Muller, Daniel J
    Imaging and detecting molecular interactions of single transmembrane proteins2006In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 27, no 4, p. 546-561Article in journal (Refereed)
    Abstract [en]

    Single-molecule atomic force microscopy (AFM) provides novel ways to characterize structure-function relationships of native membrane proteins. High-resolution AFM-topographs allow observing substructures of single membrane proteins at sub-nanometer resolution as well as their conformational changes, oligomeric state, molecular dynamics and assembly. Complementary to AFM imaging, single-molecule force spectroscopy experiments allow detecting molecular interactions established within and between membrane proteins. The sensitivity of this method makes it possible to detect the interactions that stabilize secondary structures such as transmembrane alpha-helices, polypeptide loops and segments within. Changes in temperature or protein-protein assembly do not change the position of stable structural segments, but influence their stability established by collective molecular interactions. Such changes alter the probability of proteins to choose a certain unfolding pathway. Recent examples have elucidated unfolding and refolding pathways of membrane proteins as well as their energy landscapes. We review current and future potential of these approaches to reveal insights into membrane protein structure, function, and unfolding as we recognize that they could help answering key questions in the molecular basis of certain neuro-pathological dysfunctions.

  • 13.
    Kalpouzos, Grégoria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Persson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Local brain atrophy accounts for functional activity differences in normal aging.2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 3, p. 623.e1-623.e13Article in journal (Refereed)
    Abstract [en]

    Functional brain imaging studies of normal aging typically show age-related under- and overactivations during episodic memory tasks. Older individuals also undergo nonuniform gray matter volume (GMv) loss. Thus, age differences in functional brain activity could at least in part result from local atrophy. We conducted a series of voxel-based blood oxygen level-dependent (BOLD)-GMv analyses to highlight whether age-related under- and overrecruitment was accounted for by GMv changes. Occipital GMv loss accounted for underrecruitment at encoding. Efficiency reduction of sensory-perceptual mechanisms underpinned by these areas may partly be due to local atrophy. At retrieval, local GMv loss accounted for age-related overactivation of left dorsolateral prefrontal cortex, but not of left dorsomedial prefrontal cortex. Local atrophy also accounted for age-related overactivation in left lateral parietal cortex. Activity in these frontoparietal regions correlated with performance in the older group. Atrophy in the overrecruited regions was modest in comparison with other regions as shown by a between-group voxel-based morphometry comparison. Collectively, these findings link age-related structural differences to age-related functional under- as well as overrecruitment.

  • 14.
    Nilsson, Lars-Göran
    et al.
    Umeå University, Faculty of Social Sciences, Centre for Population Studies (CPS).
    Sternäng, Ola
    Department of Psychology, Stockholm University, Sweden.
    Rönnlund, Michael
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Social Sciences, Centre for Population Studies (CPS).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Social Sciences, Centre for Population Studies (CPS).
    Challenging the notion of an early-onset of cognitive decline.2009In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 30, no 4, p. 521-524; discussion 530Article in journal (Other academic)
    Abstract [en]

    Salthouse claims that cognitive aging starts around 20 years of age. The basis for this claim is cross-sectional data. He dismisses longitudinal data, which typically show the cognitive decline to start much later, around 60 years of age. He states that longitudinal data cannot be trusted because they are flawed. There is a confounding between the effects of maturation and retest effects. We challenge Salthouse's strong claim on four accounts.

  • 15.
    Olofsson, Jonas K
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nordin, Steven
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Wiens, Stefan
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Hedner, Margareta
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Larsson, Maria
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Odor identification impairment in carriers of ApoE-ε4 is independent of clinical dementia2010In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 31, no 4, p. 567-577Article in journal (Refereed)
    Abstract [en]

    The ApoE gene is expressed in olfactory brain structures and is believed to play a role in neuronal regenerative processes as well as in development of Alzheimer's disease (AD), the most common form of dementia. The ε4 allele has been reported to be associated with compromised odor identification ability in the elderly, and this deficit has been interpreted as a sign of pre-diagnostic AD. However, because it has not been demonstrated that the relationship between the ε4 allele and odor identification is mediated by dementia, it is possible that the ε4 allele may have an effect on odor identification over and above any effects of dementia. The present study investigated effects of ApoE-status on odor identification in a large, population-based sample (n = 1236) of adults (45–80 years), who were assessed for dementia at time of testing and 5 years later. The results showed that the ε4 allele was associated with an odor identification deficit among elderly participants (75–80). Critically, this effect remained after current and pre-diagnostic dementia, vocabulary, global cognitive status and health variables were partialled out. The present results suggest that the ApoE gene plays a role in olfactory functioning that is independent of dementia conversion within 5 years.

  • 16.
    Persson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Psychology, Aging Research Center (ARC) at Karolinska Institute and Stockholm University, Stockholm, Sweden and Department of Psychology, Stockholm University, Stockholm, Sweden.
    Pudas, Sara
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Psychology, Stockholm University, Stockholm, Sweden.
    Nilsson, Lars-Göran
    Karolinska Inst, Aging Res Ctr ARC, S-11330 Stockholm, Sweden and Stockholm Univ, Dept Psychol, S-11330 Stockholm, Sweden.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Longitudinal assessment of default-mode brain function in aging2014In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 35, no 9, p. 2107-2117Article in journal (Refereed)
    Abstract [en]

    Age-related changes in the default-mode network (DMN) have been identified in prior cross-sectional functional magnetic resonance imaging studies. Here, we investigated longitudinal change in DMN activity and connectivity. Cognitively intact participants (aged 49-79 years at baseline) were scanned twice, with a 6-year interval, while performing an episodic memory task interleaved with a passive control condition. Longitudinal analyses showed that the DMN (control condition > memory task) could be reliably identified at both baseline and follow-up. Differences in the magnitude of task-induced deactivation in posterior DMN regions were observed between baseline and follow-up indicating reduced deactivation in these regions with increasing age. Although no overall longitudinal changes in within-network connectivity were found across the whole sample, individual differences in memory change correlated with change in connectivity. Thus, our results show stability of whole-brain DMN topology and functional connectivity over time in healthy older adults, whereas within-region DMN analyses show reduced deactivation between baseline and follow-up. The current findings provide novel insights into DMN functioning that may assist in identifying brain changes in patient populations, as well as characterizing factors that distinguish between normal and pathologic aging.

  • 17. Pihlstrom, Lasse
    et al.
    Axelsson, Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Bjornara, Kari Anne
    Dizdar, Nil
    Fardell, Camilla
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Holmberg, Björn
    Larsen, Jan Petter
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nissbrandt, Hans
    Tysnes, Ole-Bjorn
    Öhman, Eilert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Dietrichs, Espen
    Toft, Mathias
    Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 6, p. 1708.e7-1708.e13Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinson's disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted. (C) 2013 Elsevier Inc. All rights reserved.

  • 18.
    Pudas, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Psychology, Stockholm University, Stockholm.
    Persson, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Psychology, Stockholm University, Aging Research Center, Karolinska Institute and Stockholm University, Stockholm.
    Nilsson, Lars-Göran
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Aging Research Center, Karolinska Institute and Stockholm University, Stockholm.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Midlife memory ability accounts for brain activity differences in healthy aging2014In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 35, no 11, p. 2495-2503Article in journal (Refereed)
    Abstract [en]

    Cross-sectional neuroimaging studies suggest that hippocampal and prefrontal cortex functions underlie individual differences in memory ability in older individuals, but it is unclear how individual differences in cognitive ability in youth contribute to cognitive and neuroimaging measures in older age. Here, we investigated the relative influences of midlife memory ability and age-related memory change on memory-related BOLD-signal variability at one time point, using a sample from a longitudinal population-based aging study (N = 203, aged 55-80 years). Hierarchical regression analyses showed that midlife memory ability, assessed 15-20 years earlier, explained at least as much variance as memory change in clusters in the left inferior prefrontal cortex and the bilateral hippocampus, during memory encoding. Furthermore, memory change estimates demonstrated higher sensitivity than current memory levels in identifying distinct frontal regions where activity was selectively related to age-related memory change, as opposed to midlife memory. These findings highlight challenges in interpreting individual differences in neurocognitive measures as age-related changes in the absence of longitudinal data and also demonstrate the improved sensitivity of longitudinal measures.

  • 19. Rademakers, R
    et al.
    Sleegers, K
    Theuns, J
    Van den Broeck, M
    Kacem, S B
    Nilsson, L G
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    van Duijn, C M
    Van Broeckhoven, C
    Cruts, M
    Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease2005In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 26, no 8, p. 1145-1151Article in journal (Refereed)
    Abstract [en]

    Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5RI) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G > C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.

  • 20. Ran, Caroline
    et al.
    Brodin, Lovisa
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Westerlund, Marie
    Ramezani, Mehrafarin
    Gellhaar, Sandra
    Xiang, Fengqing
    Fardell, Camilla
    Nissbrandt, Hans
    Söderkvist, Peter
    Puschmann, Andreas
    Ygland, Emil
    Olson, Lars
    Willows, Thomas
    Johansson, Anders
    Sydow, Olof
    Wirdefeldt, Karin
    Galter, Dagmar
    Svenningsson, Per
    Belin, Andrea Carmine
    Strong association between glucocerebrosidase mutations and Parkinson's disease in Sweden2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 45, article id 212.e5Article in journal (Refereed)
    Abstract [en]

    Several genetic studies have demonstrated an association between mutations in glucocerebrosidase (GBA), originally implicated in Gaucher's disease, and an increased risk of Parkinson's disease (PD). We have investigated the possible involvement of genetic GBA variations in PD in the Swedish population. Three GBA variants, E326K, N370S, and L444P were screened in the largest Swedish Parkinson cohort reported to date; 1625 cases and 2025 control individuals. We found a significant association with high effect size of the rare variant L444P with PD (odds ratio 8.17; 95% confidence interval: 2.51-26.23; p-value = 0.0020) and a significant association of the common variant E326K (odds ratio 1.60; 95% confidence interval: 1.16-2.22; p-value = 0.026). The rare variant N370S showed a trend for association. Most L444P carriers (68%) were found to reside in northern Sweden, which is consistent with a higher prevalence of Gaucher's disease in this part of the country. Our findings support the role of GBA mutations as risk factors for PD and point to lysosomal dysfunction as a mechanism contributing to PD etiology.

  • 21.
    Rieckmann, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.
    Van Dijk, Koene R. A.
    Sperling, Reisa A.
    Johnson, Keith A.
    Buckner, Randy L.
    Hedden, Trey
    Accelerated decline in white matter integrity in clinically normal individuals at risk for Alzheimer's disease2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 42, p. 177-188Article in journal (Refereed)
    Abstract [en]

    Prior studies have identified white matter abnormalities in Alzheimer's disease (AD). Yet, cross-sectional studies in normal older individuals show little evidence for an association between markers of AD risk (APOE4 genotype and amyloid deposition), and white matter integrity. Here, 108 normal older adults (age, 66-87) with assessments of apolipoprotein e4 (APOE4) genotype and assessment of amyloid burden by positron emission tomography underwent diffusion tensor imaging scans for measuring white matter integrity at 2 time points, on average 2.6 years apart. Linear mixed-effects models showed that amyloid burden at baseline was associated with steeper decline in fractional anisotropy in the parahippocampal cingulum (p < 0.05). This association was not significant between baseline measures suggesting that longitudinal analyses can provide novel insights that are not detectable in cross-sectional designs. Amyloid-related changes in hippocampus volume did not explain the association between amyloid burden and change in fractional anisotropy. The results suggest that accumulation of cortical amyloid and white matter changes in parahippocampal cingulum are not independent processes in individuals at increased risk for AD.

  • 22. Sproviero, William
    et al.
    Shatunov, Aleksey
    Stahl, Daniel
    Shoai, Maryam
    van Rheenen, Wouter
    Jones, Ashley R.
    Al-Sarraj, Safa
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bonini, Nancy M
    Conforti, Francesca L
    Van Damme, Philip
    Daoud, Hussein
    Del Mar Amador, Maria
    Fogh, Isabella
    Forzan, Monica
    Gaastra, Ben
    Gellera, Cinzia
    Gitler, Aaron D
    Hardy, John
    Fratta, Pietro
    La Bella, Vincenzo
    Le Ber, Isabelle
    Van Langenhove, Tim
    Lattante, Serena
    Lee, Yi-Chung
    Malaspina, Andrea
    Meininger, Vincent
    Millecamps, Stéphanie
    Orrell, Richard
    Rademakers, Rosa
    Robberecht, Wim
    Rouleau, Guy
    Ross, Owen A
    Salachas, Francois
    Sidle, Katie
    Smith, Bradley N
    Soong, Bing-Wen
    Sorarù, Gianni
    Stevanin, Giovanni
    Kabashi, Edor
    Troakes, Claire
    van Broeckhoven, Christine
    Veldink, Jan H
    van den Berg, Leonard H
    Shaw, Christopher E
    Powell, John F
    Al-Chalabi, Ammar
    ATXN2 trinucleotide repeat length correlates with risk of ALS2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 51, p. 178.e1-178.e9Article in journal (Refereed)
    Abstract [en]

    We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10(-18)), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R(2) = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.

  • 23. Van Doormaal, Perry T. C.
    et al.
    Ticozzi, Nicola
    Gellera, Cinzia
    Ratti, Antonia
    Taroni, Franco
    Chio, Adriano
    Calvo, Andrea
    Mora, Gabriele
    Restagno, Gabriella
    Traynor, Bryan J.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lemmens, Robin
    Van Es, Michael A.
    Saris, Christiaan G. J.
    Blauw, Hylke M.
    Van Vught, Paul W. J.
    Groen, Ewout J. N.
    Corrado, Lucia
    Mazzini, Letizia
    Del Bo, Roberto
    Corti, Stefania
    Waibel, Stefan
    Meyer, Thomas
    Ludolph, Albert C.
    Goris, An
    Van Damme, Philip
    Robberecht, Wim
    Shatunov, Aleksey
    Fogh, Isabella
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    D'Alfonso, Sandra
    Hardiman, Orla
    Cronin, Simon
    Rujescu, Dan
    Al-Chalabi, Ammar
    Landers, John E.
    Silani, Vincenzo
    Van den Berg, Leonard H.
    Veldink, Jan H.
    Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study2014In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 35, no 10, p. 2420.e13-Article in journal (Refereed)
  • 24. van Rheenen, Wouter
    et al.
    Diekstra, Frank P
    van Doormaal, Perry TC
    Seelen, Meinie
    Kenna, Kevin
    McLaughlin, Russell
    Shatunov, Aleksey
    Czell, David
    van Es, Michael A
    van Vught, Paul WJ
    van Damme, Philip
    Smith, Bradley N
    Waibel, Stefan
    Schelhaas, H Jurgen
    van der Kooi, Anneke J
    de Visser, Marianne
    Weber, Markus
    Robberecht, Wim
    Hardiman, Orla
    Shawi, Pamela J
    Shaw, Christopher E
    Morrison, Karen E
    Al-Chalabi, Ammar
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ludolph, Albert C
    Veldink, Jan H
    van den Berg, Leonard H
    H63D polymorphism in HFE is not associated with amyotrophic lateral sclerosis2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 5, p. 1517.e5-1517.e7Article in journal (Refereed)
    Abstract [en]

    The H63D polymorphism in HFE has frequently been associated with susceptibility to amyotrophic lateral sclerosis (ALS). Regarding the role of HFE in iron homeostasis, iron accumulation is considered an important process in ALS. Furthermore, novel therapeutic strategies are being developed targeting this process. Evidence for this genetic association is, however, limited to several small studies. For this reason we studied the H63D polymorphism in a large European cohort including 3962 ALS patients and 5072 control subjects from 7 countries. After meta-analysis of previous studies and current findings we conclude that the H63D polymorphism in HFE is not associated with susceptibility to ALS, age at disease onset, or survival. (C) 2013 Elsevier Inc. All rights reserved.

  • 25. Weishaupt, Jochen H
    et al.
    Waibel, Stefan
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Volk, Alexander E
    Mayer, Benjamin
    Meyer, Thomas
    Ludolph, Albert C
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    A novel optineurin truncating mutation and three glaucoma-associated missense variants in patients with familial amyotrophic lateral sclerosis in Germany2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 5, p. 1516.e9-1516.e15Article in journal (Refereed)
    Abstract [en]

    Mutations in the optineurin (OPTN) gene have been associated with normal tension glaucoma and with amyotrophic lateral sclerosis (ALS). Here, we screened German familial ALS cases for OPTN mutations to gain additional insight into the spectrum and pathogenic relevance of this gene for ALS. One hundred familial German ALS cases and 148 control subjects were screened for OPTN mutations by sequence analysis of the complete OPTN coding sequence, and phenotypes of OPTN mutant patients were described. We identified a novel heterozygous truncating OPTN mutation p.Lys440Asnfs*8 in 1 ALS family with an aggressive ALS disease phenotype. This mutation abolishes protein domains crucial for nuclear factor kappa B signaling. Moreover, we detected 3 different nonsynonymous sequence variants, which have been described previously as risk factors for primary retinal ganglion cell degeneration in normal tension glaucoma. Two of them were detected on the same allele in a family that also carries a p.Asn352Ser disease mutation in the ALS gene TARDBP. All OPTN mutant patients presented with typical spinal onset ALS. Taken together, we detected a novel truncating OPTN mutation associated with an aggressive form of ALS and confirmed that OPTN mutations are a rare cause of ALS. In addition our data suggest that in some cases plausibly more than 1 mutation in OPTN or another ALS gene might be needed to cause ALS. Finally, our findings show that motoneurons and retinal ganglion cells, which are both projecting central nervous system neurons, might share common susceptibility factors. (C) 2013 Elsevier Inc. All rights reserved.

  • 26.
    Wikgren, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Karlsson, Thomas
    Linköping University, Department of Behavioral Sciences and Learning.
    Nilbrink, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nordfjäll, Katarina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Sleegers, Kristel
    VIB, Department of Molecular Genetics.
    Van Broeckhoven, Christine
    VIB, Department of Molecular Genetics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nilsson, Lars-Göran
    Stockholm University, Department of Psychology.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    APOE ε4 is associated with longer telomeres, and longer telomeres among ε4 carriers predicts worse episodic memory2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 2, p. 335-344Article in journal (Refereed)
    Abstract [en]

    Both leukocyte telomere length and the apolipoprotein epsilon4 allele have been associated with mortality, cardiovascular disease, cognition, and dementia. The authors investigated whether leukocyte telomere length was associated with APOE genotype or cognitive abilities in the context of APOE genotype. The setting for this cross-sectional study was 427 nondemented individuals aged 41-81 yr. The authors found that epsilon4 carriers overall exhibited significantly longer telomeres compared with non-carriers (difference of 268 bp, p = 0.001). This difference was greatest at the lower limit of the age span and nonsignificant at the upper limit, which translated into a significantly higher telomere attrition rate (p = 0.049) among epsilon4 carriers (37 bp/years) compared with non-carriers (21 bp/year). Further, longer telomeres among epsilon4 carriers significantly predicted worse performance on episodic memory tasks. No significant associations were found on tasks tapping semantic and visuospatial ability, or among epsilon3/epsilon3 carriers. In conclusion, APOE epsilon4 carriers had longer telomeres compared with non-carriers, but higher rate of attrition. Among them, longer telomeres predicted worse performance on episodic memory tasks. These observations suggest that the epsilon4 allele is associated with abnormal cell turnover of functional and possibly clinical significance.

  • 27.
    Wåhlin, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ambarki, Khalid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Malm, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Intracranial pulsatility is associated with regional brain volume in elderly individuals2014In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 35, no 2, p. 365-372Article in journal (Refereed)
    Abstract [en]

    Excessive intracranial pulsatility is thought to damage the cerebral microcirculation, causing cognitive decline in elderly individuals. We investigated relationships between brain structure and measures related to intracranial pulsatility among healthy elderly. Thirty-seven stroke-free, non-demented individuals (62-82 years of age) were included. We assessed brain structure, invasively measured cerebrospinal fluid (CSF) pulse pressure, and magnetic resonance-quantified arterial and CSF flow pulsatility, as well as arterial pulse pressure. Using both multivariate partial least squares and ordinary regression analyses, we identified a significant pattern of negative relationships between the volume of several brain regions and measures of intracranial pulsatility. The strongest relationships concerned the temporal lobe cortex and hippocampus. These findings were also coherent with observations of positive relationships between intracranial pulsatility and ventricular volume. In conclusion, elderly subjects with high intracranial pulsatility display smaller brain volume and larger ventricles, supporting the notion that excessive cerebral arterial pulsatility harms the brain. This calls for research investigating altered intracranial cardiac-related pulsatile stress as a potential risk factor that may cause or worsen the prognosis in subjects developing cognitive impairment and dementia.

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