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  • 1.
    Bäckman, Lars
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Karlsson, Sari
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fischer, Håkan
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Karlsson, Per
    Brehmer, Yvonne
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Rieckmann, Anna
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    MacDonald, Stuart W. S.
    Farde, Lars
    Nyberg, Lars
    Dopamine D1 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 [11C] SCH23390 to determine dopamine D1 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 D1 BP in caudate and DLPFC. Statistical control of caudate and DLPFC D1 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.

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

    Recently, we reported that 3 of the known risk factors of Alzheimer's disease (AD), i.e., advanced age, apolipoprotein E (ApoE) ε4, and female gender, are associated with differential levels of ApoE proteins and butyrylcholinesterase (BuChE) in the cerebrospinal fluid (CSF) of AD patients. The ApoE ε4 allele and certain BuChE polymorphisms synergistically affect the conversion rate of mild cognitive impairment (MCI) to AD. Here, we investigated interrelationships between ApoE and BuChE levels, and pathological markers of AD in vivo. CSF from patients with probable AD, assessed for cerebral glucose metabolism (CMRglc; n = 50) and Pittsburgh compound B (PIB) retention (β-amyloid [Aβ] load, n = 29) by positron emission tomography (PET), was used for measurement of BuChE, ApoE, Aβ, tau, phosphorylated tau (P-tau) and interleukin-1β (IL-1β) levels. Levels of ApoE and BuChE strongly correlated with CMRglc (fluorodeoxyglucose [FDG]-PET, r = 0.54, p < 0.0001, n = 50), cerebral Aβ load (PIB retention, r = 0.73, p < 0.0001, n = 29), and CSF P-tau (r = 0.73, p < 0.0001, n = 33). High ApoE protein was tied to low CMRglc and high PIB retention and P-tau. BuChE levels had opposite relationships. Other CSF covariates were levels of interleukin-1β and Aβ42peptide. The pattern of the patients' cognitive Z-scores strongly supported these observations. High ApoE protein was also linked to changes in 3 of the biodynamic properties of BuChE. In vitro analysis indicated that high ApoE protein levels were related to an increased pool of dormant BuChE molecules with an abnormally high intrinsic catalytic rate in CSF, which was “turned on” by excess Aβ peptides. The findings suggest that abnormally high levels of ApoE may play a causative role in the pathological events of AD, particularly those involving the early cholinergic deficit in the AD brain, through modulation of cholinesterases activities, hence disturbing the acetylcholine-dependent activity of neurons and nonexcitable cells such as glial cells.

  • 3. Darreh-Shori, Taher
    et al.
    Vijayaraghavan, Swetha
    Aeinehband, Shahin
    Piehl, Fredrik
    Lindblom, Rickard P. F.
    Nilsson, Bo
    Ekdahl, Kristina N.
    Långström, Bengt
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Nordberg, Agneta
    Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 11, p. 2465-2481Article in journal (Refereed)
    Abstract [en]

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

  • 4.
    Dintica, Christina S.
    et al.
    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).
    Marseglia, Anna
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Kalpouzos, Gregoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Welmer, Anna-Karin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wardh, Inger
    Bäckman, Lars
    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). Tianjin Medical University, China.
    Tooth loss is associated with accelerated cognitive decline and volumetric brain differences: a population-based study2018In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 67, p. 23-30Article in journal (Refereed)
    Abstract [en]

    Tooth loss has been related to cognitive impairment; however, its relation to structural brain differences in humans is unknown. Dementia-free participants (n = 2715) of age >= 60 years were followed up for up to 9 years. A subsample (n = 394) underwent magnetic resonance imaging at baseline. Information on tooth loss was collected at baseline, and cognitive function was assessed using the Mini-Mental State Examination at baseline and at follow-ups. Data were analyzed using linear mixed effects models and linear regression models. At baseline, 404 (14.9%) participants had partial tooth loss, and 206 (7.6%) had complete tooth loss. Tooth loss was significantly associated with a steeper cognitive decline (beta: -0.18, 95% confidence interval [CI]: -0.24 to -0.11) and remained significant after adjusting for or stratifying by potential confounders. In cross-sectional analyses, persons with complete or partial tooth loss had significantly lower total brain volume (beta: -28.89, 95% CI: -49.33 to -8.45) and gray matter volume (beta: -22.60, 95% CI: -38.26 to -6.94). Thus, tooth loss may be a risk factor for accelerated cognitive aging.

  • 5. Enache, Daniela
    et al.
    Solomon, Alina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska Institutet, Sweden; University of Eastern Finland, Finland.
    Cavallin, Lena
    Kåreholt, Ingemar
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Jönköping University, Sweden.
    Gregoric Kramberger, Milica
    Aarsland, Dag
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden; University of Eastern Finland, Finland.
    Eriksdotter, Maria
    Winblad, Bengt
    Jelic, Vesna
    CAIDE Dementia Risk Score and biomarkers of neurodegeneration in memory clinic patients without dementia2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 42, p. 124-131Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to explore cross-sectional associations between Cardiovascular Risk Factors, Aging and Dementia Study (CAIDE) Dementia Risk Score and dementia-related cerebrospinal fluid and neuroimaging biomarkers in 724 patients without dementia from the Memory Clinic at Karolinska University Hospital, Huddinge, Sweden. We additionally evaluated the score's capacity to predict dementia. Two risk score versions were calculated: one including age, gender, obesity, hyperlipidemia, and hypertension; and one additionally including apolipoprotein E (APOE) epsilon 4 carrier status. Cerebrospinal fluid was analyzed for amyloid beta (A beta), total tau, and phosphorylated tau. Visual assessments of medial temporal lobe atrophy (MTA), global cortical atrophy-frontal subscale, and Fazekas scale for white matter changes (WMC) were performed. Higher CAIDE Dementia Risk Score (version without APOE) was significantly associated with higher total tau, more severe MTA, WMC, and global cortical atrophy-frontal subscale. Higher CAIDE Dementia Risk Score (version with APOE) was associated with reduced A beta, more severe MTA, and WMC. CAIDE Dementia Risk Score version with APOE seemed to predict dementia better in this memory clinic population with short follow-up than the version without APOE.

  • 6.
    Ferrari, Camilla
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Xu, Wei-Li
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Hui-Xin
    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).
    Sorbi, Sandro
    Qiu, Chengxuan
    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).
    How can elderly apolipoprotein E epsilon 4 carriers remain free from dementia?2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 1, p. 13-21Article in journal (Refereed)
    Abstract [en]

    Apolipoprotein E (APOE) epsilon 4 is a major risk factor for Alzheimer's disease (AD) and dementia, but not all epsilon 4 carriers develop dementia. We sought to identify factors that may play a role in modifying the risk of dementia due to epsilon 4. A cognitively intact cohort (n = 932, age >= 75) was followed for 9 years to detect incident dementia cases. At baseline, information on education, leisure activities, and vascular risk factors was collected, and APOE was genotyped. During the follow-up, 324 subjects developed dementia, including 247 AD cases. The hazard ratio (HR, 95% confidence interval [95% CI]) of dementia related to the epsilon 4 was 1.39 (1.11-1.76), while the risk was reduced when epsilon 4 carriers had high education, no vascular risk factors, or high score of leisure activities. Among epsilon 4 carriers, the multiadjusted HRs of dementia that were associated with high education, high level of leisure activities, and absence of vascular risk factors were 0.59 (0.40-0.87), 0.49 (0.29-0.85), and 0.61 (0.41-0.90), respectively. The epsilon 4 carriers with these factors had about 1.2 years delayed time to dementia onset compared with those without these factors. High education, active leisure activities, or maintaining vascular health seems to reduce the risk of dementia related to APOE epsilon 4. The epsilon 4 carriers with these characteristics appear to have similar dementia-free survival time to non-epsilon 4 carriers.

  • 7. Forsberg, Anton
    et al.
    Engler, Henry
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Blomquist, Gunnar
    Hagman, Göran
    Wall, Anders
    Ringheim, Anna
    Långström, Bengt
    Nordberg, Agneta
    PET imaging of amyloid deposition in patients with mild cognitive impairment2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 10, p. 1456-1465Article in journal (Refereed)
    Abstract [en]

    It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3 ± 7.8 (S.D.) years) underwent PET studies with 11C-PIB, and 18F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1 ± 6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps < 0.01). The PIB retention in MCI converters was comparable to AD patients (p > 0.01). Correlations were observed in the MCI patients between PIB retention and CSF Aβ1-42, total Tau and episodic memory, respectively.

  • 8. Forsell, Charlotte
    et al.
    Björk, Behnosh Fakhri
    Lilius, Lena
    Axelman, Karin
    Fabre, Susanne Froelich
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, Bengt
    Graff, Caroline
    Genetic association to the amyloid plaque associated protein gene COL25A1 in Alzheimer's disease2010In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 31, no 3, p. 409-415Article in journal (Refereed)
    Abstract [en]

    The COL25A1 gene, located in 4q25, encodes the CLAC protein, which has been implicated in Alzheimer's disease (AD) pathogenesis. CLAC was originally identified in amyloid preparations from AD brain and has been shown to be associated with amyloid plaques, inhibition of Abeta-fibril elongation and increased protease resistance of Abeta-fibrils through direct binding to Abeta. These biochemical data as well as the genomic location of the COL25A1 gene in chromosome 4q25 where we previously have reported a weak linkage-signal in Swedish AD families encouraged us to perform a case-control association study of two LD blocks in COL25A1 using 817 AD cases and 364 controls. The LD blocks cover a putative Abeta-binding motif and the variable 3' end of the gene. The analyses indicated association to three of eight analysed SNPs. We found further support for the association by replication in a Swedish population-based longitudinal sample set (n=926). Thus, in addition to the biochemical data, there is now genetic evidence of association between COL25A1 and risk for Alzheimer's disease.

  • 9. Gorbach, Tetiana
    et al.
    Pudas, Sara
    Lundquist, Anders
    Orädd, Greger
    Josefsson, Maria
    Salami, Alireza
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Umeå University, Sweden.
    de Luna, Xavier
    Nyberg, Lars
    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. Horta, Marilyn
    et al.
    Ziaei, Maryam
    Lin, Tian
    Porges, Eric C.
    Fischer, Håkan
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology.
    Feifel, David
    Spreng, R. Nathan
    Ebner, Natalie C.
    Oxytocin alters patterns of brain activity and amygdalar connectivity by age during dynamic facial emotion identification2019In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 78, p. 42-51Article in journal (Refereed)
    Abstract [en]

    Aging is associated with increased difficulty in facial emotion identification, possibly due to age-related network change. The neuropeptide oxytocin (OT) facilitates emotion identification, but this is understudied in aging. To determine the effects of OT on dynamic facial emotion identification across adulthood, 46 young and 48 older participants self-administered intranasal OT or a placebo in a randomized, double-blind procedure. Older participants were slower and less accurate in identifying emotions. Although there was no behavioral treatment effect, partial least squares analysis supported treatment effects on brain patterns during emotion identification that varied by age and emotion. For young participants, OT altered the processing of sadness and happiness, whereas for older participants, OT only affected the processing of sadness (15.3% covariance, p = 0.004). Furthermore, seed partial least squares analysis showed that older participants in the OT group recruited a large-scale amygdalar network that was positively correlated for anger, fear, and happiness, whereas older participants in the placebo group recruited a smaller, negatively correlated network (7% covariance, p = 0.002). Advancing the literature, these findings show that OT alters brain activity and amygdalar connectivity by age and emotion.

  • 11.
    Kadir, Ahmadul
    et al.
    Karolinska Institutet.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Forsberg, Anton
    Karolinska Institutet.
    Wall, Anders
    Engler, Henry
    Uppsala University Hospital.
    Långström, Bengt
    Uppsala Universitet.
    Nordberg, Agneta
    Karolinska Institutet.
    Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 1, p. 198.e1-198.e14Article in journal (Refereed)
    Abstract [en]

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

  • 12. Kadir, Ahmadul
    et al.
    Darreh-Shori, T.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Wall, Anders
    Grut, M.
    Strandberg, B.
    Ringheim, A.
    Eriksson, B.
    Blomquist, G.
    Långström, B.
    Nordberg, A.
    PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD2008In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 29, no 8, p. 1204-1217Article in journal (Refereed)
    Abstract [en]

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

  • 13.
    Kalpouzos, Gregoria
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Persson, Jonas
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Nyberg, Lars
    Local brain atrophy accounts for functional activity differences in normal aging2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 3, p. 623.e1-Article 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.
    Köhncke, Ylva
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Laukka, Erika J.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Brehmer, Yvonne
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Kalpouzos, Grégoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Li, Tie-Qiang
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Lövdén, Martin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Three-year changes in leisure activities are associated with concurrent changes in white matter microstructure and perceptual speed in individuals aged 80 years and older2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 41, p. 173-186Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence suggests that engagement in leisure activities is associated with favorable trajectories of cognitive aging, but little is known about brain changes related to both activities and cognition. White matter microstructure shows experience-dependent plasticity and declines in aging. Therefore, we investigated the role of change in white matter microstructure in the activities-cognition link. We used repeated assessments of engagement, perceptual speed, and white matter microstructure (probed with diffusion tensor imaging) in a population-based sample of individuals over 80 years without dementia (n = 442, M-age = 85.1; n = 70 for diffusion tensor imaging; 2 occasions 3 years apart). Using multivariate latent change modeling, we observed positive correlations among changes in predominantly social activities, white matter microstructure, and perceptual speed. Interindividual differences in change in white matter microstructure statistically accounted for the association between change in leisure activities and change in perceptual speed. However, as analyses are based on observational data from 2 measurement occasions, causality remains unclear.

  • 15.
    Larsson, Maria
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Perception and psychophysics.
    Hedner, Margareta
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Papenberg, Goran
    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).
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Laukka, Erika J.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Olfactory memory in the old and very old: relations to episodic and semantic memory and APOE genotype2016In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 38, p. 118-126Article in journal (Refereed)
    Abstract [en]

    The neuroanatomical organization that underlies olfactory memory is different from that of other memory types. The present work examines olfactory memory in an elderly population-based sample (Swedish National Study on Aging and Care in Kungsholmen) aged 60-100 years (n = 2280). We used structural equation modeling to investigate whether olfactory memory in old age is best conceptualized as a distinct category, differentiated from episodic and semantic memory. Further, potential olfactory dedifferentiation and genetic associations (APOE) to olfactory function in late senescence were investigated. Results are in support of a 3-factor solution where olfactory memory, as indexed by episodic odor recognition and odor identification, is modeled separately from episodic and semantic memory for visual and verbal information. Increasing age was associated with poorer olfactory memory performance, and observed age-related deficits were further exacerbated for carriers of the APOE epsilon 4 allele; these effects tended to be larger for olfactory memory compared to episodic and semantic memory pertaining to other sensory systems (vision, auditory). Finally, stronger correlations between olfactory and episodic memory, indicating dedifferentiation, were observed in the older age groups.

  • 16. Li, Shu-Chen
    et al.
    Papenberg, Goran
    Nagel, Irene E.
    Preuschhof, Claudia
    Schröder, Julia
    Nietfeld, Wilfried
    Bertram, Lars
    Heekeren, Hauke R.
    Lindenberger, Ulman
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Aging magnifies the effects of dopamine transporter and D2 receptor genes on backward serial memory2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 1, p. 358.e1-358.e10Article in journal (Refereed)
    Abstract [en]

    Aging compromises dopamine transporter (DAT) and receptor mechanisms in the frontostriatal circuitry. In a sample of 1288 younger and older adults, we investigated (i) whether individual differences in genotypes of the DAT gene (i.e., SLC6A3, the DAT variable number of tandem repeat 9/9, 9/10, and 10/10) and in the D2 receptor (DRD2) gene (i.e., the C957T [rs6277] CC and any T) interactively contribute to phenotype variations in episodic memory performance; and (ii) whether these genetic effects are magnified in older adults, because of considerable declines in the dopamine functions. Our results showed that carrying genotypes associated with higher levels of striatal synaptic dopamine (DAT 9/9) and higher density of extrastriatal D2 receptors (C957T CC) were associated with better backward serial recall, an episodic memory task with high encoding and retrieval demands. Critically, the gene-gene interaction effect was reliably stronger in older than in younger adults. In line with the resource modulation hypothesis, our findings suggest that aging-related decline in brain phenotypes (e.g., dopamine functions) could alter the relations between genotypes and behavioral phenotypes (e.g., episodic memory).

  • 17.
    Li, Xin
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Persson, Jonas
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    The relationship of age and DRD2 polymorphisms to frontostriatal brain activity and working memory performance2019In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 84, p. 189-199Article in journal (Refereed)
    Abstract [en]

    Dopamine (DA) in both prefrontal cortex (PFC) and caudate nucleus is critical for working memory (WM) function. The C957T and Taq1A polymorphisms of the DRD2 gene are related to DA D2 receptor densities in PFC and striatum. Using functional MRI, we investigated the relationship of age and these 2 DRD2 gene polymorphisms to WM function and examined possible age by gene interactions. Results demonstrated less caudate activity for older adults (70-80 years; n = 112) compared with the younger age group (25 -65 years; n = 191), suggesting age-related functional differences in this region. Importantly, there was a gene-related difference regarding WM performance and frontostriatal brain activity. Specifically, better WM performance and greater activity in PFC were found among C957T C allele carriers. Combined genetic markers for increased DA D2 receptor density were associated with greater caudate activity and higher WM updating performance. The genetic effects on blood oxygen level-dependent activity were only observed in older participants, suggesting magnified genetic effects in aging. Our findings emphasize the importance of DA-related genes in regulating WM functioning in aging and demonstrate a positive link between DA and brain activation in the frontostriatal circuitry. 

  • 18. Liu, Yawu
    et al.
    Spulber, Gabriela
    Lehtimäki, Kimmo K
    Könönen, Mervi
    Hallikainen, Ilona
    Gröhn, Heidi
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Hallikainen, Merja
    Vanninen, Ritva
    Soininen, Hilkka
    Diffusion tensor imaging and tract-based spatial statistics in Alzheimer's disease and mild cognitive impairment2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 9, p. 1558-1571Article in journal (Refereed)
    Abstract [en]

    We aimed to explore the changes in fractional anisotropy (FA) in subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by analyzing diffusion tensor imaging (DTI) data using the Tract-Based Spatial Statistics (TBSS). DTI data were collected from 17 AD patients, 27 MCI subjects and 19 healthy controls. Voxel-based analysis with TBSS was used to compare FA among the three groups. Additionally, guided by TBSS findings, a region of interest (ROI)-based analysis along the TBSS skeleton was performed on group-level and the accuracy of the method was assessed by the back-projection of ROIs to the native space FA. Neurofiber tracts with decreased FA included: the parahippocampal white matter, cingulum, uncinate fasciculus, inferior and superior longitudinal fasciculus, corpus callosum, fornix, tracts in brain stem, and cerebellar tracts. Quantitative ROI-analysis further demonstrated the significant decrease on FA values in AD patients relative to controls whereas FA values of MCI patients were found in between the controls and AD patients. We conclude that TBSS is a promising method in examining the degeneration of neurofiber tracts in MCI and AD patients.

  • 19.
    Lövdén, Martin
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Schaefer, Sabine
    Max Planck Inst Human Dev, Ctr Lifespan Psychol, Berlin, Germany.
    Noack, Hannes
    Max Planck Inst Human Dev, Ctr Lifespan Psychol, Berlin, Germany.
    Bodammer, Nils Christian
    Max Planck Inst Human Dev, Ctr Lifespan Psychol, Berlin, Germany.
    Kühn, Simone
    Max Planck Inst Human Cognit & Brain Sci, Dept Psychol, Leipzig, Germany .
    Heinze, Hans-Jochen
    DZNE German Ctr Neurodegenerat Disorders, Magdeburg, Germany .
    Düzel, Emrah
    Univ Magdeburg, Dept Neurol, Magdeburg, Germany .
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Lindenberger, Ulman
    Max Planck Inst Human Dev, Ctr Lifespan Psychol, D-14195 Berlin, Germany .
    Spatial navigation training protects the hippocampus against age-related changes during early and late adulthood2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 3, p. 620.e9-620.e22Article in journal (Refereed)
    Abstract [en]

    It is unknown whether lifestyle, including mental stimulation, and appropriate training interventions, may directly improve spatial navigation performance and its underlying neural substrates. Here we report that healthy younger and older men performing a cognitively demanding spatial navigation task every other day over 4 months display navigation-related gains in performance and stable hippocampal volumes that were maintained 4 months after termination of training. In contrast, control groups displayed volume decrements consistent with longitudinal estimates of age-related decline. Hippocampal barrier density, as indicated by mean diffusivity estimated from diffusion tensor imaging, showed a quadratic shape of increased density after training followed by a return to baseline in the right hippocampus, but declined in the control groups and in the left hippocampus. We conclude that sustained experiential demands on spatial ability protect hippocampal integrity against age-related decline. These results provide the first longitudinal evidence indicating that spatial navigation experience modifies hippocampal volumes in humans, and confirm epidemiological results suggesting that mental stimulation may have direct effects on neural integrity.

  • 20.
    Mangialasche, Francesca
    et al.
    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).
    Kivipelto, Miia
    Costanzi, Emanuela
    Ercolani, Sara
    Pigliautile, Martina
    Cecchetti, Roberta
    Baglioni, Mauro
    Simmons, Andrew
    Soininen, Hilkka
    Tsolaki, Magda
    Kloszewska, Iwona
    Vellas, Bruno
    Lovestone, Simon
    Mecocci, Patrizia
    Tocopherols and tocotrienols plasma levels are associated with cognitive impairment2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 10, p. 2282-2290Article in journal (Refereed)
    Abstract [en]

    Vitamin E includes 8 natural compounds (4 tocopherols, 4 tocotrienols) with potential neuroprotective activity. alpha-Tocopherol has mainly been investigated in relation to cognitive impairment. We examined the relation of all plasma vitamin E forms and markers of vitamin E damage (alpha-tocopherylquinone, 5-nitro-gamma-tocopherol) to mild cognitive impairment (MCI) and Alzheimer's disease (AD). Within the AddNeuroMed-Project, plasma tocopherols, tocotrienols, alpha-tocopherylquinone, and 5-nitro-gamma-tocopherol were assessed in 168 AD cases, 166 MCI, and 187 cognitively normal (CN) people. Compared with cognitively normal subjects, AD and MCI had lower levels of total tocopherols, total tocotrienols, and total vitamin E. In multivariable-polytomous-logistic regression analysis, both MCI and AD cases had 85% lower odds to be in the highest tertile of total tocopherols and total vitamin E, and they were, respectively, 92% and 94% less likely to be in the highest tertile of total tocotrienols than the lowest tertile. Further, both disorders were associated with increased vitamin E damage. Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD.

  • 21.
    Marengoni, Alessandra
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Qiu, Chengxuan
    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).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Atrial fibrillation, stroke and dementia in thevery old: a population-based study2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 7, p. 1336-1337Article in journal (Refereed)
    Abstract [en]

    We explored the association of chronic AF with stroke, dementia and Alzheimer's disease (AD) among community-dwelling elderly people. The study population consisted of 685 individuals from Stockholm (The Kungsholmen Project) who were aged 78 years and were free of dementia and clinical stroke. During the 6-year follow-up, 170 subjects developed dementia, and 86 persons experienced first-ever stroke. The incidence rate (per 1000 person-years) of dementia, AD and first-ever stroke was 72.3, 52.2, and 52.2 in persons with AF and 63.8, 54.6 and 30.6 in those without AF, respectively. AF was associated with the hazard ratio of 1.8 (95%CI, 1.0–3.4) for first-ever stroke, but not significantly associated with dementia or AD.

  • 22.
    Nilsson, Lars-Göran
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Sternäng, Ola
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Rönnlund, Michael
    Umeå universitet.
    Nyberg, Lars
    Umeå universitet.
    Challenging the notion of an early-onset of cognitive decline2009In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 30, no 4, p. 521-524Article in journal (Refereed)
    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.

  • 23.
    Olofsson, Jonas K.
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Perception and psychophysics.
    Nordin, Steven
    Umeå universitet.
    Wiens, Stefan
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Perception and psychophysics.
    Hedner, Margareta
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Perception and psychophysics.
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Cognitive psychology.
    Larsson, Maria
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Perception and psychophysics.
    Odor identification impairment in carriers of ApoE-epsilon 4 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 acme 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 epsilon 4 allele lots 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 epsilon 4 allele and odor identification is mediated by dementia, it is possible that the epsilon 4 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 lame, 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 epsilon 4 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

  • 24. Olomon, A. S.
    et al.
    Kareholt, I
    Stockholm University, Faculty of Social Sciences, Department of Social Work.
    Ngandu, T.
    Wolozin, B.
    MacDonald, S. W. S.
    Winblad, B.
    Nissinen, A.
    Tuomilehto, J.
    Soininen, H.
    Kivipelto, M.
    Serum total cholesterol, statins and cognition in non-demented elderly2009In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 30, no 6, p. 1006-1009Article in journal (Refereed)
    Abstract [en]

    Background: The association between serum total cholesterol (TC), lipid-lowering drugs and cognition in the elderly is currently controversial. Objective: To investigate the relationship between TC, lipid-lowering drugs and cognitive functions in non-demented elderly. Design and Setting: Participants of the Cardiovascular risk factors, aging and dementia (CAIDE) study were derived from random, population-based samples previously studied in 1972, 1977, 1982 or 1987. Analyses are based on 1382 non-demented participants re-examined in 1998 after an average follow-up of 21 years. Results: High midlife TC was associated with poorer late-life episodic memory and category fluency. TC decreased in most individuals over time. A more pronounced decrease was related to poorer late-life episodic memory and psychomotor speed, but not if subjects used statins. Conclusions: The TC-cognition relationship seems bidirectional. High midlife TC is associated with poorer late-life cognition, but decreasing TC after midlife may reflect poorer cognitive status. Statins may be beneficial for cognition in non-demented elderly.

  • 25.
    Papenberg, Goran
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Bäckman, Lars
    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 Center, Sweden.
    Laukka, Erika J.
    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).
    Anticholinergic drug use is associated with episodic memory decline in older adults without dementia2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 55, p. 27-32Article in journal (Refereed)
    Abstract [en]

    Anticholinergic drug use is common in older adults and has been related to increased dementia risk. This suggests that users of these drugs may experience accelerated cognitive decline. So far, however, longitudinal data on this topic are absent and the available evidence is inconclusive with respect to effects on specific cognitive domains due to suboptimal control of confounding variables. We investigated whether anticholinergic medication use is associated with cognitive decline over 6 years in a population-based study of older adults (aged 60-90; n = 1473) without dementia. We found that users (n = 29) declined more on episodic memory over 6 years compared to nonusers (n = 1418). These results were independent of age, sex, education, overall drug intake, physical activity, depression, cardiovascular risk burden, and cardiovascular disease. By contrast, anticholinergic drug use was unrelated to performance in processing speed, semantic memory, short-term memory, verbal fluency, and global cognition (the Mini-Mental-State Examination). Our results suggest that effects of anticholinergics may be particularly detrimental to episodic memory in older adults, which supports the assertion that the cholinergic system plays an important role in episodic memory formation.

  • 26.
    Papenberg, Goran
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Institute for Human Development, Germany.
    Li, Shu-Chen
    Nagel, Irene E.
    Nietfeld, Wilfried
    Schjeide, Brit-Maren
    Schröder, Julia
    Bertram, Lars
    Heekeren, Hauke R.
    Lindenberger, Ulman
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Dopamine and glutamate receptor genes interactively influence episodic memory in old age2014In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 35, no 5, article id 1213.e3Article in journal (Refereed)
    Abstract [en]

    Both the dopaminergic and glutamatergic systems modulate episodic memory consolidation. Evidence from animal studies suggests that these two neurotransmitters may interact in influencing memory performance. Given that individual differences in episodic memory are heritable, we investigated whether variations of the dopamine D2 receptor gene (rs6277, C957T) and the N-methyl-D-aspartate 3A (NR3A) gene, coding for the N-methyl-D-aspartate 3A subunit of the glutamate N-methyl-D-aspartate receptor (rs10989591, Val362Met), interactively modulate episodic memory in large samples of younger (20-31 years; n = 670) and older (59-71 years; n = 832) adults. We found a reliable gene-gene interaction, which was observed in older adults only: older individuals carrying genotypes associated with greater D2 and N-methyl-D-aspartate receptor efficacy showed better episodic performance. These results are in line with findings showing magnification of genetic effects on memory in old age, presumably as a consequence of reduced brain resources. Our findings underscore the need for investigating interactive effects of multiple genes to understand individual difference in episodic memory.

  • 27.
    Persson, Jonas
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Umeå center for Functional Brain Imaging (UFBI), Sweden.
    Pudas, Sara
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Umeå center for Functional Brain Imaging (UFBI), Sweden.
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Nyberg, Lars
    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.

  • 28.
    Pudas, Sara
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Umeå universitet.
    Persson, Jonas
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Nilsson, Lars-Göran
    ARC och Umeå universitet.
    Nyberg, Lars
    Umeå universitet.
    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.

  • 29.
    Qiu, Chengxuan
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Cotch, Mary Frances
    Sigurdsson, Sigurdur
    Eiriksdottir, Gudny
    Jonasson, Fridbert
    Klein, Ronald
    Klein, Barbara E. K.
    Harris, Tamara B.
    van Buchem, Mark A.
    Gudnason, Vilmundur
    Launer, Lenore J.
    Cerebral microbleeds and age-related macular degeneration: the AGES-Reykjavik Study2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 12, p. 2935-2937Article in journal (Refereed)
    Abstract [en]

    We test the hypothesis that cerebral microbleeds (CMB) and age-related macular degeneration (AMD), both linked to amyloid-beta deposition, are correlated. This study includes 4205 participants (mean age 76.2; 57.8% women) in the Age, Gene/Environment Susceptibility (AGES)Reykjavik Study (2002-2006). CMB were assessed from magnetic resonance images, and AMD was assessed using digital retinal images. Data were analyzed with multinomial logistic models controlling for major confounders. Evidence of CMB was detected in 476 persons (272 with strict lobar CMB and 204 with nonlobar CMB). AMD was detected in 1098 persons (869 with early AMD, 140 with exudative AMD, and 89 with pure geographic atrophy). Early and exudative AMD were not associated with CMB. The adjusted odds ratio of pure geographic atrophy was 1.62 (95% confidence interval 0.93-2.82, p = 0.089) for having any CMB, 1.43 (0.66-3.06, p = 0.363) for strict lobar CMB, and 1.85 (0.89-3.87, p = 0.100) for nonlobar CMB. This study provides no evidence that amyloid deposits in the brain and AMD are correlated. However, the suggestive association of geographic atrophy with CMB warrants further investigation.

  • 30. Sapkota, Shraddha
    et al.
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Dixon, Roger A.
    Executive function performance and change in aging is predicted by apolipoprotein E, intensified by catechol-O-methyltransferase and brain-derived neurotrophic factor, and moderated by age and lifestyle2017In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 52, p. 81-89Article in journal (Refereed)
    Abstract [en]

    Recent studies have reported several genetic, health, and aging interaction effects in predicting cognitive performance and change. We used an accelerated longitudinal design to examine interactions among genetic, lifestyle, and aging for executive function (EF) in non-demented older adults (n = 634; age range = 53-95 years). The polymorphisms were apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF). We tested (1) independent and additive effects of APOE, COMT, and BDNF and (2) APOE effect modification for COMT + BDNF, on EF performance and 9-year change as separated by age and lifestyle activities. First, APOE epsilon 4+ carriers had poorer EF performance and steeper 9-year decline. Second, APOE epsilon 4+ carriers with (1) BDNF Met/Met genotype and (2) increasing allelic risk in the COMT + BDNF risk panel had poorer EF performance; these effects were moderated by lifestyle activities (composite of everyday social, physical, and cognitive activities). Examining APOE effect modification for COMT + BDNF risk panel effects with other moderating factors may help identify complex neurobiological and genetic underpinnings of polygenic phenotypes such as EF in aging.

  • 31. Schöll, Michael
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Axelman, Karin
    Stefanova, Elka
    Wall, Anders
    Westman, Eric
    Långström, Bengt
    Lannfelt, Lars
    Graff, Caroline
    Nordberg, Agneta
    Glucose metabolism and PIB binding in carriers of a His163Tyr presenilin 1 mutation2011In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 8, p. 1388-1399Article in journal (Refereed)
    Abstract [en]

    Six young related pre-symptomatic carriers of a His 163Tyr mutation in the presenilin 1 gene who will develop early onset familial Alzheimer's disease (eoFAD), and a control group of 23 non-carriers underwent (18)F-fluorodeoxyglucose positron emission tomography (FDG PET). The mutation carriers were followed-up after 2 years. Multivariate analysis showed clear separation of carriers from non-carriers on both occasions, with the right thalamus being the region contributing most to group differentiation. Statistical parametric mapping (SPM) revealed in the carriers non-significantly lower thalamic cerebral glucos metabolism (CMRglc) at baseline and significantly decreased CMRglc in the right thalamus at follow-up. One mutation carrier was followed-up with FDG PET 10 years after baseline and showed reductions in cognition and CMRglc in the posterior cingulate and the frontal cortex. This subject was diagnosed with AD 1 year later and assessed with an additional FDG as well as an (11)C-PIB PET scan 12 years after baseline. Global cortical CMRglc and cognition were distinctly decreased. PIB binding was comparable with sporadic AD patterns but showing slightly higher striatal levels.

  • 32. Smailovic, Una
    et al.
    Koenig, Thomas
    Kåreholt, Ingemar
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Jönköping University, Sweden.
    Andersson, Thomas
    Kramberger, Milica Gregoric
    Winblad, Bengt
    Jelic, Vesna
    Quantitative EEG power and synchronization correlate with Alzheimer's disease CSF biomarkers2018In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 63, p. 88-95Article in journal (Refereed)
    Abstract [en]

    Synaptic dysfunction is the best anatomical correlate of early cognitive impairment in Alzheimer's disease (AD). Electroencephalography (EEG) directly reflects brain electrical activity at the level of synapses. The aim of the present study was to investigate correlations of quantitative EEG measures, global field power (GFP) and global field synchronization (GFS), with conventional cerebrospinal fluid (CSF) biomarkers of neurodegeneration in patients diagnosed with subjective cognitive decline (n = 210), mild cognitive impairment (n = 230), and AD (n = 197). Decreased CSF amyloid beta 42 significantly correlated with increased theta and delta GFP, whereas increased p- and t-tau with decreased alpha and beta GFP. Decreased CSF amyloid beta 42 and increased p- and t-tau were significantly associated with decreased GFS alpha and beta. Subanalysis of the separate diagnostic groups demonstrated significant correlations between CSF biomarkers and generalized power and synchronization already in the subjective cognitive decline and mild cognitive impairment group. These results provide evidence that quantitative EEG measures are associated and possibly sensitive to distinct AD-like CSF biomarker profiles in cognitively impaired patients and are therefore promising early noninvasive markers of AD.

  • 33. Spulber, Gabriela
    et al.
    Niskanen, Eini
    MacDonald, Stuart
    Smilovici, Oded
    Chen, Kewei
    Reiman, Eric M
    Jauhiainen, Anne M
    Hallikainen, Merja
    Tervo, Susanna
    Wahlund, Lars-Olof
    Vanninen, Ritva
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Soininen, Hilkka
    Whole brain atrophy rate predicts progression from MCI to Alzheimer's disease2010In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 31, no 9, p. 1601-1605Article in journal (Refereed)
    Abstract [en]

    For both clinical and research reasons, it is essential to identify which mild cognitive impairment (MCI) subjects subsequently progress to Alzheimer's disease (AD). The prediction may be facilitated by accelerated whole brain atrophy exhibited by AD subjects. Iterative principal component analysis (IPCA) was used to characterize whole brain atrophy rates using sequential MRI scans for 102 MCI subjects from the Kuopio University Hospital. We modelled the likelihood of progression to probable AD, and found that each additional percent of annualized whole brain atrophy rate was associated with a higher odds ratio (OR) of progression (OR=1.30, p=0.01, 95% CI=1.05-1.60). Our study demonstrates an association between whole brain atrophy rate and subsequent rate of clinical progression from MCI to AD. These findings suggest that IPCA could be an effective brain-imaging marker of progression to AD and useful tool for the evaluation of disease-modifying treatments.

  • 34. Varrone, Andrea
    et al.
    Svenningsson, Per
    Forsberg, Anton
    Varnäs, Katarina
    Tiger, Mikael
    Nakao, Ryuji
    Halldin, Christer
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Stockholm Brain Institute, Sweden.
    Farde, Lars
    Positron emission tomography imaging of 5-hydroxytryptamine(1B) receptors in Parkinson's disease2014In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 35, no 4, p. 867-875Article in journal (Refereed)
    Abstract [en]

    Impairment of the central serotonin system in Parkinson's disease (PD) has been shown postmortem and in vivo with positron emission tomography (PET). The aim of this PET study was to examine and compare the availability of the 5-hydroxytryptamine (5-HT)(1B)-receptor subtype in patients with PD and age-matched control subjects. Twelve control subjects and 12 PD patients were examined with PET using the 5-HT1B-radioligand [C-11]AZ10419369. In PD patients, 5-HT1B-receptor availability in the right orbitofrontal cortex was lower than in control subjects. A statistically significant negative correlation between 5-HT1B-receptor availability and age was obtained for the right temporal cortex in control subjects and for the right midbrain and left parahippocampal gyrus in PD patients. The lower regional 5-HT1B-receptor availability is in line with previous studies showing a decrease of serotonin imaging markers in PD and corroborates a role of the serotonin system in the pathophysiology of PD. The demonstrated age effect on 5-HT1B receptors suggest a physiologic and PD-related decline of serotonin function, indicating the importance of controlling for age in clinical studies.

  • 35. Vuorinen, Miika
    et al.
    Kåreholt, Ingemar
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Julkunen, Valtteri
    Spulber, Gabriela
    Niskanen, Eini
    Paajanen, Teemu
    Soininen, Hilkka
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Eastern Finland, Finland; Karolinska Institute-Alzheimer Disease Research Center (KI-ADRC), Sweden.
    Solomon, Alina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Eastern Finland, Finland; Karolinska Institute-Alzheimer Disease Research Center (KI-ADRC), Sweden.
    Changes in vascular factors 28 years from midlife and late-life cortical thickness2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 1, p. 100-109Article in journal (Refereed)
    Abstract [en]

    We assessed midlife blood pressure (BP), body mass index, total cholesterol, and their changes over time in relation to cortical thickness on magnetic resonance imaging 28 years later in 63 elderly at risk of dementia. Participants in the population-based Cardiovascular Risk Factors, Aging, and Dementia study were first examined at midlife. A first follow-up was conducted after 21 years, and a second follow-up after an additional 7 years. Magnetic resonance images from the second follow-up were analyzed using algorithms developed at McGill University, Montreal, Canada. Midlife hypertension was related to thinner cortex in several brain areas, including insular, frontal, and temporal cortices. In elderly with thinner insular cortex, there was a continuous decline in systolic BP and an increase in pulse pressure after midlife, while in elderly with thicker insular cortex the decline in systolic BP started at older ages, paralleled by a decline in pulse pressure. No associations were found between body mass index, cholesterol, or apolipoprotein E ε4 allele and cortical thickness in this group of elderly at risk individuals.

  • 36.
    Wang, Hui-Xin
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Gustafson, Deborah R.
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska Institutet, Sweden; University of Eastern Finland, Finland.
    Pedersen, Nancy L.
    Skoog, Ingmar
    Windblad, Bengt
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Education halves the risk of dementia due to apolipoprotein ε4 allele: a collaborative study from the Swedish brain power initiative2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 5, p. 1007.e1-1007.e7Article in journal (Refereed)
    Abstract [en]

    A number of studies have explored the relationships of apolipoprotein E (APOE) genotype and education with dementia over the last decade. However, observations concerning the possible modifying effect of education on the APOE-dementia association are limited. The objective of this study was to test the hypothesis that education may decrease the risk of APOE ε4 on dementia. Pooled data from 3 major population-based studies in Northern Europe were used in this study, with a total of 3436 participants aged 65 and older derived from the Kungsholmen project and the Gothenburg Birth Cohort studies in Sweden, and the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) project in Finland. The main outcome measure was dementia, which was diagnosed in 219 persons according to standard criteria. APOE ε4 was associated with increased risk of dementia independent of the effect of education (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.9-3.4 for 1 ε4 carrier and OR, 3.7; 95% CI, 1.8-7.2 for 2 ε4 carriers). High education (8 years and more) was related to a lower dementia risk (OR, 0.5; 95% CI, 0.3-0.6). An interaction between education and APOE ε4 was observed. Compared with those with less education and no ε4, the odds of dementia among persons with low education who carried any ε4 allele was 2.7 (95% CI, 1.9-3.9), and 1.2 (0.7-1.8) if they had higher education. This study suggests that genetic (APOE ε4) and environmental (education) factors are not only independently but also interactively related to dementia risk and that high education may buffer the negative effect of APOE ε4 on dementia occurrence.

  • 37.
    Wikgren, Mikael
    et al.
    Umeå universitet.
    Karlsson, Thomas
    Linköpings universitet.
    Nilbrink, Therese
    Umeå universitet.
    Nordfjäll, Katarina
    Umeå universitet.
    Hultdin, Johan
    Umeå universitet.
    Sleegers, Kristel
    University of Antwerp, Antwerp, Belgium.
    Van Broeckhoven, Christine
    University of Antwerp, Antwerp, Belgium.
    Nyberg, Lars
    Umeå universitet.
    Roos, Göran
    Umeå universitet.
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Adolfsson, Rolf
    Umeå universitet.
    Norrback, Karl-Fredrik
    Umeå universitet.
    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 ε4 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 ε4 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 ε4 carriers (37 bp/years) compared with non-carriers (21 bp/year). Further, longer telomeres among ε4 carriers significantly predicted worse performance on episodic memory tasks. No significant associations were found on tasks tapping semantic and visuospatial ability, or among ε3/ε3 carriers. In conclusion, APOE ε4 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 ε4 allele is associated with abnormal cell turnover of functional and possibly clinical significance.

  • 38. Zuo, Nianming
    et al.
    Salami, Alireza
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Umeå University, Sweden.
    Liu, Hao
    Yang, Zhengyi
    Jiang, Tianzi
    Functional maintenance in the multiple demand network characterizes superior fluid intelligence in aging2020In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 85, p. 145-153Article in journal (Refereed)
    Abstract [en]

    The multiple demand network (MDN) is conceptualized as the core processing system for multi-tasking. Increasing evidence also provides strong support for the involvement of the MDN in fluid intelligence (gF), that is, the ability to solve new problems. However, the underlying neural mechanisms of declining intelligence in old age are poorly explored, particularly whether maintenance of the functional architecture of the MDN can characterize superior intelligence in successful aging. Here, we used eigenvector centrality (EC) to explore the resting-state functional architecture of the MDN in terms of its communication across the entire brain. We found gF to be negatively associated with age and that the MDN EC competitively mediated age-related decline in gF over the aging lifespan, suggesting that excessive cross-talk from the MDN is deleterious for intelligence. Critically, older individuals with comparable MDN EC as younger individuals exhibited superior gF compared with their age-matched counterparts. Taken together, these data provide support for the maintenance of youth-like functional architecture of the MDN and its implication for superior intelligence in successful aging.

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