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  • 1. Aarne, Päivikki
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institute, Sweden.
    Risholm Mothander, Pia
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Tallberg, Ing-Mari
    Parent-rated socio-emotional development in children with language impairment in comparison with typically developed children2014In: European Journal of Developmental Psychology, ISSN 1740-5629, E-ISSN 1740-5610, Vol. 11, no 3, p. 279-291Article in journal (Refereed)
    Abstract [en]

    Children with language impairment (LI) and children with typical development (TD) were assessed by their respective parents using The MacArthur Communicative Development Inventories (Swedish version SECDI) and Greenspan Socio Emotional Growth Chart (GSEGC). The aim was to investigate socio-emotional and language development in children with LI and TD with respect to possible differential patterns and relations between the groups. The results highlight a clear association between language and socio-emotional development. Children with LI were rated similar to young language-matched children with TD, but significantly lower relative to age-matched TD children, particularly concerning symbolic stages of development: the use of linguistic symbols as well as related areas such as symbol play and symbolic mental ability. The results are discussed in light of presumable background factors and possible consequences for children or sub-groups of children with LI.

  • 2.
    Almkvist, Ove
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Bosnes, Ole
    Bosnes, Ingunn
    Stordal, Eystein
    Selective impact of disease on short-term and long-term components of self-reported memory: a population-based HUNT study2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 5, article id e013586Article in journal (Refereed)
    Abstract [en]

    Background: Subjective memory is commonly considered to be a unidimensional measure. However, theories of performance-based memory suggest that subjective memory could be divided into more than one dimension. Objective: To divide subjective memory into theoretically related components of memory and explore the relationship to disease. Methods: In this study, various aspects of self-reported memory were studied with respect to demographics and diseases in the third wave of the HUNT epidemiological study in middle Norway. The study included all individuals 55 years of age or older, who responded to a nine-item questionnaire on subjective memory and questionnaires on health (n=18 633). Results: A principle component analysis of the memory items resulted in two memory components; the criterion used was an eigenvalue above 1, which accounted for 54% of the total variance. The components were interpreted as long-term memory (LTM; the first component; 43% of the total variance) and short-term memory (STM; the second component; 11% of the total variance). Memory impairment was significantly related to all diseases (except Bechterew's disease), most strongly to brain infarction, heart failure, diabetes, cancer, chronic obstructive pulmonary disease and whiplash. For most diseases, the STM component was more affected than the LTM component; however, in cancer, the opposite pattern was seen. Conclusions: Subjective memory impairment as measured in HUNT contained two components, which were differentially associated with diseases.

  • 3.
    Almkvist, Ove
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Kadir, Ahmadul
    Nordberg, Agneta
    Degree of abnormality is associated with rate of change in measures of beta-amyloid, glucose metabolism and cognition in an autopsy-verified Alzheimer’s disease case2015In: Neurocase, ISSN 1355-4794, E-ISSN 1465-3656, Vol. 21, no 6, p. 738-747Article in journal (Refereed)
    Abstract [en]

    The degree of abnormality and rate of change in cognitive functions, positron emission tomography Pittsburg compound B (PET PIB), and fluorodeoxyglucose (FDG) measures were studied for 8 years in an autopsy-confirmed Alzheimer’s disease (AD) patient, who died 61 years old (Mini-Mental State Examination (MMSE) score 7). At first encounter with medical care, the patient was very mildly demented (MMSE score 27). She had four cognitive assessments and two examinations with PET PIB and FDG in 23 bilateral brain regions. The onset of cognitive decline was retrospectively estimated to have started in the early forties. The degree of impairment was inversely related to the rate of decline. A similar relationship was seen between the rate of change and the level of abnormality in both PIB and FDG. To conclude, rate of change in cognition, PIB, and FDG was associated with the degree of abnormality.

  • 4.
    Almkvist, Ove
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden; Karolinska University Hospital at Huddinge, Sweden.
    Rodriguez-Vieitez, Elena
    Thordardottir, Steinunn
    Amberla, Kaarina
    Axelman, Karin
    Basun, Hans
    Kinhult-Ståhlbom, Anne
    Lilius, Lena
    Remes, Anne
    Wahlund, Lars-Olof
    Viitanen, Matti
    Lannfelt, Lars
    Graff, Caroline
    Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease2017In: Journal of the International Neuropsychological Society, ISSN 1355-6177, E-ISSN 1469-7661, Vol. 23, no 3, p. 195-203Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    Almkvist, Ove
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology. KI, Stockholm, Sweden.
    Tallberg, Ing-Mari
    Cognitive decline from estimated premorbid status predicts neurodegeneration in Alzheimer's disease2009In: Neuropsychology, ISSN 0894-4105, E-ISSN 1931-1559, Vol. 23, no 1, p. 117-124Article in journal (Refereed)
    Abstract [en]

    This study investigated the relationship between premorbid and current cognitive function with respect to the clinical features of patients with various types of neurodegeneration in the form of Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive impairment (SCI), as compared with a healthy control group (C). Clinical features (MMSE, cognitive and depressive symptoms), genetics (apolipoprotein E; APOE) and measures of neurodegeneration (Aβ-sub(42), t-tau, and p-tau) were examined, as well as present cognitive function. Various methods of assessing premorbid cognitive function were compared, including a Swedish NART-analogous test (Irregularly Spelled Words; ISW), a Swedish lexical decision test (SLDT), a Hold test (Information in WAIS-R), Best current performance test, and combined demographic characteristics. Results showed that cognitive decline (premorbid minus current cognitive function) based on SLDT and ISW was a significant predictor for MMSE and Aβ-sub(42), whereas corresponding associations for present cognitive function and decline measures based on other methods were less powerful. Results also showed that specific verbal abilities (e.g., SLDT and ISW) were insensitive to AD and that these abilities indicated premorbid cognitive function in retrospect. In conclusion, cognitive decline from premorbid status reflects the disease processes.

  • 6. Andersson, C.
    et al.
    Lindau, M.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Engfeldt, P.
    Johansson, S.E.
    Eriksdotter Jönhagen, M.
    Identifying patients at high and low risk for cognitive decline using Rey Auditory Verbal Learning test among middle-aged memory clinic out-patients.2006In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, Vol. 21, p. 251-259Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate whether application of cutoff levels in an episodic memory test (Rey Auditory Verbal Learning Test, RAVLT) is a useful method for identifying patients at high and low risk of cognitive decline and subsequent dementia. Methods: 224 patients with memory complaints (mean age = 60.7 years, mean MMSE = 28.2) followed-up at a memory clinic over 3 years were assigned retrospectively to one of three memory groups from their baseline results in RAVLT [severe (SIM), moderate (MIM) or no impairment (NIM)]. These groups were investigated regarding cognitive decline. Results: Patients assigned to SIM showed significant cognitive decline and progressed to dementia at a high rate, while a normal performance in RAVLT at baseline (NIM) predicted normal cognition after 3 years. Patients with MIM constituted a heterogeneous group; some patients deteriorated cognitively, while the majority remained stable or improved. Conclusions: The application of cutoff levels in RAVLT at baseline showed that patients with severely impaired RAVLT performance were at a high risk of cognitive decline and progression to dementia, while patients with normal RAVLT results did not show cognitive decline during 3 years. Furthermore, the initial degree of memory impairment was decisive in the cognitive prognosis 3 years later.

  • 7. Andersson, Christin
    et al.
    Blennow, Kaj
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Andreasen, Niels
    Engfeldt, Peter
    Johansson, Sven-Erik
    Lindau, Maria
    Eriksdotter-Jönhagen, Maria
    Increasing CSF phospho-tau levels during cognitive decline and progression to dementia2008In: Neurobiology of Aging, ISSN 0197-4580, Vol. 29, no 10, p. 1466-1473Article in journal (Refereed)
    Abstract [en]

    Background: Little is known about longitudinal changes of cerebrospinal fluid (CSF) biomarkers during cognitive decline in neurodegenerative disease progression.

    Objective: To investigate longitudinal changes in CSF biomarkers – total-tau (T-tau), phospho-tau (P-tau) and β-amyloid (Aβ42) – during cognitive decline.

    Methods: Forty memory clinic patients (47.5% females), aged 61.3 ± 7.6 (S.D.) years, non-demented at baseline, underwent lumbar puncture and neuropsychological testing at two occasions. Baseline mean MMSE-score was 28.3 ± 1.8. Patients were divided into three groups based on baseline memory functioning; severely impaired (SIM), moderately impaired (MIM) and no impairment (NIM).

    Results: There was a significant increase in P-tau in the SIM-group during follow-up, while P-tau in MIM and NIM did not change. Eighty-three percent of the SIM-patients converted to dementia (80% AD), while most MIM- and NIM-patients remained non-demented. T-tau- and Aβ42-levels did not change in any of the memory groups during follow-up.

    Conclusion: Increasing P-tau levels during cognitive decline and conversion to dementia suggest that P-tau may be useful as a longitudinal marker of the neurodegenerative process.

  • 8. Ausen, Birgitta
    et al.
    Edman, Gunnar
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Bogdanovic, Nenad
    Self- and Informant Ratings of Personality in Mild Cognitive Impairment, Reviewed2011In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 32, no 6, p. 387-393Article in journal (Refereed)
    Abstract [en]

    Aims: To examine the degree of agreement between self-and informant ratings of personality in relation to cognitive function in patients with mild cognitive impairment (MCI), subjective cognitive impairment (SCI) and healthy controls (HC). Methods: Thirty-two patients and informants with MCI, 23 with SCI and 22 HC completed the Swedish universities Scales of Personality (SSP). Correlations and incongruence between self-and informant ratings were calculated. The Mini Mental State Examination (MMSE) was used to assess cognitive function. Results: The correlations between self-and and informant ratings were fair-to-moderate on a majority of SSP scales and significant in 44%. The incongruence between patients and informants was significantly larger in MCI than in HC across SSP scales. There was a significant negative correlation between the incongruence index and the MMSE for all subjects. Conclusions: Self-informant agreement on ratings of patients' personality was reasonable. Incongruence between patients and their informants was associated with MCI but not SCI or HC. Disagreement between patients and informants indicates cognitive impairment. Copyright (C) 2012 S. Karger AG, Basel

  • 9.
    Ausén, Birgitta
    et al.
    Karolinska Institutet.
    Edman, Gunnar
    Danderyds sjukhus.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
    Bogdanovic, Nenad
    Karolinska Institutet.
    Personality Features in Subjective Cognitive Impairment and Mild Cognitive Impairment - Early Indicators of Dementia?2009In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 28, no 6, p. 528-535Article in journal (Refereed)
    Abstract [en]

    Objectives: The purpose of the present study was to investigate patterns of personality in patients with subjective cognitive impairment (SCI) and mild cognitive impairment (MCI), compared to healthy controls. Methods: We assessed24 patients with SCI, 35 patients with MCI and 26 healthy controls with the self-report questionnaire Swedish Universities Scales of Personality measuring aspects of neuroticism/anxiety proneness, extraversion, and aggression-hostility. Results: Patients with SCI and MCI showed significantly more Somatic Trait Anxiety, Psychic Trait Anxiety and Stress Susceptibility than healthy controls. Moreover, there was a significant increase in Detachment in patients with MCI and a significant decrease in Adventure Seeking in patients with SCI, relative to healthy controls. Conclusions: Patients with SCI and MCI presented specific patterns of personality alterations with higher scores in traits related to anxiety proneness and aggression-hostility and lower in traits of extraversion. In most subscales differences followed a sequential pattern with gradually increasing scores from healthy controls, to patients with SCI and further to MCI. The groups differed in amount and type of symptoms, suggesting that patterns of personality may be related to degree of cognitive impairment.

  • 10. Basun, H.
    et al.
    Bogdanovic, N.
    Ingelsson, M.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Näslund, J.
    Axelman, K.
    Bird, T.D.
    Nochlin, D.
    Schellenberg, G.D.
    Wahlund, Lars-Olof
    Lannfelt, L.
    Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease2008In: Archives of neurology, ISSN 0003-9942, Vol. 65, no 4, p. 499-505Article in journal (Refereed)
    Abstract [en]

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

  • 11. Bergendal, G.
    et al.
    Fredrikson, S.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Selective decline in information processing in subgroups of multiple sclerosis: An 8-year longitudinal study2007In: European Neurology, ISSN 0014-3022, E-ISSN 1421-9913, Vol. 57, no 4, p. 193-202Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system (CNS) that causes white matter and cortical lesions over many years. The CNS is selectively affected by the disease with a great variety of symptoms between patients. In this study, we describe the impact on various aspects of cognition over an 8-year follow-up period in 31 consecutive MS patients subgrouped as relapsing remitting (RR) MS, secondary progressive (SP) MS, and primary progressive (PP) MS. Results showed a differential pattern of cognitive decline already at baseline in speed of information processing. During the follow-up, a pronounced decline occurred in speed of information processing, finger-motor speed, copying geometrical designs, episodic memory, and visuospatial short-term memory. A striking difference was observed between a marked decline in visual reaction time, whereas no significant change was seen in auditory reaction time. In contrast, there was no time-related decline in verbal abilities. However, an initial marked cognitive impairment predicted further cognitive decline over the 8-year follow-up. Information-processing tests were found to be an especially strong predictor of long-term cognitive decline. In addition, high EDSS score at followup was associated with decline in information processes. Results also showed that SP-MS patients deteriorated significantly more than the other two groups, particularly in visual compared to auditory information processing. To conclude, cognitive decline appeared particularly in SP-MS patients and in visual information processing.

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

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

  • 13. Bergman, Ingvar
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    The effect of age on fluid intelligence is fully mediated by physical health2013In: Archives of gerontology and geriatrics (Print), ISSN 0167-4943, E-ISSN 1872-6976, Vol. 57, no 1, p. 100-109Article in journal (Refereed)
    Abstract [en]

    The present study investigated the extent to which the effect of age on cognitive ability is predicted by individual differences in physical health. The sample consisted of 118 volunteer subjects who were healthy and ranging in age from 26 to 91. The examinations included a clinical investigation, magnetic resonance imaging (MRI) brain neuroimaging, and a comprehensive neuropsychological assessment. The effect of age on fluid IQ with and without visual spatial praxis and on crystallized IQ was tested whether being fully-, partially-or non-mediated by physical health. Structural equation analyses showed that the best and most parsimonious fit to the data was provided by models that were fully mediated for fluid IQ without praxis, non-mediated for crystallized IQ and partially mediated for fluid IQ with praxis. The diseases of the circulatory and nervous systems were the major mediators. It was concluded from the pattern of findings that the effect of age on fluid intelligence is fully mediated by physical health, while crystallized intelligence is non-mediated and visual spatial praxis is partially mediated, influenced mainly by direct effects of age. Our findings imply that improving health by acting against the common age-related circulatory-and nervous system diseases and risk factors will oppose the decline in fluid intelligence with age.

  • 14. Bergman, Ingvar
    et al.
    Blomberg, Mari
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    The importance of impaired physical health and age in normal cognitive aging2007In: Scandinavian Journal of Psychology, ISSN 0036-5564, E-ISSN 1467-9450, Vol. 48, no 2, p. 115-125Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to investigate the importance of impaired physical health and age in normal cognitive aging. In our cross-sectional, clinical and explorative study, medical and neuropsychological data from 118 voluntary healthy controls aged 26-91 years were collected from five recruitment occasions. Health was assessed according to a criterion reflecting clinical and subclinical severity. The examinations included a clinical investigation, brain neuroimaging, and a comprehensive neuropsychological assessment. Regression analyses showed a significant incidence of clinical and subclinical medical disorders that explained 10.8% of the variation in cognitive performance, while age-related impairment explained 5.6%. Findings of the central nervous system were important but various other medical findings explained about half of the health-related variation. Cognitively demanding tasks were more susceptible to impaired physical health while tasks comprising salient motor- and visual spatial elements were more prone to be impaired by age. Our findings suggest (1) that impaired physical health is more important than chronological age in accounting for cognitive impairment across the adult lifespan, (2) that age and health dissociate with regard to cognitive functions affected, and (3) that selection for so-called ""super healthy"" elderly people might be justified in cognitive research. Because the prevalent diseases in normal aging are potentially preventable, the present findings promise good prospect for prevention of future cognitive disability among elderly people.

  • 15. Bergman, Ingvar
    et al.
    Johansson, Kurt
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Lundberg, Catarina
    Health-adjusted neuropsychological test norms based on 463 older Swedish car drivers2016In: Scandinavian Journal of Psychology, ISSN 0036-5564, E-ISSN 1467-9450, Vol. 57, no 2, p. 93-107Article in journal (Refereed)
    Abstract [en]

    There is a need for improved normative information in particular for older persons. The present study provides neuropsychological test norms on seven cognitive tests used in a sample representing the general older driving population, when uncontrolled and controlled for physical health. A group of 463 healthy Swedish car drivers, aged 65 to 84 years, participated in a medical and neuropsychological examination. The latter included tests of visual scanning, mental shifting, visual spatial function, memory, reaction time, selective attention, and simultaneous capacity. Hierarchical regression analyses demonstrated that, when uncontrolled for health, old age was associated with significant impairment on all seven tests. Education was associated with a significant advantage for all tests except most reaction time subtests. Women outperformed men on selective attention. Controlling for health did not consistently change the associations with education, but generally weakened those with age, indicating rises in normative scores of up to 0.36 SD (residual). In terms of variance explained, impaired health predicted on average 2.5%, age 2.9%, education 2.1% and gender 0.1%. It was concluded (1)that individual regression-based predictions of expected values have the advantage of allowing control for the impact of health on normative scores in addition to the adjustment for various demographic and performance-related variables and (2) that health-adjusted norms have the potential to classify functional status more accurately, to the extent that these norms diverge from norms uncontrolled for physical health.

  • 16. Bosnes, Ingunn
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Bosnes, Ole
    Stordal, Eystein
    Romild, Ulla
    Nordahl, Hans M.
    Prevalence and correlates of successful aging in a population-based sample of older adults: the HUNT study2017In: International psychogeriatrics, ISSN 1041-6102, E-ISSN 1741-203X, Vol. 29, no 3, p. 431-440Article in journal (Refereed)
    Abstract [en]

    The factors influencing successful aging (SA) are of great interest in an aging society. The aims of this study were to investigate the prevalence of SA, the relative importance across age of the three components used to define it (absence of disease and disability, high cognitive and physical function, and active engagement with life), and its correlates. Data were extracted from the population-based cross-sectional Nord-Trøndelag Health Study (HUNT3 2006–2008). Individuals aged 70–89 years with complete datasets for the three components were included (N = 5773 of 8,040, 71.8%). Of the respondents, 54.6% were women. Univariate and multivariate regression analyses were used to analyze possible correlates of SA. Overall, 35.6% of the sample met one of the three criteria, 34.1% met combinations, and 14.5% met all of the three criteria. The most demanding criterion was high function, closely followed by absence of disease, while approximately two-thirds were actively engaged in life. The relative change with age was largest for the high cognitive and physical function component and smallest for active engagement with life. The significant correlates of SA were younger age, female gender, higher education, weekly exercise, more satisfaction with life, non-smoking, and alcohol consumption, whereas marital status was not related to SA. The prevalence of SA in this study (14.5%) is comparable to previous studies. It may be possible to increase the prevalence by intervention directed toward more exercise, non-smoking, and better satisfaction with life.

  • 17. Bosnes, O.
    et al.
    Dahl, O. -P.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Including a subject-paced trial may make the PASAT more acceptable for MS patients2015In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 132, no 4, p. 219-225Article in journal (Refereed)
    Abstract [en]

    The Paced Auditory Serial Addition Test (PASAT) is regularly used in the evaluation of cognition in multiple sclerosis (MS). However, the test may impose frustration, distress, and anxiety in patients, which may result in refusal to participate by many patients. ObjectivesIn this study, a subject- and experimenter-paced PASAT was compared and analyzed, with regard to independent measures of cognitive functions, as well as disability, fatigue, depression, and anxiety. MethodsA population-based sample of patients with MS (n=34; mean age 47.28.6) was examined with the PASAT, including a subject-paced condition, in addition to the standard experimenter-paced conditions using three levels of interstimuli intervals (ISI: 3.0, 2.5, and 2.0s). A comprehensive set of neuropsychological tests, measures of disease severity, fatigue, anxiety, and depression were studied as potentially associated factors. ResultsSubject- and experimenter-paced PASAT performance correlated significantly and the subject-paced administration correlated even higher with measures of information processing speed, executive function, attention, and working memory than standard experimenter-paced administration of PASAT. DiscussionThe associations between PASAT performance and measures of fatigue, anxiety, and depression were not significant. ConclusionThe results indicate that the altered PASAT procedure measures the same cognitive functions in MS as the standard procedure. At the same time, the altered procedure may make the PASAT more user-friendly for patients with MS.

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

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

  • 19. Choo, Il Han
    et al.
    Ni, Ruiqing
    Scholl, Michael
    Wall, Anders
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Nordberg, Agneta
    Combination of f 18 fdg pet and cerebrospinal fluid biomarkers as a better predictor of the progression to alzheimer's disease in mild cognitive impairment patients2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 33, no 4, p. 929-939Article in journal (Refereed)
    Abstract [en]

    The biomarker-based new diagnostic criteria have been proposed for Alzheimer's disease (AD) spectrum. However, any biomarker alone has not been known to have satisfactory AD predictability. We explored the best combination model with baseline demography, neuropsychology, F-18-fluorodeoxyglucose positron emission tomography (FDG-PET), cerebrospinal fluid (CSF) biomarkers, and apolipoprotein E (APOE) genotype evaluation to predict progression to AD in mild cognitive impairment (MCI) patients. Alongitudinal clinical follow-up (mean, 44 months; range, 1.6-161.7 months) of MCI patients was done. Among 83 MCI patients, 26 progressed to AD (MCI-AD) and 51 did not deteriorate (MCI-Stable). We applied that univariate and multivariate logistic regression analyses, and multistep model selection for AD predictors including biomarkers. In univariate logistic analysis, we selected age, Rey Auditory Verbal Retention Test, parietal glucose metabolic rate, CSF total tau, and presence or not of at least one APOE epsilon 4 allele as predictors. Through multivariate stepwise logistic analysis and model selection, we found the combination of parietal glucose metabolic rate and total tau representing the best model for AD prediction. In conclusion, our findings highlight that the combination of regional glucose metabolic assessment by PET and CSF biomarkers evaluation can significantly improve AD predictive diagnostic accuracy of each respective method.

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

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

  • 21. Darreh-Shori, T.
    et al.
    Brimijoin, S.
    Kadir, A.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Nordberg, A.
    Differential CSF butyrylcholinesterase levels in Alzheimer's disease patients with the ApoE ε4 allele in relation to cognitive function and cerebral glucose metabolism.2006In: Neurobiology of Disease, ISSN 0969-9961, Vol. 24, no 2, p. 326-333Article in journal (Refereed)
    Abstract [en]

    Butyrylcholinesterase (BuChE) is increased in the cerebral cortex of Alzheimer's disease (AD) patients, particularly those carrying ε4 allele of the apolipoprotein E gene (ApoE) and certain BuChE variants that predict increased AD risk and poor response to anticholinesterase therapy. We measured BuChE activity and protein level in CSF of eighty mild AD patients in relation to age, gender, ApoE ε4 genotype, cognition and cerebral glucose metabolism (CMRglc). BuChE activity was 23% higher in men than women ( p<0.03) and 40–60% higher in ApoE ε4 negative patients than in those carrying one or two ε4 alleles ( p<0.0004). CSF BuChE level correlated with cortical CMRglc. Patients with high to moderate CSF BuChE showed better cognitive function scores than others. We hypothesize that CSF BuChE varies inversely with BuChE in cortical amyloid plaques. Thus, low BuChE in a patient's CSF may predict extensive incorporation in neuritic plaques, increased neurotoxicity and greater central neurodegeneration.

  • 22. Darreh-Shori, T.
    et al.
    Kadir, A.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Grut, M.
    Wall, Anders
    Blomquist, G.
    Eriksson, B.
    Långström, B.
    Nordberg, A.
    Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine2008In: Neurobiology of Aging, ISSN 0197-4580, Vol. 29, no 2, p. 168-184Article in journal (Refereed)
    Abstract [en]

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

  • 23. 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.

  • 24. 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.

  • 25.
    Ek, Lena
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Kristoffersen Wiberg, Maria
    Stragliotto, Giuseppe
    Smits, Anja
    Early cognitive impairment in a subset of patients with presumed low-grade glioma 2010In: Neurocase, ISSN 1355-4794, E-ISSN 1465-3656, Vol. 16, no 6, p. 503-511Article in journal (Refereed)
    Abstract [en]

    We investigated the presence of cognitive impairment, in adults with presumed low-grade glioma at early stage of disease prior to major treatments, in relation to neurological symptoms and radiological characteristics of the tumour. Sixteen patients were evaluated. A subset of patients was identified with clearly impaired cognition. Patients with cognitive impairment often had large tumours in the left frontal lobe, were relatively young, and most of them were males. We conclude that cognitive dysfunction may be present already at early stage of disease, and that early identification of patients at risk is warranted.

  • 26.
    Ek, Lena
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Smits, Anja
    Department of Neurosciences, Neurology, University Hospital Uppsala.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Cognitive Deficits in Early Phase of Slowly Growing Glial TumorsManuscript (preprint) (Other academic)
  • 27.
    Ek, Lena
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Smits, Anja
    Department of Neuroscience, Neurology, University Hospital Uppsala.
    Påhlson, Anneli
    Department of Neurology, Örebro University Hospital.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Analysis of Cognitive Dysfunction in Patients with Low-Grade Glioma2005In: Journal of clinical psychology in medical settings, ISSN 1068-9583, E-ISSN 1573-3572, Vol. 12, no 2, p. 165-173Article in journal (Refereed)
    Abstract [en]

    All living adults with histopatologically proven diagnosis of low-grade glioma in a Swedish county were identified with help of the Regional Cancer Register, half of them (n = 24) participated in a neuropsychological evaluation. A considerable variation was found in cognitive function within this group of patients, ranging from good ability to severe disturbance. Different patterns of cognitive dysfunction emerged resulting in three subgroups; patients with severe, mild, and minimal selective dysfunction. The patients with severe disturbance had a global dysfunction covering most assessed cognitive domains. Slow information-processing speed was obvious in the subgroups with both severe and mild dysfunction. Cognitive problems present in the best performing group seemed related to tumor localization. Cognitive function in the whole sample was related to histopathological diagnosis of the tumor, as well as to educational level of the patients. The nonworking patients had significantly poorer performance than the working patients.

  • 28. Engler, Henry
    et al.
    Forsberg, Anton
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Blomquist, Gunnar
    Larsson, Emma
    Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease.2006In: Brain: A journal of neurology, ISSN 0006-8950, Vol. 129, no 11, p. 2856-2866Article in journal (Refereed)
    Abstract [en]

    Beta amyloid is one of the major histopathological hallmarks of Alzheimer's disease. We recently reported in vivo imaging of amyloid in 16 Alzheimer patients, using the PET ligand N-methyl[11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (PIB). In the present study we rescanned these 16 Alzheimer patients after 2.0 ± 0.5 years and have described the interval change in amyloid deposition and regional cerebral metabolic rate for glucose (rCMRGlc) at follow-up. Sixteen patients with Alzheimer's disease were re-examined by means of PET, using PIB and 2-[18F]fluoro-2-deoxy-D-glucose (FDG) after 2.0 ± 0.5 years. The patients were all on cholinesterase inhibitor treatment and five also on treatment with the N-methyl-D-aspartate (NMDA) antagonist memantine. In order to estimate the accuracy of the PET PIB measurements, four additional Alzheimer patients underwent repeated examinations with PIB within 20 days (test–retest). Relative PIB retention in cortical regions differed by 3–7% in the test–retest study. No significant difference in PIB retention was observed between baseline and follow-up while a significant (P < 0.01) 20% decrease in rCMRGlc was observed in cortical brain regions. A significant negative correlation between rCMRGlc and PIB retention was observed in the parietal cortex in the Alzheimer patients at follow-up (r = 0.67, P = 0.009). A non-significant decline in Mini-Mental State Examination (MMSE) score from 24.3 ± 3.7 (mean ± standard deviation) to 22.7 ± 6.1 was measured at follow-up. Five of the Alzheimer patients showed a significant decline in MMSE score of >3 (21.4 ± 3.5 to 15.6 ± 3.9, P < 0.01) (AD-progressive) while the rest of the patients were cognitively more stable (MMSE score = 25.6 ± 3.1 to 25.9 ± 3.7) (AD-stable) compared with baseline. A positive correlation (P = 0.001) was observed in the parietal cortex between Rey Auditory Verbal Learning (RAVL) test score and rCMRGlc at follow-up while a negative correlation (P = 0.018) was observed between RAVL test and PIB retention in the parietal at follow-up. Relatively stable PIB retention after 2 years of follow-up in patients with mild Alzheimer's disease suggests that amyloid deposition in the brain reaches a plateau by the early clinical stages of Alzheimer's disease and therefore may precede a decline in rCMRGlc and cognition. It appears that anti-amyloid therapies will need to induce a significant decrease in amyloid load in order for PIB PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer's disease.

  • 29. Engstad, Torgeir
    et al.
    Viitanen, Matti
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Kognitiv svikt etter hjerneslag - diagnostikk åg håndtering2007In: Tidskrift for Norsk Laegeforening, Vol. 127Article in journal (Refereed)
  • 30.
    Eriksdotter-Jönhagen, Maria
    et al.
    Karolinska Institutet.
    Linderoth, Bengt
    Karolinska Institutet.
    Lind, Göran
    Karolinska Institutet.
    Aladellie, Layth
    Karolinska universitetssjukhuset.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Andreasen, Niels
    Karolinska Institutet.
    Blennow, Kaj
    Göteborgs universitet.
    Bogdanovic, Nenad
    Karolinska Institutet.
    Jelic, Vesna
    Karolinska Institutet.
    Kadir, Ahmadul
    Karolinska Institutet.
    Nordberg, Agneta
    Karolinska Institutet.
    Sundström, Erik
    Karolinska Institutet.
    Wahlund, Lars-Olof
    Karolinska Institutet.
    Wall, Anders
    Uppsala Universitet.
    Wiberg, Maria
    Karolinska Institutet.
    Winblad, Bengt
    Karolinska Institutet.
    Seiger, Åke
    Karolinska Institutet.
    Almkvist, Per
    Karolinska Institutet.
    Wahlberg, Lars
    Karolinska Institutet.
    Encapsulated Cell Biodelivery of Nerve Growth Factor to the Basal Forebrain in Patients with Alzheimer’s Disease2012In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 33, no 1, p. 18-28Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Degeneration of cholinergic neurons in the basal forebrain correlates with cognitive decline in patients with Alzheimer’s disease (AD). Targeted delivery of exogenous nerve growth factor (NGF) has emerged as a potential AD therapy due to its regenerative effects on the basal forebrain cholinergic neurons in AD animal models. Here we report the results of a first-in-man study of encapsulated cell (EC) biodelivery of NGF to the basal forebrain of AD patients with the primary objective to explore safety and tolerability. Methods: This was an open-label, 12-month study in 6 AD patients. Patients were implanted stereotactically with EC-NGF biodelivery devices targeting the basal forebrain. Patients were monitored with respect to safety, tolerability, disease progression and implant functionality. Results: All patients were implanted successfully with bilateral single or double implants without complications or signs of toxicity. No adverse events were related to NGF or the device. All patients completed the study, including removal of implants at 12 months. Positive findings in cognition, EEG and nicotinic receptor binding in 2 of 6 patients were detected. Conclusions: This study demonstrates that surgical implantation and removal of EC-NGF biodelivery to the basal forebrain in AD patients is safe, well tolerated and feasible.

  • 31. Forsberg, A.
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Engler, H.
    Wall, A.
    Langström, B.
    Nordberg, A.
    High PIB Retention in Alzheimer's Disease is an Early Event with Complex Relationship with CSF Biomarkers and Functional Parameters2010In: Current Alzheimer research, ISSN 1567-2050, Vol. 7, no 1, p. 56-66Article in journal (Refereed)
    Abstract [en]

    Background: New in vivo amyloid PET imaging tracers, such as C-11-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimer's disease (AD). In this study we investigated how C-11-PIB retention is related to cerebral glucose metabolism, episodic memory and CSF biomarkers. Method: Thirty-seven patients with mild AD and 21 patients with mild cognitive impairment (MCI) underwent PET examinations with the amyloid tracer C-11-PIB, F-18-FDG for measurement of regional cerebral metabolic rate of glucose (rCMRglc), assessment of episodic memory and assay of cerebral spinal fluid (CSF) levels of amyloid-beta (A beta(1-42)), total tau and phosphorylated tau respectively. Analyses were performed using Statistical Parametric Mapping (SPM) and regions of interest (ROIs). Results: Pooled data from AD and MCI patients showed strong correlations between C-11-PIB retention, levels of CSF biomarkers (especially A beta(1-42)), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between C-11-PIB retention and CSF biomarkers and between CSF biomarkers and episodic memory respectively. A strong correlation was observed in the AD group between rCMRglc and episodic memory as well as a significant correlation between C-11-PIB retention and rCMRglc in some cortical regions. Regional differences were observed as sign for changes in temporal patterns across brain regions. Conclusions: A complex pattern was observed between pathological and functional markers with respect to disease stage (MCI versus AD) and brain regions. Regional differences over time were evident during disease progression. C-11-PIB PET and CSF A beta(1-42) allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.

  • 32. Forsberg, Anton
    et al.
    Engler, Henry
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    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, 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.

  • 33. Hedman, Annicka
    et al.
    Nygard, Louise
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Kottorp, Anders
    Amount and type of everyday technology use over time in older adults with cognitive impairment2015In: Scandinavian Journal of Occupational Therapy, ISSN 1103-8128, E-ISSN 1651-2014, Vol. 22, no 3, p. 196-206Article in journal (Refereed)
    Abstract [en]

    Objectives: This two-year study examined everyday technology (ET) use in older adults with mild cognitive impairment (MCI) testing five predefined theoretical assumptions regarding factors potentially influencing the amount of ET used in everyday life. Methods: Data from 37 participants with MCI were collected at inclusion, six, 12, and 24 months, on the type and amount of ET used and how difficult this was, activity involvement, and cognitive and diagnostic status. These variables were, together with age group (55-64, 65-74, or 75-84 years) and educational level, analysed in a mixed-linear-effect model. Results: A significant decrease in the overall amount of ET used was found over time, but the number of users of specific ETs both decreased and increased. Increasing perceived difficulty in ET use, less activity involvement, decreasing cognitive status, and belonging to the oldest age group significantly decreased ET use. Two years after inclusion 42% of the participants had converted to dementia, but neither change in diagnostic status nor length of education contributed significantly to the predictive model. Conclusion: Over time, a decreasing use of ET was shown in this sample with MCI. This process was influenced by several aspects important to consider in occupational therapy intervention planning.

  • 34. Hedman, Annicka
    et al.
    Nygård, Louise
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Kottorp, Anders
    Patterns of functioning in older adults with mild cognitive impairment: a two-year study focusing on everyday technology use2013In: Aging & Mental Health, ISSN 1360-7863, E-ISSN 1364-6915, Vol. 17, no 6, p. 679-688Article in journal (Refereed)
    Abstract [en]

    Objectives: Early detection is vital for persons with mild cognitive impairment (MCI) who are at risk of activity and participation limitations, and crosssectional studies suggest the ability to use everyday technology (ET) to be a sensible tool. However, group level analyses fail to inform us about how functioning can vary over time for individuals. This study aimed at exploring and describing patterns of functioning over two years in a sample newly classified with MCI, with a special focus on perceived difficulty in ET use and involvement in everyday activities. In addition, cognitive functioning and conversion to dementia were studied. Method: 37 older adults (aged 55) with MCI were assessed at inclusion, and at 6, 12, and 24 months. Longitudinal case plots for the variables under study were analyzed based on strict criteria using a person-oriented approach. Paired t-tests from baseline and 24 months were also conducted to analyze change. Results: The 32 participants who remained in the study after two years showed three distinct patterns of functioning over time: stable/ascending (n = 10), fluctuating (n = 10), and descending (n = 12), with the highest conversion to dementia in the descending pattern (58%). The perceived ability to use ET decreased or fluctuated in 50% of the sample. However, on a group level, a significant difference between baseline and 24 months was found only regarding cognitive function. Conclusion: As the need for support is individual and likely to alter over time, repeated evaluations of activity involvement and difficulty in ET use are suggested to target timely interventions for persons with MCI.

  • 35. Hedman, Annicka
    et al.
    Nygård, Louise
    Malinowsky, Camilla
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Kottorp, Anders
    Changing everyday activities and technology use in mild cognitive impairment2016In: British Journal of Occupational Therapy, ISSN 0308-0226, E-ISSN 1477-6006, Vol. 79, no 2, p. 111-119Article in journal (Refereed)
    Abstract [en]

    Introduction: Knowledge of the conditions under which older adults facing cognitive decline engage in everyday activities is of major importance for occupational therapists in designing supportive interventions. This study aimed to investigate perceived activity involvement over time and its longitudinal relationship to perceived ability to use everyday technology in older adults with mild cognitive impairment.

    Method: Thirty-seven older adults with mild cognitive impairment at inclusion were assessed over 4 years. Overall and item-specific activity involvement were analyzed using mixed-linear-effect modeling and differential item functioning. Furthermore, overall activity involvement and ability in everyday technology use were correlated.

    Results: Overall activity involvement decreased significantly over time. When adjusting for declining ability in the sample, actual differential item functioning indicated descending involvement in seven of 15 activities, while eight activities were stable. All leisure activities descended. The positive correlations between activity involvement and ability in everyday technology use became stronger over time.

    Conclusion: Variations across activities and time-points suggest that occupational therapists should repeatedly monitor the increasingly associated aspects of activity involvement and ability to use everyday technology in persons with cognitive decline.

  • 36. Huang, Chaorui
    et al.
    Wahlund, Lars-Olof
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Elehu, Dagmawi
    Svensson, Leif
    Jonsson, Tomas
    Winblad, Bengt
    Julin, Per
    Voxel- and VOI-based analysis of SPECT CBF in relation to clinical and psychological heterogeneity of mild cognitive impairment.2003In: NeuroImage, ISSN 1053-8119, Vol. 19, no 3, p. 1137-1144Article in journal (Refereed)
    Abstract [en]

    This study aimed to explore the heterogeneity of mild cognitive impairment (MCI) and detect differences in regional cerebral blood flow (rCBF) and cognitive function between progressive mild cognitive impairment (PMCI) and stable mild cognitive impairment (SMCI) in order to identify specific changes useful for early diagnosis of dementia. SPECT was performed in 82 MCI subjects and 20 controls using Tc-99m hexamethylpropyleneamine oxime. Cognitive functions were tested in five domains which included episodic memory, semantic memory, visuospatial function, attention, and general cognitive function. After the initial examination, MCI subjects were clinically followed for an average of 2 years. Twenty-eight subjects progressed to dementia and were defined as PMCI at baseline and 54 subjects remained stable and were defined as SMCI at baseline. The baseline rCBF and cognitive function of PMCI, SMCI, and controls were compared. PMCI had decreased relative rCBF in the parietal lobes and increased relative rCBF in prefrontal cortex compared to SMCI and controls at baseline. The cognitive function of PMCI was more severely impaired compared to SMCI with respect to episodic memory and visuospatial and general cognitive function. Both SPECT and neuropsychological tests had moderate discriminant function between PMCI and SMCI at baseline with the area under the receiver operating characteristic (ROC) curve at 75–77%. The combination of these two methods improved the diagnostic accuracy with the area under the ROC curve at 82–84%. Semantic memory and attention were negatively correlated with left prefrontal relative rCBF among the study population. The results show that the clinical heterogeneity of MCI is reflected in different patterns of psychological and CBF changes. Combined SPECT investigation and neuropsychological testing might predict the future development of dementia in patients with MCI.

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

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

  • 38.
    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.

  • 39. Kadir, Ahmadul
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Wall, Anders
    Långström, Bengt
    Nordberg, Agneta
    PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer´s disease.2006In: Psychopharmacology, ISSN 0033-3158, Vol. 188, no 4, p. 509-520Article in journal (Refereed)
    Abstract [en]

    Rationale: Patients suffering from Alzheimer's disease (AD) experience a marked reduction in cortical nicotinic acetylcholine receptors (nAChRs). In particular, selective loss of the α-sub-4β-sub-2 nAChR subtype was observed in postmortem AD brain tissue. The α-sub-4 and α-sub-7 nAChR subunits were suggested to play an important role in cognitive function. Positron emission tomography (PET) has so far been used to visualize neuronal nAChRs in vivo by 11C-nicotine binding. Objectives: To investigate the relationship between measures of cognitive function and in vivo 11C-nicotine binding in mild AD brain as assessed by PET. Materials and methods: Twenty-seven patients with mild AD were recruited in this study. A dual tracer model with administration of 1-sup-5O-water for regional cerebral blood flow and (S)(-)11C-nicotine was used to assess nicotine binding sites in the brain by PET. Cognitive function was assessed using neuropsychological tests of global cognition, episodic memory, attention, and visuospatial ability. Results: Mean cortical 11C-nicotine binding significantly correlated with the results of attention tests (r = -0.44 and p = 0.02) and Trail Making Test A (TMT-A) (r = 0.42 and p = 0.03)]. No significant correlation was observed between 11C-nicotine binding and the results of tests of episodic memory or visuospatial ability. Regional analysis showed that 11C-nicotine binding in the frontal and parietal cortex, which are the main areas for attention, correlated significantly with the Digit Symbol test and TMT-A results. Conclusion: Cortical nicotinic receptors in vivo in mild AD patients are robustly associated with the cognitive function of attention.

  • 40. Kadir, Ahmadul
    et al.
    Andreasen, Niels
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Wall, Anders
    Forsberg, Anton
    Engler, Henry
    Hagman, Göran
    Lärksäter, Marie
    Winblad, Bengt
    Zetterberg, Henrik
    Blennow, Kaj
    Långström, Bengt
    Nordberg, Agneta
    Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease2008In: Annals of Neurology, ISSN 0364-5134, Vol. 63, no 5, p. 621-631Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The effects of (-)-phenserine (phenserine) and placebo/donepezil treatment on regional cerebral metabolic rate for glucose (rCMRglc) and brain amyloid load were investigated by positron emission tomography in 20 patients with mild Alzheimer's disease in relation to cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive function.

    METHODS: The first 3 months of the study was a randomized, double-blind, placebo-controlled phase, during which 10 patients received phenserine (30 mg/day) and 10 patients the placebo. Three to 6 months was an open-label extension phase, during which the placebo group received donepezil (5 mg/day) and the phenserine group remained on phenserine. After 6 months, all patients received phenserine treatment up to 12 months. The patients underwent positron emission tomography examinations to measure rCMRglc (8F-FDG) and amyloid load (11C-PIB) at baseline and after 3 and 6 months of the treatment. Neuropsychological and biomarker data were collected at the three times of positron emission tomography imaging.

    RESULTS: Statistically significant effects on a composite neuropsychological test score were observed in the phenserine-treated group compared with the placebo and donepezil group at 3 and 6 months, respectively. Values of rCMRglc were significantly increased in several cortical regions after 3 months of phenserine treatment, compared with baseline, and correlated positively with cognitive function and CSF beta-amyloid 40 (Abeta40). Cortical Pittsburgh Compound B retention correlated negatively with CSF Abeta40 levels and the ratio Abeta/beta-secretase-cleaved amyloid precursor protein. In CSF, Abeta40 correlated positively with the attention domain of cognition.

    INTERPRETATION: Phenserine treatment was associated with an improvement in cognition and an increase in rCMRglc.

  • 41. Kadir, Ahmadul
    et al.
    Darreh-Shori, T.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    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 AD.2008In: Neurobiology of Aging, ISSN 0197-4580, 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.

  • 42. Kadir, Ahmadul
    et al.
    Darreh-Shori, Taher
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Wall, Anders
    Langstrom, Bengt
    Nordberg, Agneta
    Changes in brain C-11-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 191, no 4, p. 1005-1014Article in journal (Refereed)
    Abstract [en]

    Rationale Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer's disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD. Objectives To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment. Materials and methods Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of O-15-water and (S)(-)C-11-nicotine was used to assess C-11-nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically. Results The 11C-nicotine binding sites were significantly increased 12-19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical C-11-nicotine binding. The C-11-nicotine binding positively correlated with attentional task at the 12-month follow-up. Conclusions Changes in the C-11-nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.

  • 43. Kadir, Ahmadul
    et al.
    Marutle, Amelia
    Gonzalez, Daniel
    Schöll, Michael
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Mousavi, Malahat
    Mustafiz, Tamanna
    Darreh-Shori, Taher
    Nennesmo, Inger
    Nordberg, Agneta
    Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease2011In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 134, no 1, p. 301-317Article in journal (Refereed)
    Abstract [en]

    The accumulation of &#946;-amyloid in the brain is an early event in Alzheimer’s disease. This study presents the first patient with Alzheimer’s disease who underwent positron emission tomography imaging with the amyloid tracer, Pittsburgh Compound B to visualize fibrillar &#946;-amyloid in the brain. Here we relate the clinical progression, amyloid and functional brain positron emission tomography imaging with molecular neuropathological alterations at autopsy to gain new insight into the relationship between &#946;-amyloid accumulation, inflammatory processes and the cholinergic neurotransmitter system in Alzheimer’s disease brain. The patient underwent positron emission tomography studies with 18F-fluorodeoxyglucose three times (at ages 53, 56 and 58 years) and twice with Pittsburgh Compound B (at ages 56 and 58 years), prior to death at 61 years of age. The patient showed a pronounced decline in cerebral glucose metabolism and cognition during disease progression, while Pittsburgh Compound B retention remained high and stable at follow-up. Neuropathological examination of the brain at autopsy confirmed the clinical diagnosis of pure Alzheimer’s disease. A comprehensive neuropathological investigation was performed in nine brain regions to measure the regional distribution of &#946;-amyloid, neurofibrillary tangles and the levels of binding of 3H-nicotine and 125I-&#945;-bungarotoxin to neuronal nicotinic acetylcholine receptor subtypes, 3H-L-deprenyl to activated astrocytes and 3H-PK11195 to microglia, as well as butyrylcholinesterase activity. Regional in vivo 11C-Pittsburgh Compound B-positron emission tomography retention positively correlated with 3H-Pittsburgh Compound B binding, total insoluble &#946;-amyloid, and &#946;-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. There was a negative correlation between regional fibrillar &#946;-amyloid and levels of 3H-nicotine binding. In addition, a positive correlation was found between regional 11C-Pittsburgh Compound B positron emission tomography retention and 3H-Pittsburgh Compound B binding with the number of glial fibrillary acidic protein immunoreactive cells, but not with 3H-L-deprenyl and 3H-PK-11195 binding. In summary, high 11C-Pittsburgh Compound B positron emission tomography retention significantly correlates with both fibrillar &#946;-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of &#946;-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes.

  • 44. Larsson, Maria U.
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology.
    Luszcz, Mary A.
    Wahlin, Tarja-Brita Robins
    Phonemic fluency deficits in asymptomatic gene carriers for Huntington's disease2008In: Neuropsychology, ISSN 0894-4105, Vol. 22, no 5, p. 596-605Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to investigate verbal fluency in preclinical Huntington's disease (HD). Phonemic and semantic fluency and the rate of word production over time were assessed for 29 asymptomatic gene carriers and 34 noncarriers of HD. The relationship between fluency tasks and other cognitive domains was investigated. Compared to noncarriers, carriers produced fewer words and produced them more slowly in the phonemic fluency task but not in the semantic fluency task. When the carrier group was divided on the basis of Predicted-Years-To-Onset (PYTO), only carriers with <12 PYTO performed worse than noncarriers on both fluency tasks. Correlational analyses revealed that phonemic fluency was associated with cognitive speed and working memory, while semantic fluency was linked with crystallized abilities. The difference between carriers and noncarriers in phonemic fluency and a difference between the two carrier groups (<12 PYTO and ≥12 PYTO) in semantic fluency, but not in phonemic fluency, suggest that frontostriatal deficits may precede temporal involvement in preclinical HD.

  • 45. Lehmann, Christoph
    et al.
    Vannini, Patrizia
    Wahlund, Lars-Olof
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Dierks, Thomas
    Increased sensitivity and specificity in mapping task demand in visuo-spatial processing using reaction-time convolved hemodynamic response predictors in rapid event-related fMRI.2006In: NeuroImage, ISSN 1053-8119, Vol. 31, no 2, p. 505-512Article in journal (Refereed)
    Abstract [en]

    Searching for the neural correlates of visuospatial processing using functional magnetic resonance imaging (fMRI) is usually done in an event-related framework of cognitive subtraction, applying a paradigm comprising visuospatial cognitive components and a corresponding control task. Besides methodological caveats of the cognitive subtraction approach, the standard general linear model with fixed hemodynamic response predictors bears the risk of being underspecified. It does not take into account the variability of the blood oxygen level-dependent signal response due to variable task demand and performance on the level of each single trial. This underspecification may result in reduced sensitivity regarding the identification of task-related brain regions. In a rapid event-related fMRI study, we used an extended general linear model including single-trial reaction-time-dependent hemodynamic response predictors for the analysis of an angle discrimination task. In addition to the already known regions in superior and inferior parietal lobule, mapping the reaction-time-dependent hemodynamic response predictor revealed a more specific network including task demand-dependent regions not being detectable using the cognitive subtraction method, such as bilateral caudate nucleus and insula, right inferior frontal gyrus and left precentral gyrus.

  • 46. Leuzy, Antoine
    et al.
    Carter, Stephen F.
    Chiotis, Konstantinos
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Wall, Anders
    Nordberg, Agneta
    Concordance and Diagnostic Accuracy of [C-11]PIB PET and Cerebrospinal Fluid Biomarkers in a Sample of Patients with Mild Cognitive Impairment and Alzheimer's Disease2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 45, no 4, p. 1077-1088Article in journal (Refereed)
    Abstract [en]

    Background: Alzheimer's disease (AD) pathology can be quantified in vivo using cerebrospinal fluid (CSF) levels of amyloid-beta(1-42) (A beta(1-42)), total-tau (t-tau), and phosphorylated tau (p- tau(181p)), as well as with positron emission tomography (PET) using [C-11]Pittsburgh compound-B ([C-11]PIB). Studies assessing concordance between these measures, however, have provided conflicting results. Moreover, it has been proposed that [C-11]PIB PET may be of greater clinical utility in terms of identifying patients with mild cognitive impairment (MCI) who will progress to the dementia phase of AD. Objective: To determine concordance and classification accuracy of CSF biomarkers and [C-11]PIB PET in a cohort of patients with MCI and AD. Methods: 68 patients (MCI, n = 33; AD, n = 35) underwent [C-11]PIB PET and CSF sampling. Cutoffs of >1.41 ([C-11]PIB), <450 pg/mL-and a more lenient cutoff of 550 pg/mL-(A beta(1-42)), <6.5 (A beta(1-42)/p-tau181p), and 1.14 (A beta(1- 42)/t-tau), were used to determine concordance. Logistic regression was used to determine classification accuracy with respect to stable MCI (sMCI) versus MCI who progressed to AD (pMCI). Results: Concordance between [C-11]PIB and A beta(1-42) was highest for sMCI (67%), followed by AD (60%) and pMCI (33%). Agreement was increased across groups using A beta(1-42) < 550 pg/mL, or A beta(1-42) to tau ratios. Logistic regression showed that classification accuracy of [11C] PIB, between sMCI and pMCI, was superior to A beta(1-42) (73% versus 58%), A beta(1-42)/t-tau (63%), and A beta(1-42)/p-tau181p (65%). Conclusion: In the present study, [C-11]PIB proved a better predictor of progression to AD in patients with MCI, relative to CSF measures of A beta(1-42) or A beta(1-42)/tau. Discordance between PET and CSF markers for A beta(1-42) suggests they cannot be used interchangeably, as is currently the case.

  • 47. Li, X.
    et al.
    Westman, E.
    Ståhlbom, A. K.
    Thordardottir, S.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Blennow, K.
    Wahlund, L. -O.
    Graff, C.
    White matter changes in familial Alzheimer's disease2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, no 2, p. 211-218Article in journal (Refereed)
    Abstract [en]

    BackgroundFamilial Alzheimer's disease (FAD) resulting from gene mutations in PSEN1, PSEN2 and APP is associated with changes in the brain. ObjectiveThe aim of this study was to investigate changes in grey matter (GM), white matter (WM) and the cerebrospinal fluid (CSF) in FAD. SubjectsTen mutation carriers (MCs) with three different mutations in PSEN1 and APP and 20 noncarriers (NCs) were included in the study. Three MCs were symptomatic and seven were presymptomatic (pre-MCs). MethodsWhole-brain GM volume as well as fractional anisotropy (FA) and mean diffusivity (MD) using voxel-based morphometry and tract-based spatial statistics analyses, respectively, were compared between MCs and NCs. FA and MD maps were obtained from diffusion tensor imaging. ResultsA significant increase in MD was found in the left inferior longitudinal fasciculus, cingulum and bilateral superior longitudinal fasciculus in pre-MCs compared with NCs. After inclusion of the three symptomatic MCs in the analysis, the regions became wider. The mean MD of these regions showed significant negative correlation with the CSF level of A42, and positive correlations with P-tau(181p) and T-tau. No differences were observed in GM volume and FA between the groups. ConclusionsThe results of this study suggest that FAD gene mutations affect WM diffusivity before changes in GM volume can be detected. The WM changes observed were related to changes in the CSF, with similar patterns previously observed in sporadic Alzheimer's disease.

  • 48. Li, Xiaozhen
    et al.
    Westman, Eric
    Thordardottir, Steinunn
    Ståhlbom, Anne Kinhult
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Blennow, Kaj
    Wahlund, Lars-Olof
    Graff, Caroline
    The Effects of Gene Mutations on Default Mode Network in Familial Alzheimer’s Disease2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 56, no 1, p. 327-334Article in journal (Refereed)
    Abstract [en]

    Familial Alzheimer’s disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel’s time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function.

  • 49.
    Lindau, Maria
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Cognitive psychology.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology.
    Mohammed, A.
    Effects of Stress on Learning and Memory2016In: Stress: concepts, cognition, emotion, and behavior / [ed] George Fink, Amsterdam: Academic Press, 2016, 1, p. 153-159Chapter in book (Other academic)
  • 50. Lofkvist, Ulrika
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Lyxell, Bjoern
    Tallberg, Ing-Mari
    Lexical and semantic ability in groups of children with cochlear implants, language impairment and autism spectrum disorder2014In: International Journal of Pediatric Otorhinolaryngology, ISSN 0165-5876, E-ISSN 1872-8464, Vol. 78, no 2, p. 253-263Article in journal (Refereed)
    Abstract [en]

    Objective: Lexical-semantic ability was investigated among children aged 6-9 years with cochlear implants (CI) and compared to clinical groups of children with language impairment (LI) and autism spectrum disorder (ASD) as well as to age-matched children with normal hearing (NH). In addition, the influence of age at implantation on lexical-semantic ability was investigated among children with Cl. Methods: 97 children divided into four groups participated, CI (n = 34), LI (n = 12), ASD (n = 12), and NH (n = 39). A battery of tests, including picture naming, receptive vocabulary and knowledge of semantic features, was used for assessment. A semantic response analysis of the erroneous responses on the picture-naming test was also performed. Results: The group of children with Cl exhibited a naming ability comparable to that of the age-matched children with NH, and they also possessed a relevant semantic knowledge of certain words that they were unable to name correctly. Children with CI had a significantly better understanding of words compared to the children with LI and ASD, but a worse understanding than those with NH. The significant differences between groups remained after controlling for age and non-verbal cognitive ability. Conclusions: The children with Cl demonstrated lexical-semantic abilities comparable to age-matched children with NH, while children with LI and ASD had a more atypical lexical-semantic profile and poorer sizes of expressive and receptive vocabularies. Dissimilar causes of neurodevelopmental processes seemingly affected lexical-semantic abilities in different ways in the clinical groups.

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