Authors: Almkvist, Ove | Brüggen, Katharina | Nordberg, Agneta
Article Type: Research Article
Abstract: Background: The effect of regional brain amyloid-β (Aβ) pathology on specific cognitive functions is incompletely known. Objective: The relationship between Aβ and cognitive functions was investigated in this cross-sectional multicenter study of memory clinic patients. Methods: The participants were patients diagnosed with Alzheimer’s disease (AD, n = 83), mild cognitive impairment (MCI, n = 60), and healthy controls (HC, n = 32), who had been scanned by 11 C-PiB PET in 13 brain regions of both hemispheres and who had been assessed by cognitive tests covering seven domains. Results: Hierarchic multiple regression analyses were performed on each cognitive test as dependent variable, controlling …for demographic characteristics and APOE status (block 1) and PiB measures in 13 brain regions (block 2) as independent variables. The model was highly significant for each cognitive test and most strongly for tests of episodic memory (learning and retention) versus PiB in putamen, visuospatially demanding tests (processing and retention) versus the occipital lobe, semantic fluency versus the parietal lobe, attention versus posterior gyrus cinguli, and executive function versus nucleus accumbens. In addition, education had a positively and APOE status a negatively significant effect on cognitive tests. Conclusion: Five subcortical and cortical regions with Aβ pathology are differentially associated with cognitive functions and stages of disease in memory clinic patients. Show more
Keywords: Alzheimer’s disease, amyloid-β, cognitive functions, mild cognitive impairment, pittsburgh compound-B (PiB), positron emission tomography, regional Aβ pathology
DOI: 10.3233/JAD-201612
Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1613-1624, 2021
Authors: Almkvist, Ove | Larsson, Maria | Graff, Caroline
Article Type: Research Article
Abstract: Background: Impaired odor identification is a characteristic of sporadic Alzheimer’sdisease(AD), but its presence in autosomal-dominantAD (adAD) remains uncertain. Objective: To investigate odor identification ability in mutation carriers (MC) and non-carriers (NC) of adAD in relation to years to estimated clinical onset clinical onset (YECO) of disease. Methods: Participants from six families with autosomal-dominant mutations (APP Swedish, APP Arctic, and PSEN1 mutations) included 20 MC and 20 NC. The groups were comparable in age, gender, education, number of APOE ɛ4 alleles, and YECO, but differed in global cognition (Mini-Mental State Examination). The MC group included individuals in asymptomatic, symptomatic cognitively unimpaired, …mild cognitive impairment, and dementia stages of disease, spanning approximately 40 years of the AD continuum. All NC were asymptomatic. Olfactory function was assessed by means of free and cued identification of common odors summarized as total identification. Results: MC performed poorer than NC in free and total identification. Four MC and none of the NC were anosmic. Olfactory functions in MC and NC were significantly and inversely related to time course (YECO) for both free and total identification. The decline in free identification began approximately 10 years prior to the estimated clinical onset of AD in MC. Odor identification proficiency was associated with episodic memory and executive function in MC and NC. Conclusions: Impaired odor identification is present well before the clinical diagnosis of AD in MC and is associated with disease progression. Odor identification ability may be a useful early biomarker for adAD. Show more
Keywords: Alzheimer’s disease, autosomal-dominant Alzheimer’s disease, cognition, mutation carriers, non-carriers, odor identification
DOI: 10.3233/JAD-230618
Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 587-598, 2024
Authors: Choo, IL Han | Ni, Ruiqing | Schöll, Michael | Wall, Anders | Almkvist, Ove | Nordberg, Agneta
Article Type: Research Article
Abstract: 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, 18 F-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. A longitudinal 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 ε4 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. Show more
Keywords: Biomarkers, combination, mild cognitive impairment, predictor
DOI: 10.3233/JAD-2012-121489
Citation: Journal of Alzheimer's Disease, vol. 33, no. 4, pp. 929-939, 2013
Authors: Thordardottir, Steinunn | Almkvist, Ove | Johansson, Charlotte | Zetterberg, Henrik | Blennow, Kaj | Graff, Caroline
Article Type: Research Article
Abstract: Background: YKL-40 and neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) which reflect different underlying disease mechanisms. Objective: To compare the levels of CSF YKL-40 and neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and neurogranin, from the presymptomatic to clinical phase of FAD. Methods: YKL-40 and neurogranin, as well as Aβ 42 , total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G), and PSEN1 (p.H163Y), …as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up. Results: In this pilot study, there was no difference in either CSF YKL-40 or neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC. Conclusion: These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not neurogranin. Show more
Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, chitinases, genetics, mutation, neurogranin
DOI: 10.3233/JAD-191261
Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 941-953, 2020
Authors: Nordberg, Agneta | Kadir, Ahmadul | Andreasen, Niels | Almkvist, Ove | Wall, Anders | , Kaj Blennow | Långström, Bengt | Zetterberg, Henrik
Article Type: Research Article
Abstract: New therapeutic strategies in Alzheimer’s disease (AD) are focused on targeting amyloid-β (Aβ) to modify the underlying cause of the disease rather than just the symptoms. The aim of this study was to investigate the long-term effects of treatment with the anti-Aβ compound phenserine on (i) cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and (ii) brain metabolism as assessed by the regional cerebral metabolic rate for glucose (rCMRglc), using positron emission tomography. Twenty patients with mild AD were included in the study and after 12 months treatment with phenserine, CSF Aβ 40 and α- and β-secretase-cleaved soluble amyloid-β …protein precursor (sAβPP) levels had significantly increased and rCMRglc had stabilized. Levels of CSF Aβ 40 and sAβPP correlated positively with rCMRglc and cognition while CSF Aβ 42 levels, the Aβ 42/40 ratio, P-tau, and T-tau correlated negatively with rCMRglc and cognition. In summary, long-term phenserine treatment resulted in increased levels of CSF Aβ 40 , sAβPPα, and sAβPPβ, which positively correlated with improvements in rCMRglc and cognition. The study illustrates the value of using biomarkers in the CSF and brain for evaluation of drug effects. Show more
Keywords: Alzheimer’s disease, cerebral glucose metabolism, cerebrospinal fluid, phenserine, positron emission tomography
DOI: 10.3233/JAD-132474
Citation: Journal of Alzheimer's Disease, vol. 47, no. 3, pp. 691-704, 2015
Authors: Leuzy, Antoine | Carter, Stephen F. | Chiotis, Konstantinos | Almkvist, Ove | Wall, Anders | Nordberg, Agneta
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) pathology can be quantified in vivo using cerebrospinal fluid (CSF) levels of amyloid-β1-42 (Aβ1-42 ), total-tau (t-tau), and phosphorylated tau (p-tau181p ), as well as with positron emission tomography (PET) using [11 C]Pittsburgh compound-B ([11 C]PIB). Studies assessing concordance between these measures, however, have provided conflicting results. Moreover, it has been proposed that [11 C]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 [11 C]PIB PET in …a cohort of patients with MCI and AD. Methods: 68 patients (MCI, n = 33; AD, n = 35) underwent [11 C]PIB PET and CSF sampling. Cutoffs of >1.41 ([11 C]PIB), <450 pg/mL—and a more lenient cutoff of 550 pg/mL—(Aβ1-42 ), <6.5 (Aβ1-42 /p-tau181p ), and 1.14 (Aβ1-42 /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 [11 C]PIB and Aβ1-42 was highest for sMCI (67%), followed by AD (60%) and pMCI (33%). Agreement was increased across groups using Aβ1-42 <550 pg/mL, or Aβ1-42 to tau ratios. Logistic regression showed that classification accuracy of [11 C]PIB, between sMCI and pMCI, was superior to Aβ1-42 (73% versus 58%), Aβ1-42 /t-tau (63%), and Aβ1-42 /p-tau181p (65%). Conclusion: In the present study, [11 C]PIB proved a better predictor of progression to AD in patients with MCI, relative to CSF measures of Aβ1-42 or Aβ1-42 /tau. Discordance between PET and CSF markers for Aβ1-42 suggests they cannot be used interchangeably, as is currently the case. Show more
Keywords: [11C]PIB, Alzheimer's disease, amyloid, cerebrospinal fluid, mild cognitive impairment, positron emission tomography, tau
DOI: 10.3233/JAD-142952
Citation: Journal of Alzheimer's Disease, vol. 45, no. 4, pp. 1077-1088, 2015
Authors: Schöll, Michael | Almkvist, Ove | Bogdanovic, Nenad | Wall, Anders | Långström, Bengt | Viitanen, Matti | Nordberg, Agneta
Article Type: Research Article
Abstract: Studies in carriers of mutations that cause early-onset familial Alzheimer's disease (eoFAD) are of significant interest. We showed previously that regional glucose hypometabolism could be detected many years before disease onset in presenilin 1 (PSEN1) mutation carriers. Here we studied four members of a family with a Met146Val PSEN1 mutation, two symptomatic carriers and two non-carriers, longitudinally with 18 F-FDG PET over a period of about two and four years, respectively. The two mutation carriers showed global cortical glucose hypometabolism over time with the most distinct decline occurring in the posterior cingulate, the parietal and parietotemporal cortex, which was also …observed when compared with a group of 23 healthy controls and a group 27 sporadic Alzheimer's disease (sAD) patients. This decline correlated with cognitive deterioration over time as measured by neuropsychological tests. Postmortem examination of brain tissue revealed substantially elevated levels of AD type neuropathology in terms of neuritic plaques and neurofibrillary tangles in the two mutation carriers compared with a reference group of sAD patients. In the mutation carriers, the amount of neuritic plaques but not neurofibrillary tangles correlated hereby significantly with regional glucose metabolism as measured by 18 F-FDG on the last scanning occasions, which were performed four and approximately five years before death, respectively. We here show that FDG PET can depict in vivo the aggressive disease progression in eoFAD mutation carriers in relationship to neuropathology. Show more
Keywords: Early-onset familial Alzheimer's disease, FDG, longitudinal studies, neuritic plaques, neurofibrillary tangles, postitron emission tomography, postmortem pathology, presenilin 1
DOI: 10.3233/JAD-2011-101563
Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 495-506, 2011
Authors: Li, Xiaozhen | Westman, Eric | Thordardottir, Steinunn | Ståhlbom, Anne Kinhult | Almkvist, Ove | Blennow, Kaj | Wahlund, Lars-Olof | Graff, Caroline
Article Type: Research Article
Abstract: 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. Show more
Keywords: Cerebrospinal fluid biomarkers, default mode network, familial Alzheimer’s disease, mutation carrier, resting-state functional MRI, synaptic function
DOI: 10.3233/JAD-160730
Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 327-334, 2017
Authors: Iaccarino, Leonardo | Chiotis, Konstantinos | Alongi, Pierpaolo | Almkvist, Ove | Wall, Anders | Cerami, Chiara | Bettinardi, Valentino | Gianolli, Luigi | Nordberg, Agneta | Perani, Daniela
Article Type: Research Article
Abstract: Assessments of brain glucose metabolism (18 F-FDG-PET) and cerebral amyloid burden (11 C-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 18 F-FDG-PET and 11 C-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for 18 F-FDG-PET and of standardized uptake value ratio semiquantification for 11 C-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, 18 F-FDG-PET and 11 C-PiB-PET. 18 F-FDG-PET, compared to 11 C-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 18 F-FDG-PET and 11 C-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. Show more
Keywords: Alzheimer’s disease, 11C-PiB-PET, conversion prediction, dementia, early diagnosis, 18F-FDG-PET, mild cognitive impairment, prognosis
DOI: 10.3233/JAD-170158
Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 603-614, 2017
Authors: Thordardottir, Steinunn | Ståhlbom, Anne Kinhult | Ferreira, Daniel | Almkvist, Ove | Westman, Eric | Zetterberg, Henrik | Eriksdotter, Maria | Blennow, Kaj | Graff, Caroline
Article Type: Research Article
Abstract: Background: It is currently believed that therapeutic interventions will be most effective when introduced at the preclinical stage of Alzheimer's disease (AD). This underlines the importance of biomarkers to detect AD pathology in vivo before clinical disease onset. Objective: To examine the evolution of cerebrospinal fluid (CSF) biomarker and brain structure changes in the preclinical phase of familial AD. Methods: The study included members from four Swedish families at risk for carrying an APPswe, APParc, PSEN1 H163Y, or PSEN1 I143T mutation. Magnetic resonance imaging (MRI) scans were obtained from 13 mutation carriers (MC) and 20 non-carriers (NC) and analyzed using …vertex-based analyses of cortical thickness and volume. CSF was collected from 10 MC and 12 NC from familial AD families and analyzed for Aβ42 , total tau (T-tau) and phospho-tau (P-tau). Results: The MC had significantly lower levels of CSF Aβ42 and higher levels T-tau and P-tau than the NC. There was a trend for a decrease in Aβ42 15–20 years before expected onset of clinical symptoms, while increasing T-tau and P-tau was not found until close to the expected clinical onset. The MC had decreased volume on MRI in the left precuneus, superior temporal gyrus, and fusiform gyrus. Conclusions: Aberrant biomarker levels in CSF as well as regional brain atrophy are present in preclinical familial AD, several years before the expected onset of clinical symptoms. Show more
Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, genetics, magnetic resonance imaging, natural history studies, preclinical
DOI: 10.3233/JAD-140339
Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1393-1402, 2015