| 1. |
- Barrantes, Alejandro, et al.
(author)
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Alzheimer’s Disease Amyloid Peptides Interact with DNA, As Proved by Surface Plasmon Resonance
- 2012
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In: Current Alzheimer Research. - : Bentham eBooks. - 1567-2050 .- 1875-5828. ; 9:8, s. 924-934
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Journal article (peer-reviewed)abstract
- According to the amyloid hypothesis, abnormal processing of the β-amyloid precursor protein in Alzheimer's disease patients increases the production of β-amyloid toxic peptides, which, after forming highly aggregated fibrillar structures, lead to extracellular plaques formation, neuronal loss and dementia. However, a great deal of evidence has point to intracellular small oligomers of amyloid peptides, probably transient intermediates in the process of fibrillar structures formation, as the most toxic species. In order to study the amyloid-DNA interaction, we have selected here three different forms of the amyloid peptide: Aβ1-40, Aβ25-35 and a scrambled form of Aβ25-35. Surface Plasmon Resonance was used together with UV-visible spectroscopy, Electrophoresis and Electronic Microscopy to carry out this study. Our results prove that, similarly to the full length Aβ1-42, all conformations of toxic amyloid peptides, Aβ1-40 and Aβ25-35, may bind DNA. In contrast, the scrambled form of Aβ25-35, a non-aggregating and nontoxic form of this peptide, could not bind DNA. We conclude that although the amyloid-DNA interaction is closely related to the amyloid aggregation proneness, this cannot be the only factor which determines the interaction, since small oligomers of amyloid peptides may also bind DNA if their predominant negatively charged amino acid residues are previously neutralized.
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| 2. |
- Chakrabarti, Sankha Shubhra, et al.
(author)
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Ceramide and Sphingosine-1-Phosphate in Cell Death Pathways: Relevance to the Pathogenesis of Alzheimers Disease
- 2016
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In: Current Alzheimer Research. - : BENTHAM SCIENCE PUBL LTD. - 1567-2050 .- 1875-5828. ; 13:11, s. 1232-1248
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Research review (peer-reviewed)abstract
- The metabolic turnover of sphingolipids produces several signaling molecules that profoundly affect the proliferation, differentiation and death of cells. In particular, an enormous body of information is available that defines the varied role of ceramide and sphingosine-1-phosphate in cell death and survival. This review specifically examines the role of ceramide and sphingosine-1-phosphate in triggering neuronal death in Alzheimers disease by analyzing the data from post-mortem studies and experimental research. There is compelling evidence that ceramide plays a key role in the neurodegeneration and amyloidogenesis occurring in the brain in Alzheimers disease. Further, it appears that ceramide and amyloid beta protein orchestrate an attack on mitochondria to set in the pathways of cell death. However, the complexity of metabolic and signaling pathways of sphingolipid derivatives precludes an immediate identification of effective drug targets for the therapy of Alzheimers disease.
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| 3. |
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| 4. |
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| 5. |
- Forsberg, A, et al.
(author)
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High PIB Retention in Alzheimer's Disease is an Early Event with Complex Relationship with CSF Biomarkers and Functional Parameters
- 2010
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In: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 7:1, s. 56-66
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Journal article (peer-reviewed)abstract
- Background:New in vivo amyloid PET imaging tracers, such as 11C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimers disease (AD). In this study we investigated how 11C-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 11C-PIB, 18F-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-ß (Aβ1-42), 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 11C-PIB retention, levels of CSF biomarkers (especially Aß1-42), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between 11C-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 11C-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. 11C-PIB PET and CSF Aß1-42 allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.
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| 6. |
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| 7. |
- Hall, Anette, et al.
(author)
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Predicting Progression from Cognitive Impairment to Alzheimer's Disease with the Disease State Index
- 2015
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In: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1875-5828 .- 1567-2050. ; 12:1, s. 69-79
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Journal article (peer-reviewed)abstract
- We evaluated the performance of the Disease State Index (DSI) method when predicting progression to Alzheimer's disease (AD) in patients with subjective cognitive impairment (SCI), amnestic or non-amnestic mild cognitive impairment (aMCI, naMCI). The DSI model measures patients' similarity to diagnosed cases based on available data, such as cognitive tests, the APOE genotype, CSF biomarkers and MRI. We applied the DSI model to data from the DE-SCRIPA cohort, where non-demented patients (N=775) with different subtypes of cognitive impairment were followed for 1 to 5 years. Classification accuracies for the subgroups were calculated with the DSI using leave-one-out cross-validation. The DSI's classification accuracy in predicting progression to AD was 0.75 (AUC=0.83) in the total population, 0.70 (AUC=0.77) for aMCI and 0.71 (AUC=0.76) for naMCI. For a subset of approximately half of the patients with high or low DSI values, accuracy reached 0.86 (all), 0.78 (aMCI), and 0.85 (naMCI). For patients with MRI or CSF biomarker data available, they were 0.78 (all), 0.76 (aMCI) and 0.76 (naMCI), while for clear cases the accuracies rose to 0.90 (all), 0.83 (aMCI) and 0.91 (naMCI). The results show that the DSI model can distinguish between clear and ambiguous cases, assess the severity of the disease and also provide information on the effectiveness of different biomarkers. While a specific test or biomarker may confound analysis for an individual patient, combining several different types of tests and biomarkers could be able to reveal the trajectory of the disease and improve the prediction of AD progression.
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| 8. |
- Herrmann, Francois R., et al.
(author)
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Determinants of Cognitive Trajectories in Normal Aging : A Longitudinal PET-MRI Study in a Community-based Cohort
- 2021
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In: Current Alzheimer Research. - : Bentham Science Publishers. - 1567-2050 .- 1875-5828. ; 18:6, s. 482-491
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Journal article (peer-reviewed)abstract
- Background: The determinants of the progressive decrement of cognition in normal aging are still a matter of debate. Alzheimer disease (AD)-signature markers and vascular lesions, but also psychological variables such as personality factors, are thought to have an impact on the longitudinal trajectories of neuropsychological performances in healthy elderly individuals.Objective: The current research aimed to identify the main determinants associated with cognitive trajectories in normal aging.Methods: We performed a 4.5-year longitudinal study in 90 older community-dwellers coupling two neuropsychological assessments, medial temporal atrophy (MTA), number of cerebral microbleeds (CMB), and white matter hyperintensities (WMH) at inclusion, visual rating of amyloid and FDG PET at follow-up, and APOE genotyping. Personality factors were assessed at baseline using the NEO-PIR. Univariate and backward stepwise regression models were built to explore the association between the continuous cognitive score (CCS) and both imaging and personality variables.Results: The number of strictly lobar CMB at baseline (4 or more) was related to a significant increase in the risk of cognitive decrement. In multivariable models, amyloid positivity was associated with a 1.73 unit decrease of the CCS at follow-up. MTA, WMH and abnormal FDG PET were not related to the cognitive outcome. Among personality factors, only higher agreeableness was related to better preservation of neuropsychological performances.Conclusion: CMB and amyloid positivity are the only imaging determinants of cognitive trajectories in this highly selected series of healthy controls. Among personality factors, higher agreeableness confers a modest but significant protection against the decline of cognitive performances.
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| 9. |
- Jaremo, Petter, et al.
(author)
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Alzheimers Disease: Erythrocyte 2,3-diphosphoglycerate Content and Circulating Erythropoietin
- 2019
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In: Current Alzheimer Research. - : BENTHAM SCIENCE PUBL LTD. - 1567-2050 .- 1875-5828. ; 16:9, s. 834-835
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Journal article (peer-reviewed)abstract
- Background: Alzheimers Disease (AD) features the accumulation of beta-amyloid in erythrocytes. The subsequent red cell damage may well affect their oxygen-carrying capabilities. 2,3-diphosphoglycerate (2,3-DPG) binds to the hemoglobin thereby promoting oxygen release. It is theorized that 2,3-DPG is reduced in AD and that the resulting hypoxia triggers erythropoietin (EPO) release. Methods amp; Objective: To explore this theory, we analyzed red cell 2,3-DPG content and EPO in AD, mild cognitive impairment, and the control group, subjective cognitive impairment. Results: We studied (i) 2,3-DPG in red cells, and (ii) circulating EPO in AD, and both markers were unaffected by dementia. Disturbances of these oxygen-regulatory pathways do not appear to participate in brain hypoxia in AD.
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| 10. |
- Jaremo, Petter, et al.
(author)
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Erythrocyte Amyloid Beta Peptide Isoform Distributions in Alzheimer and Mild Cognitive Impairment
- 2019
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In: Current Alzheimer Research. - : BENTHAM SCIENCE PUBL LTD. - 1567-2050 .- 1875-5828. ; 16:11, s. 1050-1054
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Journal article (peer-reviewed)abstract
- Introduction: We recently showed that Amyloid Beta (A beta)(40) accumulates in erythrocytes and possibly causes cell damage as evidenced by an increased number of assumed injured low-density (kg/L) erythrocytes. Furthermore, we have suggested a separation technique to isolate and concentrate such damaged red blood cells for subsequent analysis. Objectives: We isolated high- and low-density erythrocytes and investigated the accumulation patterns of the A beta peptides (A beta(40), A beta(42), and A beta(43) ) in Alzheimer (AD), mild cognitive impairment (MCI), and Subjective Cognitive Impairment (SCI). Methods: Whole blood was fractionated through a density gradient, resulting in two concentrated high-and presumed injured low-density erythrocyte fractions. After cell lysis, intracellular A beta(40) , A beta 4(2), and A beta (43) were quantified by ELISA. Results: In both high- and low-density erythrocytes, A beta(40) displayed the lowest concentration in MCI, while it was equal and higher in AD and SCI. A beta(40) was detected at a 10-fold higher level than A beta(42), and in injured low-density erythrocytes, the lowest quantity of A beta(42) was found in AD and MCI. A beta(40) exhibited a 100-fold greater amount than A beta(43). and lighter erythrocytes of MCI subjects displayed less intracellular A beta(43) than SCI. Conclusion: Red blood cell accumulation patterns of A beta(40), A beta(42), and A beta(43) differ significantly between AD, MCI, and SCI. The data must be verified through larger clinical trials. It is, however, tenable that AP peptide distributions in erythrocyte subpopulations have the potential to be used for diagnostic purposes.
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| 11. |
- Klein-Koerkamp, Yanica, et al.
(author)
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Amygdalar atrophy in early Alzheimer's disease
- 2014
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In: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 11:3, s. 239-252
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Journal article (peer-reviewed)abstract
- Current research suggests that amygdalar volumes in patients with Alzheimer's disease (AD) may be a relevant measure for its early diagnosis. However, findings are still inconclusive and controversial, partly because studies did not focus on the earliest stage of the disease. In this study, we measured amygdalar atrophy in 48 AD patients and 82 healthy controls (HC) by using a multi-atlas procedure, MAPER. Both hippocampal and amygdalar volumes, normalized by intracranial volume, were significantly reduced in AD compared with HC. The volume loss in the two structures was of similar magnitude (~24%). Amygdalar volume loss in AD predicted memory impairment after we controlled for age, gender, education, and, more important, hippocampal volume, indicating that memory decline correlates with amygdalar atrophy over and above hippocampal atrophy. Amygdalar volume may thus be as useful as hippocampal volume for the diagnosis of early AD. In addition, it could be an independent marker of cognitive decline. The role of the amygdala in AD should be reconsidered to guide further research and clinical practice. © 2014 Bentham Science Publishers.
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| 12. |
- Kullenberg, Helena, et al.
(author)
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Associations between the use of metformin and behavioral and psychological symptoms in patients with Alzheimer's disease, and type 2 diabetes mellitus : A register-based study
- 2023
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In: Current Alzheimer Research. - 1567-2050 .- 1875-5828. ; 20:2, s. 109-119
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Journal article (peer-reviewed)abstract
- BACKGROUND: Metformin, the first-line anti-diabetic drug treatment in patients with type 2 diabetes mellitus (T2DM), is suggested to be anti-inflammatory, antioxidative, and improve cognitive function, making it a promising contribution to treating Alzheimer´s disease (AD). However, the effect of metformin on behavioral and psychological symptoms of dementia (BPSD) in patients with AD has not been explored.OBJECTIVE: To investigate the associations between metformin and BPSD in patients with AD and T2DM and explore possible interaction with other antidiabetic drugs.METHODS: This cross-sectional study was based on data from the Swedish BPSD register. A total of 3745 patients with AD and antidiabetic drug treatment were included. Associations and interactions between antidiabetic drugs and BPSD were investigated by binary logistic regression.RESULTS: The use of metformin was associated with lower odds for symptoms of depression (OR 0.77, CI (95%) 0.61-0.96, p = 0.022) and anxiety (OR 0.74, CI (95%) 0.58-0.94, p = 0.015) after adjustment for age, gender, specific diagnosis, and drugs. We could not demonstrate this association with another antidiabetic drug. Interaction effects were limited to an increasing association in eating and appetite disorders using metformin and other antidiabetic drugs (i.e., drugs other than insulin, sulfonylurea, or dipeptidyl peptidase-4 inhibitors).CONCLUSION: The result of this study suggests that metformin could be beneficial for patients diagnosed with AD, other than for blood glucose control. Although, more knowledge is needed before assigning metformin a role in treating BPSD.
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| 13. |
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| 14. |
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| 15. |
- Ma, Fei, et al.
(author)
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Effects of Folic Acid and Vitamin B-12, Alone and in Combination on Cognitive Function and Inflammatory Factors in the Elderly with Mild Cognitive Impairment : A Single-blind Experimental Design
- 2019
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In: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 16:7, s. 622-632
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Journal article (peer-reviewed)abstract
- Background: Folate and vitamin B-12 are well-known as essential nutrients that play key roles in the normal functions of the brain. Inflammatory processes play at least some role in the pathology of AD. Effective nutritional intervention approaches for improving cognitive deficits that reduce the peripheral inflammatory cytokine levels have garnered special attention. Objective: The present study aimed to determine whether supplementation with folic acid and vitamin B-12, alone and in combination improves cognitive performance via reducing levels of peripheral inflammatory cytokines. Methods: 240 participants with MCI were randomly assigned in equal proportion to four treatment groups: folic acid alone, vitamin B-12 alone, folic acid plus vitamin B-12 or control without treatment daily for 6 months. Cognition was measured with WAIS-RC. The levels of inflammatory cytolcines were measured using ELISA. Changes in cognitive function or blood biomarkers were analyzed by repeated-measure analysis of variance or mixed-effects models. This trial has been registered with trial number ChiCTR-ROC-16008305. Results: Compared with control group, the folic acid plus vitamin B-12 group had significantly greater improvements in serum folate, homocysteine, vitamin B(1)(2 )and IL-6, TNF-alpha, MCP-1. The folic acid plus vitamin B-12 supplementation significantly changed the Full Scale IQ (effect size d = 0.169; P = 0.024), verbal IQ (effect size d= 0.146; P= 0.033). Information (d= 0.172; P= 0.019) and Digit Span (d= 0.187; P = 0.009) scores. Post hoc Turkey tests found that folic acid and vitamin B-12 supplementation was significantly more effective than folic acid alone for all endpoints. Conclusions: The combination of oral folic acid plus vitamin B-12 in MCI elderly for six months can significantly improve cognitive performance and reduce the levels of inflammatory cytokines in human peripheral blood. The combination of folic acid and vitamin B-12 was significantly superior to either folic acid or vitamin B-12 alone.
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| 16. |
- McFall, GP, et al.
(author)
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Nuances in Alzheimer's Genetic Risk Reveal Differential Predictions of Non-demented Memory Aging Trajectories: Selective Patterns by APOE Genotype and Sex
- 2019
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In: Current Alzheimer research. - : Bentham Science Publishers Ltd.. - 1875-5828 .- 1567-2050. ; 16:4, s. 302-315
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Journal article (peer-reviewed)abstract
- Apolipoprotein E (APOE) is a prominent genetic risk factor for Alzheimer’s disease (AD) and a frequent target for associations with non-demented and cognitively impaired aging. APOE offers a unique opportunity to evaluate two dichotomous comparisons and selected gradations of APOE risk. Some evidence suggests that APOE effects may differ by sex and emerge especially in interaction with other AD-related biomarkers (e.g., vascular health).Methods:Longitudinal trajectories of non-demented adults (n = 632, 67% female, Mage = 68.9) populated a 40-year band of aging. Focusing on memory performance and individualized memory trajectories, a sequence of latent growth models was tested for predictions of (moderation between) APOE and pulse pressure (PP) as stratified by sex. The analyses (1) established robust benchmark PP effects on memory trajectories, (2) compared predictions of alternative dichotomous groupings (ε4- vs ε4+, ε2- vs ε2+), and (3) examined precision-based predictions by disaggregated APOE genotypes.Results:Healthier (lower) PP was associated with better memory performance and less decline. Therefore, all subsequent analyses were conducted in the interactive context of PP effects and sex stratification. The ε4-based dichotomization produced no differential genetic predictions. The ε2-based analyses showed sex differences, including selective protection for ε2-positive females. Exploratory follow-up disaggregated APOE genotype analyses suggested selective ε2 protection effects for both homozygotic and heterozygotic females.Conclusion:Precision analyses of AD genetic risk will advance the understanding of underlying mechanisms and improve personalized implementation of interventions.
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| 17. |
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| 18. |
- Musaeus, Christian S., et al.
(author)
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Pharmacological Medical Treatment of Epilepsy in Patients with Dementia : A Systematic Review
- 2021
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In: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 18:9, s. 689-694
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Research review (peer-reviewed)abstract
- Background: Patients with dementia have an increased risk of developing epilepsy, es-pecially in patients with vascular dementia and Alzheimer’s disease. In selecting the optimal an-ti-epileptic drug (AED), the possible side effects such as drowsiness and worsening of cognitive function should be taken into consideration, together with co-morbidities and type of epilepsy. Objective: The current systematic review investigates the efficacy, tolerability, and changes in cognitive function after administration of AED in patients with dementia and epilepsy. Methods: We searched six databases, including MEDLINE and CENTRAL, checked reference lists, contacted experts, and searched Google Scholar to identify studies reporting randomized trials. Studies identified were independently screened, data extracted, and quality appraised by two researchers. A narrative synthesis was used to report findings. Results: We included one study with 95 patients with Alzheimer’s disease randomized to either lev-etiracetam, lamotrigine, or phenobarbital. No significant differences were found for efficacy, but patients receiving levetiracetam showed an improvement in mini-mental state examination scores and had fewer adverse events. Conclusion: High-quality evidence in the form of randomized controlled trials to guide clinicians in choosing an AED in patients with dementia and concomitant epilepsy remains scarce. However, levetiracetam has previously been shown to possibly improve cognition in patients with both mild cognitive impairment and Alzheimer’s disease, is better tolerated in the elderly population, and has no clinically relevant interaction with either cholinesterase inhibitors or NMDA receptor antagon-ists. Registration No: The protocol was registered in the PROSPERO database (ID: CRD42020176252).
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| 19. |
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| 20. |
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| 21. |
- Rizzuto, Debora, et al.
(author)
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Dementia after age 75 : survival in different severity stages and years of life lost
- 2012
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In: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 9:7, s. 795-800
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Journal article (peer-reviewed)abstract
- Dementia is a known predictor of mortality, but little is known about disease duration. We therefore aimed to investigate the impact of dementia on survival by estimating years lived with the disease, in total and in different severity stages, and by comparing dementia to other major chronic disorders such as cancer and cardiovascular disease (CVD). During a 7.4-year follow-up of the Kungsholmen project, 371 incident dementia cases of the 1,307 dementia-free persons, aged 75+ at baseline, were clinically diagnosed (DSM-III-R criteria). Diagnoses of cancer and CVD were obtained from the national Stockholm Inpatient Registry System, active since 1969. Disease duration, hazard ratio (HR), and potential years of life lost (PYLL) were derived from Kaplan-Meier survival estimation, the Cox model, and standard life-table analysis, respectively. Dementia was a significant predictor of mortality (HR=1.7; 95% CI: 1.47-1.92) after adjustment for several covariates including comorbidity, accounting for 16% of all deaths. The mean (�SD) survival time after dementia diagnosis was 4.1 (�2.6) years, and more than 2 years were spent in moderate (14-month) and severe (12-month) stages. Women with dementia lived longer than men, as they survived longer in the severe stage (2.1 vs. 0.5 years among 75-84-year-old women compared to coetaneous men). The PYLL were 3.4 for dementia, 3.6 for CVD, and 4.4 for cancer. We found a similar impact of dementia and CVD on survival, but following diagnosis, persons with dementia, and especially women, spent half of their remaining lives in the severe disabling stages of the disease.
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| 22. |
- Rolstad, Sindre, 1976, et al.
(author)
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All cognitive systems but speed and visuospatial functions reduce the effect of CSF pathology on other systems.
- 2012
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In: Current Alzheimer research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 9:9, s. 1043-1049
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Journal article (peer-reviewed)abstract
- The concept of reserve can be conceived as differences in the ability to compensate for pathology by recruiting additional or alternative networks. The purpose of this study was to examine whether certain cognitive systems may compensate for the effect of CSF amyloid beta 42 (Aβ42) and total tau (T-tau) on other cognitive systems. Five hundred and nine participants underwent neuropsychological examination and lumbar puncture. Multiple regression was performed with interaction terms to test whether a cognitive system reduced the impact of CSF pathology on other systems. All cognitive systems except speed and visuospatial functions were associated with reduced effects of T-tau and Aβ42 on semantic memory, working memory and visuospatial abilities. The burden of Aβ42 was reduced more often than that of T-tau. Our results suggest that most cognitive systems may be beneficial to maintenance of cognitive performance despite CSF burden. The results support the notion of cognitive reserve.
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| 23. |
- Rusanen, Minna, et al.
(author)
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Chronic Obstructive Pulmonary Disease and Asthma and the Risk of Mild Cognitive Impairment and Dementia : A Population Based CAIDE Study
- 2013
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In: CURRENT ALZHEIMER RESEARCH. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 10:5, s. 549-555
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Journal article (peer-reviewed)abstract
- Background: Previous research indicates that persons with chronic obstructive pulmonary disease (COPD) and asthma may have more cognitive impairment compared to persons without these diseases. However, there are no previous studies regarding long-term effects of these diseases on the risk of clinically diagnosed mild cognitive impairment (MCI) and dementia. We examined the association between midlife and late-life self-reported COPD and asthma and the lifelong risk of cognitive impairment (MCI/dementia) in a population-based study with a follow-up of over 25 years. Methods: Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study includes 2000 participants who were randomly selected from four separate, population-based samples originally studied in midlife (1972, 1977, 1982 or 1988). Re-examinations were carried out in 1998 and 2005-8 (N=1511, 75.6 %) during which 172 persons were diagnosed with MCI and 117 with dementia. Results: Midlife COPD (HR 1.85, 95% CI 1.05 - 3.28), asthma (HR 1.88, 95% CI 0.77 - 4.63) and both pulmonary diseases combined (HR 1.94, 95% CI 1.16 - 3.27) increased the later risk of cognitive impairment even after full adjustments. However, pulmonary diseases diagnosed later in life seemed to be inversely related to cognitive impairment (fully adjusted model for both pulmonary diseases combined HR 0.42, 95% CI 0.19 - 0.93). Conclusions: In this population-based study, with more than 25 years of follow-up, midlife COPD and asthma were associated with an almost two-fold risk of MCI and dementia later in life. Pulmonary diseases diagnosed later in life seemed to have an inverse relationship with cognitive impairment probably reflecting survival bias.
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| 24. |
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| 25. |
- Sköldunger, Anders, et al.
(author)
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Mortality and treatment costs have a great impact on the cost-effectiveness of disease modifying drugs in Alzheimer's disease - a simulation study
- 2013
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In: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 10:2, s. 207-216
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Journal article (peer-reviewed)abstract
- Background: The societal costs of Alzheimer's Disease (AD) are enormous and pose a great challenge for the health and social care in any society. It is of vital importance to develop and identify cost effective treatment. The aim of the study was to present a hypothetical economic model of Disease Modifying Treatment (DMT) in AD. Methods: A 20 year Markov cohort model of DMT was constructed, based on Swedish care conditions. States and progression were defined according to the Mini Mental State Examination (MMSE). Epidemiological studies of incidence of dementia, prevalence and costs of Mild Cognitive Impairment (MCI) and AD as well as conversion studies of MCI and demographic statistics were used as inputs in the model. Results: Total costs were 113,797 million SEK for patients treated with DMT vs 88,562 million SEK for untreated patients. The corresponding gained QALYs were 529,945 and 450,307 respectively, giving an incremental cost effectiveness ratio of 293,002 SEK/QALY in the base option. Survival in the model was 8.72 years with DMT and 7.77 years for untreated. With an assumed Willingness to pay (WTP) of 600,000 SEK (about 86,200 US$ and 62,000 €) per gained QALY, the model indicated cost effectiveness with DMT. The sensitivity analysis implied no cost savings with DMT, but most options indicated cost effectiveness vs. the chosen WTP. Conclusion: The main reasons for the higher costs with DMT were the costs of DMT itself and the prolonged survival with DMT. Even if costs increase with DMT, the model indicates cost effectiveness.
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| 26. |
- Solomon, Alina, et al.
(author)
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Practical Lessons from Amyloid Immunotherapy Trials in Alzheimer Disease
- 2012
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In: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 9:10, s. 1126-1134
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Journal article (peer-reviewed)abstract
- Objectives: Amyloid immunotherapy trials are central in Alzheimer disease (AD) drug development, with the potential to influence all future disease-modifying randomized controlled trials (RCTs). This study investigates practical experiences of staff and participants in immunotherapy RCTs. Setting and methods: The Clinical Trial Research Unit of the Memory Clinic at Karolinska University Hospital, Sweden is an experienced centre specialized in Alzheimer RCTs, where four active and passive phase I/II immunotherapy trials are currently ongoing. Meetings were held with staff members, who were asked to describe their experiences and suggest necessary improvements. In addition, a pilot study was conducted to investigate motivations and expectations of participants in immunotherapy RCTs. A questionnaire was sent to 20 patients, and another similar questionnaire to their caregivers. Results: The main issues emphasized by staff members concerned the critical window of opportunity for recruiting RCTs participants, the much higher level of effort required of patients and caregivers in immunotherapy RCTs compared to classical cholinesterase inhibitor RCTs, problematic informed consent procedures, and confidentiality limitations in trials with different sponsors. For patients and caregivers, the main reason for participating in RCTs was the wish to help research and other people, followed by the need for information, continuity of care, safety and support. Compared to patients, caregivers' expectations of trial results were more realistic. Conclusions: More open debates of practical experiences from different trial centres and sponsors are essential for optimizing trial designs and improving conditions for participants.
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| 27. |
- Spulber, Gabriela, et al.
(author)
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Evolution of global and local grey matter atrophy on serial MRI scans during the progression from MCI to AD
- 2012
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In: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 9:4, s. 516-524
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Journal article (peer-reviewed)abstract
- Mild cognitive impairment (MCI) often represents a prodromal form of dementia, conferring a significantly higher risk of converting to probable Alzheimer's disease (AD). The aim of this study is to characterise the differences of grey matter (GM) distribution and dynamics between progressive and stable MCI subjects during a 2 year period preceding the conversion to AD. We included 48 stable MCI and 12 progressive MCI cases based on the availability of 3 serial scans acquired with approximately 1 year scan interval. For the progressive MCI group, the third scan was acquired at the time of the clinical diagnosis of AD, while the first two scans were acquired approximately 2 and 1 years earlier. For the stable MCI group, the three scans were acquired at approximately 1 year intervals during a period free from significant cognitive decline. We used longitudinal voxel-based morphometry (VBM) for mapping the progression of GM loss over time. For the progressive MCI group, the cross-sectional analysis revealed areas of lower GM volumes in the parahippocampal gyrus, precuneus and posterior cingulate 12 months before the AD diagnosis. For the longitudinal VBM analysis the progressive MCI group revealed increased GM loss in cortical regions belonging to the temporal neocortex, parahippocampal cortex, and cingulate gyrus. The frontal lobe, insula and the cerebellum were also affected. This accelerated atrophy may offer new insights into the understanding of neurodegenerative pathology and the clinical relevance of these changes remains to be verified by subsequent studies.
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| 28. |
- Straten, Guido, et al.
(author)
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Influence of Lithium Treatment on GDNF Serum and CSF Concentrations in Patients with Early Alzheimer΄s Disease
- 2011
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In: Current Alzheimer research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 8:8, s. 853-859
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Journal article (peer-reviewed)abstract
- Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer΄s disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebocontrolled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.
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| 29. |
- Subic, Ana, et al.
(author)
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Stroke as a Cause of Death in Death Certificates of Patients with Dementia : A Cohort Study from the Swedish Dementia Registry
- 2018
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In: Current Alzheimer Research. - : Bentham Science Publishers. - 1567-2050 .- 1875-5828. ; 15:14, s. 1322-1330
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Patients with dementia may be at a higher risk for death from stroke. We aimed to describe characteristics of dementia patients that died from ischemic stroke (IS) in Sweden.METHODS: A retrospective longitudinal analysis of prospectively collected data of patients registered into the Swedish Dementia Registry was conducted. Data on causes of death, drugs and comorbidities were acquired from the Swedish nationwide health registers. Deaths were attributed to stroke if the death certificate contained stroke as a cause of death and the patient had a stroke registered in Riksstroke, the Swedish Stroke Register, in the year preceding death. Demographic data at the time of dementia diagnosis was compared between patients dying from IS and registered in Riksstroke, patients dying from IS without being registered in Riksstroke and those dying from other causes.RESULTS: Out of 49823 patients diagnosed with dementia between 2007 and 2014 in primary care or specialist clinics, 14170 (28.4%) had died by the end of 2014. Of these 1180 (8.3%) had IS in their death certificate, of which 459 (38.9%) had been registered in Riksstroke. In patients who died of IS the most common type of dementia was vascular dementia while those died from other causes were most often diagnosed with Alzheimer's dementia (AD). Patients who died from IS and were registered in Riksstroke had higher MMSE score compared to other groups. Patients who died from IS took more cardiovascular medications. There were no differences in the use of antipsychotics, antidepressants, acetylcholinesterase inhibitors, memantine, anxiolytics, or hypnotics between the groups.CONCLUSIONS: There was a relatively high number of patients who died from IS as shown in their death certificate but had not been registered in Riksstroke in the year before death. This creates concerns on the accuracy of death certificate stroke diagnoses, particularly for deaths taking place outside hospitals.
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| 30. |
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| 31. |
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| 32. |
- Wattmo, Carina, et al.
(author)
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Cerebrospinal Fluid Biomarker Levels as Markers for Nursing Home Placement and Survival Time in Alzheimer's Disease.
- 2021
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In: Current Alzheimer research. - : Bentham Science Publishers Ltd.. - 1875-5828 .- 1567-2050. ; 18:7, s. 573-584
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Journal article (peer-reviewed)abstract
- Cerebrospinal Fluid (CSF) biomarkers are associated with conversion from mild cognitive impairment to Alzheimer's Disease (AD), but their predictive value for later end-points has been less evaluated with inconsistent results.We investigated potential relationships between CSF amyloid-β1-42 (Aβ42), Phosphorylated tau (P-tau), and Total tau (T-tau) with time to Nursing Home Placement (NHP) and life expectancy after diagnosis.This prospective observational study included 129 outpatients clinically diagnosed with mild-to-moderate AD who underwent a lumbar puncture. The CSF biomarkers were analysed with xMAP technology. Dates of institutionalisation and death were recorded.After 20 years of follow-up, 123 patients (95%) were deceased. The participants with abnormal P-tau and T-tau (A+ T+ (N)+) died earlier than those with normal P-tau/abnormal T-tau (A+ T- (N)+) (mean, 80.5 vs. 85.4 years). Linear associations were demonstrated between lower Aβ42 and shorter time to NHP (p = 0.017), and higher P-tau and younger age at death (p = 0.016). No correlations were detected between survival after AD diagnosis and CSF biomarkers. In sexand- age-adjusted Cox regression models, higher P-tau and T-tau were independent predictors of shorter lifespan after diagnosis. In multivariate Cox models, older age and lower baseline cognitive status, but not elevated tau, significantly precipitated both institutionalisation and death.These findings suggest that CSF biomarker levels plateau in the dementia phase of AD, which may limit their possible relationships with clinical end-points, such as NHP and survival time. However, the biomarkers reflect the central pathophysiologies of AD. In particular, pathologic tau is associated with more advanced disease, younger age at onset, and earlier death.
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| 33. |
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| 34. |
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| 35. |
- Bengtsson, Sara, 1978-, et al.
(author)
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Brief but Chronic Increase in Allopregnanolone Cause Accelerated ADPathology Differently in Two Mouse Models
- 2013
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In: Current Alzheimer Research. - : Bentham Science Publishers. - 1567-2050. ; 10:1, s. 38-47
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Journal article (peer-reviewed)abstract
- Abstract: Previously, we have shown that chronic treatment with allopregnanolone (ALLO) for three months impaired learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Aβ in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels. learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Ab in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels.
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| 36. |
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| 37. |
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| 38. |
- Nielsen, Henrietta, et al.
(author)
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Gender-dependent levels of hyaluronic acid in cerebrospinal fluid of patients with neurodegenerative dementia.
- 2012
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In: Current Alzheimer Research. - 1875-5828. ; 9:3, s. 257-266
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Journal article (peer-reviewed)abstract
- Numerous reports over the years have described neuroinflammatory events and vascular changes in neurodegenerative diseases such as Alzheimers disease (AD) and dementia with Lewy bodies (DLB). Interestingly, recent reports from other research areas suggest that the inflammatory and vascular processes are influenced by gender. These findings are intriguing from the perspective that women show a higher incidence of AD and warrant investigations on how gender influences various processes in neurodegenerative dementia. In the current study we measured the cerebrospinal fluid (CSF) and plasma concentrations of hyaluroinic acid (HA), an adhesionmolecule known to regulate both vascular and inflammatory processes, in AD and DLB patients as well as in healthy elders. Our analysis showed that male AD and DLB patients had almost double the amount of HA compared to female patients whereas no gender differences was observed in the controls. Furthermore, we found that CSF levels of HA in foremost female AD patients correlated with various AD related biomarkers. Correlations between HA levels and markers of inflammation and vascular changes were only detected in female AD patients but in both male and female DLB patients. We conclude that HA may be linked to several pathological events present in AD, as reflected in CSF protein concentrations. The HA profile in CSF, but not in plasma, and associations to other markers appear to be genderdependent which should be taken into account in clinical examinations and future biomarker studies.
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| 39. |
- Soukup, Ondrej, et al.
(author)
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A Resurrection of 7-MEOTA: A Comparison with Tacrine
- 2013
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In: Current Alzheimer Research. - 1567-2050. ; 10:8, s. 893-906
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Journal article (peer-reviewed)abstract
- Alzheimer´s disease (AD) is a progressive neurodegenerative dementia which currently represents one of the biggest threats for the human kind. The cure is still unknown and various hypotheses (cholinergic, amyloidal, oxidative, vascular etc.) are investigated in order to understand the pathophysiology of the disease and on this basis find an effective treatment. Tacrine, the first approved drug for the AD disease treatment, has been reported to be a multitargeted drug, however it was withdrawn from the market particularly due to its hepatotoxicity. Its derivative 7-methoxytacrine (7- MEOTA) probably due to the different metabolization does not exert this side effect. The aim of our study was to compare these two cholinesterase inhibitors from various, mainly cholinergic, points of view relevant for a potential AD drug. We found that 7-MEOTA does not fall behind its more well-known parent compound – tacrine. Furthermore, we found, that 7-MEOTA exerts better properties in most of the tests related to a possible AD treatment. Only the pharmacokinetics and a higher acetylcholinesterase and butyrylcholinesterase inhibitory potency would slightly give advantages to tacrine over 7-MEOTA, but concerning its lower toxicity, better antioxidant properties, interaction with muscarinic and nicotinic receptors and “safer” metabolization provide strong evidence for reconsider 7-MEOTA and its derivatives as candidate molecules for the treatment of AD.
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| 40. |
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| 41. |
- Wattmo, Carina, et al.
(author)
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Short-term response to cholinesterase inhibitors in Alzheimer’s disease delays time to nursing home placement
- 2018
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In: Current Alzheimer Research. - : Bentham Science Publishers Ltd.. - 1567-2050. ; 15:10, s. 905-916
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Journal article (peer-reviewed)abstract
- Background: A varying response to cholinesterase inhibitor (ChEI) treatment has been reported among patients with Alzheimer’s disease (AD). Whether the individual-specific response directly affects time to nursing home placement (NHP) was not investigated. Objective: We examined the relationship between the 6-month response to ChEI and institutionalization. Methods: In a prospective, observational, multicenter study, 881 outpatients with a clinical AD diagnosis and a Mini-Mental State Examination score of 10-26 at the start of ChEI therapy (baseline) were included. The participants were evaluated using cognitive, global, and activities of daily living (ADL) scales at baseline and semiannually over 3 years. The date of NHP was recorded. Results: During the study, 213 patients (24%) were admitted to nursing homes. The mean ± standard deviation time from baseline (AD diagnosis) to NHP was 20.8 ± 9.3 months. After 6 months of ChEI treatment, the improved/unchanged individuals had longer time to NHP than those who worsened. The prolonged time to NHP was 3 months for cognitive response (P=0.022), 4 months for global response (P=0.004), 6 months for basic ADL response (P<0.001), and 8 months for response in all three scales (P<0.001). No differences were detected between the improved and unchanged groups in any scales. Conclusion: Patients who exhibit a positive short-term response to ChEI can expect to stay in their own home for 3-8 months longer. These findings underline the importance of a comprehensive clinical examination including various assessment scales to evaluate treatment response and provide a more accurate prognosis.
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