| 1. |
- Abu Hamdeh, Sami, et al.
(author)
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Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury
- 2018
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In: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 28:4, s. 451-462
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Journal article (peer-reviewed)abstract
- Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.
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| 2. |
- Almkvist, Ove, et al.
(author)
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Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease
- 2017
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In: Journal of the International Neuropsychological Society. - : CAMBRIDGE UNIV PRESS. - 1355-6177 .- 1469-7661. ; 23:3, s. 195-203
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Journal article (peer-reviewed)abstract
- 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.
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| 3. |
- Eriksdotter, Maria, et al.
(author)
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Plasma Fatty Acid Profiles in Relation to Cognition and Gender in Alzheimer's Disease Patients During Oral Omega-3 Fatty Acid Supplementation : The OmegAD Study
- 2015
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 48:3, s. 805-812
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Journal article (peer-reviewed)abstract
- BACKGROUND: ω3 fatty acids (ω3 FAs) may slow the rate of decline in cognitive performance in mild forms of cognitive impairment and Alzheimer's disease (AD). However, the relationship between changes of plasma ω3 FA levels and cognitive performance, as well as effects of gender, are poorly known.OBJECTIVE: To study the effect of 6-month administration of DHA-rich ω3 FA supplementation on plasma FA profiles in patients with mild to moderate AD in relation to cognitive performance and gender. This investigation is part of the OmegAD Study.METHODS: 174 AD patients (74 ± 9 years) were randomized to a daily intake of 2.3 g ω3 FA or placebo for 6 months; subsequently all received the ω3 FA preparation for the next 6 months. Baseline as well as changes in plasma levels of the main ω3 FAs in 165 patients, while receiving ω3 FA supplementation for 6 months, were analyzed for association to cognitive performance (assessed by ADAS-cog and MMSE scores) as well as to gender.RESULTS: Preservation of cognitive functioning, assessed by ADAS-cog or its sub-items (but not MMSE) scores, was significantly associated to increasing plasma ω3 FA levels over time. Thus, the higher ω3 FA plasma levels rose, the lower was the rate of cognitive deterioration. This effect was not related to gender; since although females displayed higher ω3 FA plasma levels than did males after 6 months of supplementation, this difference disappeared when adjusted for body weight.CONCLUSIONS: Since our study suggests dose-response relationships between plasma levels of ω3 FA and preservation of cognition, future ω3 FA trials in patients with mild AD should consider exploring graded (and body weight adjusted) doses of ω3 FA.
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| 4. |
- Faxen-Irving, Gerd, et al.
(author)
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Does Fatty Acid Composition in Subcutaneous Adipose Tissue Differ between Patients with Alzheimer's Disease and Cohabiting Proxies?
- 2018
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 61:2, s. 515-519
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Journal article (peer-reviewed)abstract
- Low tissue levels of the major marine ω3 fatty acids (FAs) DHA and EPA are found in Alzheimer's disease (AD). We investigated if healthy proxies to AD patients have higher levels of these ω3 FAs. We observed lower levels of EPA and DHA in subcutaneous adipose tissue biopsies from 64 AD patients compared with 16 cognitively healthy proxies. No significant difference was observed when pairwise comparisons were made between a subset of 16 AD patients and their co-habiting proxies. Larger studies are needed to replicate these findings and to determine if they could depend on FA intake or differences in metabolism.
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| 5. |
- Gunnarsson, Malin Degerman, et al.
(author)
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High tau levels in cerebrospinal fluid predict nursing home placement and rapid progression in Alzheimer's disease
- 2016
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In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 8
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Journal article (peer-reviewed)abstract
- Background: Increased concentrations of cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau, as well as decreased amyloid-beta 42 peptide, are biomarkers of Alzheimer's disease (AD) pathology, but few studies have shown an association with AD progression rate. We hypothesized that high CSF tau, as a marker of ongoing neurodegeneration, would predict a more aggressive course of AD, using time to nursing home placement (NHP) as the main outcome. Methods: Our sample inlcuded 234 patients with mild cognitive impairment (MCI) due to AD (n = 134) or mild to moderate AD (n = 100) who underwent lumbar puncture at a memory clinic and were followed for 2-11 years (median 4.9 years). Results: Individuals with CSF t-tau in the highest quartile (>= 900 ng/L) had a higher ratio of NHP, both in the total cohort and in patients with MCI only (adjusted HR 2.17 [95 % CI 1.24-3.80]; HR 2.37 [95 % CI 1.10-5.09], respectively), than the lowest quartile. The association between high t-tau levels and future steep deterioration was confirmed in analyses with conversion to moderate dementia (HR 1.66; 95 % CI 1.08-2.56), rapid decline in Mini Mental State Examination score (>= 4-point drop/12 months), and dying in severe dementia as outcomes. Conclusions: To our knowledge, this is the first study to show that high CSF t-tau levels predict early NHP and conversion to moderate dementia in an AD cohort. Selecting patients with high CSF t-tau, indicating more aggressive neurodegeneration and steeper decline, for AD immunotherapy trials might increase the possibility of showing contrast between active treatment and placebo.
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| 6. |
- Jernerén, Fredrik, et al.
(author)
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Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer's Disease : The OmegAD Study
- 2019
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 69:1, s. 189-197
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Journal article (peer-reviewed)abstract
- Background: Trials of supplementation with omega-3 fatty acids (omega 3-FAs) in patients with mild cognitive impairment or Alzheimer's disease (AD) have produced inconsistent effects on cognitive decline. There is evidence of an interaction between B vitamin status and omega 3-FAs in relation to brain atrophy and cognitive decline.Objective: We investigated whether baseline levels of plasma total homocysteine (tHcy), a marker of B vitamin status, modify the effects of omega 3-FAs supplementation on cognitive performance in moderate AD.Methods: This post hoc analysis of the OmegAD trial included 171 community-based patients with AD (MMSE >= 15): 88 patients received daily doses of 1.7 g docosahexaenoic acid and 0.6 g eicosapentaenoic acid for 6 months. Treatment outcome on cognition was analyzed according to baseline levels of tHcy using a general linear model and ANCOVA.Results: We found significant interactions between omega 3-FA supplementation and tHcy on cognition and clinical stage assessed by MMSE (p = 0.040), global CDR (p = 0.059), and CDRsob (p = 0.023), but not on ADAS-cog (p = 0.649). In patients with tHcy levels <11.7 mu mol/L, omega 3-FA supplementation improved cognitive performance as measured by MMSE (+7.1%, 95% CI: 0.59 to 13.7%, p = 0.033) and clinical status as measured by CDRsob (-22.3%, 95% CI: -5.8 to -38.7%, p = 0.009) compared with placebo.Conclusion: The effect of omega 3-FA supplementation on MMSE and CDR appears to be influenced by baseline tHcy, suggesting that adequate B vitamin status is required to obtain beneficial effects of omega 3-FA on cognition.
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| 7. |
- Karimi, Mohsen, et al.
(author)
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DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes : the OmegAD study
- 2017
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In: American Journal of Clinical Nutrition. - : HighWire Press. - 0002-9165 .- 1938-3207. ; 106:4, s. 1157-1165
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Journal article (peer-reviewed)abstract
- Background: Dietary fish oils, rich in long-chain n-3 (ω-3) fatty acids (FAs) [e.g., docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3)], modulate inflammatory reactions through various mechanisms, including gene expression, which is measured as messenger RNA concentration. However, the effects of long-term treatment of humans with DHA and EPA on various epigenetic factors-such as DNA methylation, which controls messenger RNA generation-are poorly described.Objective: We wanted to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global DNA methylation of peripheral blood leukocytes (PBLs) and the relation to plasma EPA and DHA concentrations in Alzheimer disease (AD) patients.Design: In the present study, DNA methylation in four 5'-cytosine-phosphate-guanine-3' (CpG) sites of long interspersed nuclear element-1 repetitive sequences was assessed in a group of 63 patients (30 given the n-3 FA preparation and 33 given placebo) as an estimation of the global DNA methylation in blood cells. Patients originated from the randomized, double-blind, placebo-controlled OmegAD study, in which 174 AD patients received either 1.7 g DHA and 0.6 g EPA (the n-3 FA group) or placebo daily for 6 mo.Results: At 6 mo, the n-3 FA group displayed marked increases in DHA and EPA plasma concentrations (2.6- and 3.5-fold), as well as decreased methylation in 2 out of 4 CpG sites (P < 0.05 for all), respectively. This hypomethylation in CpG2 and CpG4 sites showed a reverse correlation to changes in plasma EPA concentration (r = -0.25, P = 0.045; and r = -0.26, P = 0.041, respectively), but not to changes in plasma DHA concentration, and were not related to apolipoprotein E-4 allele frequency.Conclusion: Supplementation with n-3 FA for 6 mo was associated with global DNA hypomethylation in PBLs. Our data may be of importance in measuring various effects of marine oils, including gene expression, in patients with AD and in other patients taking n-3 FA supplements. This trial was registered at clinicaltrials.gov as NCT00211159.
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| 8. |
- Logovinsky, Veronika, et al.
(author)
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Safety and tolerability of BAN2401 - a clinical study in Alzheimer's disease with a protofibril selective A beta antibody
- 2016
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In: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 8
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Journal article (peer-reviewed)abstract
- Background: Several monoclonal antibodies for the treatment of Alzheimer's disease (AD) have been in development over the last decade. BAN2401 is a monoclonal antibody that selectively binds soluble amyloid beta (A beta) protofibrils.Methods: Here we describe the first clinical study with BAN2401. Safety and tolerability were investigated in mild to moderate AD. A study design was used with staggered parallel single and multiple ascending doses, from 0.1 mg/kg as a single dose to 10 mg/kg biweekly for four months. The presence of amyloid related imaging abnormalities (ARIA, E for edema, H for hemorrhage) was assessed with magnetic resonance imaging (MRI). Cerebrospinal fluid (CSF) and plasma samples were analyzed to investigate pharmacokinetics (PK) and effects on biomarkers.Results: The incidence of ARIA-E/H on MRI was comparable to that of placebo. BAN2401 exposure was approximately dose proportional, with a serum terminal elimination half-life of similar to 7 days. Only a slight increase of plasma A beta((1-40)) was observed but there were no measurable effects of BAN2401 on CSF biomarkers. On the basis of these findings Phase 2b efficacy study has been initiated in early AD.Conclusions: BAN2401 was well-tolerated across all doses. The PK profile has guided us for selecting dose and dose regimens in the ongoing phase 2b study. There was no clear guidance for an effective dose based on biomarkers.
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| 9. |
- Matsunaga, Shinji, et al.
(author)
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Lithium as a Treatment for Alzheimer's Disease : A Systematic Review and Meta-Analysis
- 2015
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 48:2, s. 403-410
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Research review (peer-reviewed)abstract
- Background: This is the first meta-analysis of randomized placebo-controlled trials testing lithium as a treatment for patients with Alzheimer's disease (AD) and individuals with mild cognitive impairment (MCI). Methods: The primary outcome measure was efficacy on cognitive performance as measured through the Alzheimer's Disease Assessment Scale cognitive subscale or the Mini-Mental State Examination. Other outcome measures were drug discontinuation rate, individual side effects, and biological markers (phosphorylated tau 181, total tau, and amyloid-beta(42)) in cerebrospinal fluid (CSF). Results: Three clinical trials including 232 participants that met the study's inclusion criteria were identified. Lithium significantly decreased cognitive decline as compared to placebo (standardized mean difference = -0.41, 95% confidence interval = -0.81 to -0.02, p = 0.04, I-2 = 47%, 3 studies, n = 199). There were no significant differences in the rate of attrition, discontinuation due to all causes or adverse events, or CSF biomarkers between treatment groups. Conclusions: The results indicate that lithium treatment may have beneficial effects on cognitive performance in subjects with MCI and AD dementia.
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| 10. |
- Segernäs Kvitting, Anna, 1977-
(author)
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Dementia diagnostics in primary care : with a focus on cognitive testing
- 2019
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Doctoral thesis (other academic/artistic)abstract
- BackgroundAge is the greatest risk factor for developing dementia and the total number of people aged 60 years and above is expected to more than double globally from 2013 to 2050 (1). Primary health care (PHC) is important for basic diagnostic evaluations. Objective test measurements have been shown to be more reliable than a patient's subjective memory complaints in dementia assessments (2). However, several studies indicate the low use of objective cognitive screening tools in dementia diagnostics in PHC (3). Some general practitioners (GPs) do not perceive today’s cognitive instruments as helpful in the diagnostic process and administration problems have been reported in PHC (4, 5).The overall aim of this thesis was to investigate the accuracy of several cognitive tests used in dementia assessments in PHC, especially among older patients: A Quick Test of Cognitive Speed (AQT), Cognistat and Cognitive Assessment Battery (CAB). The normative values of the Mini Mental Status Examination (MMSE) in the oldest old was also studied.MethodsThe studies included in this thesis are from two different study populations.Studies I, II and IV. Patients with and without cognitive symptoms were recruited from four primary health care centres in Sweden between 2007 and 2009.Study III. The Elderly in Linköping Screening Assessment (ELSA 85) cohort-population examined people born in 1922 in the municipality of Linköping, Sweden.ResultsStudy I. Results showed that AQT is a usable test for dementia diagnosis in PHC. Sensitivity for AQT is superior to the Clock Drawing Test (CDT), equivalent to MMSE and the combination MMSE and CDT. The AUC for AQT was 0.773, valued good enough.Study II. Overall, the results for Cognistat in this study are superior to MMSE and CDT, also in combination. Cognistat is promising for improved dementia diagnosis in PHC with a quick and easily administered multi-domain test for dementia assessments.Study III. This study presents valuable information about normative MMSE data for the oldest patients. Results, suggest using the 25th percentile in MMSE of 25 to 26 points, and indicate that MMSE 26 is as a reasonable cut-off for cognitive decline and further medical evaluation in older persons aged from 85 to 93 years.Study IV. In summary, the additive value of the CAB test in dementia investigations in PHC is not obvious. In addition to questionable accuracy, the test is quite time consuming and normative values are scarce. By introducing the numerical sum (CABsum) the accuracy was increased.ConclusionIn conclusion, objective cognitive tests are an important part of dementia diagnosis in PHC and there is a need for improved instruments and norm-values. From our results, several cognitive quick tests are usable in PHC - MMSE, AQT and Cognistat - but they have some disadvantages. MMSE 26 is a reasonable cut-off for cognitive decline in the oldest patients 85 to 93 years from a well-educated population with quite good socioeconomic. There is a great interest in finding short and better multi-domain instruments but the additive value of CAB in dementia investigations in PHC is questionable.
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