| 171. |
- Håkansson, Krister
(författare)
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O2-07-01: Unmarried Life: Paving the way for dementia?
- 2008
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 4:4, Supplement, s. T146-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Although social networks and activities have recently been suggested to protect against dementia, few long-term follow-up studies exist. The main purpose of our study was to evaluate whether midlife marital status is related to late-life cognitive function. Methods: Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied. After an average follow-up of 21 years, 1449 individuals (73%) aged 65 to 79 years were re-examined in 1998. At re-examination 139 persons were diagnosed with some form of cognitive impairment: 82 of those with mild cognitive impairment (MCI) and 48 with Alzheimer's disease (AD)). The relation between midlife marital status and cognitive impairment was analyzed with adjustments for a number of other midlife factors, including education, BMI, cholesterol, blood pressure, occupation, physical activity, smoking habits and depression. Adjustments were also made for ApoE status, age at follow-up and gender. Results: Persons living with a partner in midlife were significantly less likely to show cognitive impairment compared to all other categories (single, separated or widowed). The highest risk increase was found for those widowed at midlife and still so at the follow-up (N=105). For Alzheimers disease specifically, the risk increase was almost eight-fold for this group compared to those married both at midlife and still so at late-life. Progressive adjustments for possible confounders did not weaken the associations. Conclusions: Living in a partner relation may imply cognitive and social challenges with a protective effect against cognitive impairment. Involvement of other factors is however suggested by the specific risk increase for widowed in relation to singles. Possible selection bias behind the strongly increased cognitive impairment risk for those widowed at midlife, in relation to the married group, seems unlikely. The long-term prospective design should also preclude any reverse causation effects behind the results.
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| 172. |
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| 173. |
- Imahori, Yume, et al.
(författare)
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Association of ischemic heart disease with long-term risk of cognitive decline and dementia : A cohort study
- 2023
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Ingår i: Alzheimer's & Dementia. - 1552-5260 .- 1552-5279. ; 19:12, s. 5541-5549
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The independent and joint effect of ischemic heart disease (IHD) and coexisting atrial fibrillation (AF) and heart failure (HF) on dementia risk is largely unknown.METHODS: This population-based cohort study included 2568 dementia-free participants (age ≥60 years) in SNAC-K, who were regularly examined from 2001–2004 through 2013–2016. Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria. Global cognitive function was assessed using a global cognitive composite z-score derived from five cognitive domains. Data were analyzed using Cox, Fine-Gray, and linear mixed-effects models.RESULTS: Overall, IHD at baseline was associated with multivariable-adjusted hazard ratio (HR) of 1.39 (95% confidence interval = 1.06−1.82) for dementia and multivariable-adjusted β-coefficient of −0.02 (−0.03 to −0.01) for annual changes in global cognitive z-score, independent of AF, HF, and cerebrovascular disease. Coexisting AF or HF did not add further risk to dementia and cognitive decline.DISCUSSION: IHD is independently associated with dementia and cognitive decline in older adults, whereas coexisting AF/HF is not associated with an increased risk.
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| 174. |
- Imahori, Yume, et al.
(författare)
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Association of resting heart rate with cognitive decline and dementia in older adults : A population-based cohort study
- 2022
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:10, s. 1779-1787
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Resting heart rate (RHR) predicts future risk for cardiovascular disease (CVD). However, longitudinal studies investigating the relationship of RHR with cognitive decline are scarce.Methods: This population-based cohort study included 2147 participants (age≥60) in SNAC-K who were free of dementia and regularly followed from 2001–2004 to 2013–2016. RHR was assessed with electrocardiogram. Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders 4th Revision criteria. Global cognitive function was assessed using Mini-Mental State Examination (MMSE). Data were analyzed using Cox and linear mixed-effects models.Results: RHR≥80 (vs. 60–69) bpm was associated with a multi-adjusted hazard ratio of 1.55 (95% confidence interval 1.06−2.27) for dementia. The association remained significant after excluding participants with prevalent and incident CVDs. Similarly, RHR≥80 bpm was associated with a multi-adjusted β-coefficient of –0.13 (–0.21 to –0.04) for MMSE score.Discussion: Higher RHR is associated with increased risk for dementia and faster cognitive decline independent of CVDs in a general population of elderly people.
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| 175. |
- Ingala, Silvia, et al.
(författare)
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Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17:7, s. 1189-1204
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Tidskriftsartikel (refereegranskat)abstract
- We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles.From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R2 =0.98, P<0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages.Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P<0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P<0.001).In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.
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| 176. |
- Insel, P. S., et al.
(författare)
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The transitional association between beta-amyloid pathology and regional brain atrophy
- 2015
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:10, s. 1171-1179
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Alzheimer's disease (AD) is characterized by the accumulation of beta-amyloid (A beta) associated with brain atrophy and cognitive decline. The functional form to model the association between A beta and regional brain atrophy has not been well defined. To determine the relationship between Ab and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) A beta to identify subjects as A beta+ and A beta- with a trilinear spline model of CSF A beta. Methods: One hundred and eighty-three subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSFA beta and up to 4 years of longitudinal magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed using mixed-effects regression. Piecewise-linear splines were used to evaluate the nonlinear nature of the association between CSF A beta and regional atrophy and to identify points of acceleration of atrophy with respect to A beta. Several parameterizations of CSFA beta were compared using likelihood ratio tests and the Akaike information criterion. Periods of acceleration of atrophy in which subjects transition from CSF A beta negativity to CSFA beta positivity were estimated from the spline models and tested for significance. Results: Spline models resulted in better fits for many temporal and parietal regions compared with the dichotomous models. The trilinear model showed that periods of acceleration of atrophy varied greatly by region with early changes seen in the insula, amygdala, precuneus, hippocampus, and other temporal regions, occurring before the clinical threshold for CSF A beta positivity. Discussion: The use of piecewise-linear splines provides an improved model of the nonlinear association between CSF A beta and regional atrophy in regions implicated in the progression of AD. The important biological finding of this work is that some brain regions show periods of accelerated volume loss well before the CSFA beta(42) threshold. This implies that signs of brain atrophy develop before the current conventional definition of "preclinical AD". (C) 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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| 177. |
- Islam, Tohidul, 1982, et al.
(författare)
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Novel ultrasensitive immunoassay for the selective quantification of tau oligomers and related soluble aggregates
- 2024
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Ingår i: ALZHEIMERS & DEMENTIA. - 1552-5260 .- 1552-5279. ; 20:4, s. 2894-2905
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTIONTau aggregation into paired helical filaments and neurofibrillary tangles is characteristic of Alzheimer's disease (AD) and related disorders. However, biochemical assays for the quantification of soluble, earlier-stage tau aggregates are lacking. We describe an immunoassay that is selective for tau oligomers and related soluble aggregates over monomers.METHODSA homogeneous (single-antibody) immunoassay was developed using a novel anti-tau monoclonal antibody and validated with recombinant and brain tissue-derived tau.RESULTSThe assay signals were concentration dependent for recombinant tau aggregates in solution but not monomers, and recognized peptides within, but not outside, the aggregation-prone microtubule binding region. The signals in inferior and middle frontal cortical tissue homogenates increased with neuropathologically determined Braak staging, and were higher in insoluble than soluble homogenized brain fractions. Autopsy-verified AD gave stronger signals than other neurodegenerative diseases.DISCUSSIONThe quantitative oligomer/soluble aggregate-specific assay can identify soluble tau aggregates, including oligomers, from monomers in human and in vitro biospecimens.Highlights The aggregation of tau to form fibrils and neurofibrillary tangles is a key feature of Alzheimer's disease. However, biochemical assays for the quantification of oligomers/soluble aggregated forms of tau are lacking. We developed a new assay that preferentially binds to soluble tau aggregates, including oligomers and fibrils, versus monomers. The assay signal increased corresponding to the total protein content, Braak staging, and insolubility of the sequentially homogenized brain tissue fractions in an autopsy-verified cohort. The assay recognized tau peptides containing the microtubule binding region but not those covering the N- or C-terminal regions only.
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| 178. |
- Izzo, N. J., et al.
(författare)
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Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification
- 2021
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279.
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Amyloid beta (A beta) oligomers are one of the most toxic structural forms of the A beta protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients' brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block A beta oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on A beta oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). Methods: Experiments were performed to measure the impact of CT1812 versus vehicle on A beta oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APP(S)(we)/PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on A beta oligomer-induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPP(Swe/Lnd+) and wild-type littermates. A multicenter, double-blind, placebo-controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini-Mental State Examination 18-26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme-linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo-treated dosing groups. Results: CT1812 significantly and dose-dependently displaced A beta oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of A beta oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. Discussion: These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and A beta oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812.
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| 179. |
- Jack, C. R., et al.
(författare)
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Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2
- 2015
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:7, s. 740-756
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. Methods: We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. Results: Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. Discussion: Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future. (C) 2015 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
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| 180. |
- Jack, Jr., et al.
(författare)
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NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease
- 2018
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:4, s. 535-562
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Forskningsöversikt (refereegranskat)abstract
- In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.
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