Showing papers by "Miia Kivipelto published in 2012"
TL;DR: There is sufficient evidence that vascular risk factors significantly contribute to the expression and progression of cognitive decline but that active engagement in social, physical, and mentally stimulating activities may delay the onset of dementia, but these findings need to be confirmed by randomized controlled trials (RCTs).
Abstract: Dementia, a major cause of disability and institutionalization in older people, poses a serious threat to public health and to the social and economic development of modern society. Alzheimer's disease (AD) and cerebrovascular diseases are the main causes of dementia; most dementia cases are attributable to both vascular and neurodegenerative brain damage. No curative treatment is available, but epidemiological research provides a substantial amount of evidence of modifiable risk and protective factors that can be addressed to prevent or delay onset of AD and dementia. Risk of late-life dementia is determined by exposures to multiple factors experienced over the life course, and the effect of specific risk/protective factors depends largely on age. Moreover, cumulative and combined exposure to different risk/protective factors can modify their effect on dementia/AD risk. Multidisciplinary research involving epidemiology, neuropathology, and neuroimaging has provided sufficient evidence that vascular risk factors significantly contribute to the expression and progression of cognitive decline (including dementia) but that active engagement in social, physical, and mentally stimulating activities may delay the onset of dementia. However, these findings need to be confirmed by randomized controlled trials (RCTs). A promising strategy for preventing dementia is to implement intervention programs that take into account both the life-course model and the multifactorial nature of this syndrome. In Europe, there are three ongoing multidomain interventional RCTs that focus on the optimal management of vascular risk factors and vascular diseases. The RCTs include medical and lifestyle interventions and promote social, mental, and physical activities aimed at increasing the cognitive reserve. These studies will provide new insights into prevention of cognitive impairment and dementia. Such knowledge can help researchers plan larger, international prevention trials that could provide robust evidence on dementia/AD prevention. Taking a step in this direction, researchers involved in these European RCTs recently started the European Dementia Prevention Initiative, an international collaboration aiming to improve strategies for preventing dementia.
174 citations
TL;DR: Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD, and both disorders were associated with increase vitamin E damage.
141 citations
TL;DR: The shared risk factor profile between cardiovascular diseases and Alzheimer's disease, observations on vascular pathology in AD, and altered cerebral blood flow in AD brains have led to the suggestion that AD might be a vascular disorder with neurodegenerative consequences.
Abstract: The shared risk factor profile between cardiovascular diseases and Alzheimer's disease (AD), observations on vascular pathology in AD, and altered cerebral blood flow in AD brains have led to the suggestion that AD might be a vascular disorder with neurodegenerative consequences. Targeting vascular and metabolic risk factors could be an effective way to prevent AD. Higher body mass index, elevated blood pressure, serum cholesterol concentrations, and impaired glucose regulation have been associated with increased risk of AD. Interestingly, the associations between these factors measured at mid-life are stronger, or even opposite, than with the risk factors measured at late-life. This may reflect true differences in the association (i.e., mid-life risk factors being a better measure of vascular load during adulthood), reverse causality, or bias. The vascular risk factors can directly increase the susceptibility to AD, or the effect can be mediated via cardio- and cerebrovascular diseases.
140 citations
TL;DR: It is suggested that CE-MS metabolomics of CSF samples can be a useful tool to predict AD progression.
Abstract: Alzheimer’s disease (AD) is the most prevalent form of dementia with an estimated worldwide prevalence of over 30 million people, and its incidence is expected to increase dramatically with an increasing elderly population. Up until now, cerebrospinal fluid (CSF) has been the preferred sample to investigate central nervous system (CNS) disorders since its composition is directly related to metabolite production in the brain. In this work, a nontargeted metabolomic approach based on capillary electrophoresis–mass spectrometry (CE–MS) is developed to examine metabolic differences in CSF samples from subjects with different cognitive status related to AD progression. To do this, CSF samples from 85 subjects were obtained from patients with (i) subjective cognitive impairment (SCI, i.e. control group), (ii) mild cognitive impairment (MCI) which remained stable after a follow-up period of 2 years, (iii) MCI which progressed to AD within a 2-year time after the initial MCI diagnostic and, (iv) diagnosed AD. A p...
136 citations
TL;DR: Collaboration within the newly founded 'European Dementia Prevention Initiative' (EDPI) will allow for a comprehensive exploration of optimal target population, intervention and outcome measures, which are currently unknown, to facilitate determining the optimal design for future multi-national clinical trials on dementia prevention.
97 citations
TL;DR: It is suggested that inflammatory mechanisms may have an important role in increasing the risk of cognitive impairment and dementia/AD in this long-term population-based study.
Abstract: Inflammation has been associated with Alzheimer's disease (AD) and dementia. The association between rheumatoid arthritis (RA) or arthritis and dementia/AD has been investigated in several case-control or hospital- and register-based studies with mixed results. This long-term population-based study investigates the association between presence of joint disorders (RA and other joint disorders) in midlife and cognitive status later in life. 1,449 participants were first evaluated in 1972, 1977, 1982, and 1987 and follow-up was performed after 21 years. A self-administered questionnaire including questions on joint disorders was used at both evaluations. Cognitive status (control, mild cognitive impairment, dementia/AD) was assessed at follow-up. The presence of any joint disorder in midlife was significantly associated with a worse cognitive status later in life: OR (95% CI) in an ordinal logistic regression analysis adjusted for age, gender, follow-up time, education, APOEe4, body mass index, smoking, drug treatment, and diabetes was 1.96 (1.17-3.28). For RA only, OR (95% CI) was 2.77 (1.26-6.10). The correlation remained significant for RA when AD was considered instead of dementia OR (95% CI) 2.49 (1.09-5.67). The presence of joint disorders, especially RA, at midlife seems to be associated with a worse cognitive status later in life. Given the chronic inflammatory component of RA, this study suggests that inflammatory mechanisms may have an important role in increasing the risk of cognitive impairment and dementia/AD.
95 citations
TL;DR: It is suggested that genetic (APOE ε4) and environmental (education) factors are not only independently but also interactively related to dementia risk and that high education may buffer the negative effect of APOEε4 on dementia occurrence.
94 citations
TL;DR: In this paper, the associations between serum homocysteine (tHcy), holotranscobalamin (holoTC, the biologically active fraction of vitamin B12) and folate and cognitive functioning in a single person were examined.
Abstract: Objectives: To examine the associations between serum homocysteine (tHcy), holotranscobalamin (holoTC, the biologically active fraction of vitamin B12) and folate and cognitive functioning in a lon ...
92 citations
01 Jan 2012
TL;DR: In this paper, the authors have indicated numerous associations between vascular and lifestyle related risk factors and incident dementia, however, evidence from randomised controlled trials (RCTs) is limited.
Abstract: Recent epidemiological studies have indicated numerous associations between vascular and lifestyle related risk factors and incident dementia. However, evidence from randomised controlled trials (R ...
75 citations
TL;DR: Investigating the relationship between blood markers of vascular dysfunction with brain microstructural changes and cognition suggests inflammation and dysregulation of the fibrynolitic system may be involved in the pathological mechanisms underlying the WM damage seen in cerebrovascular disease and subsequent cognitive impairment.
54 citations
TL;DR: Of the methods used, VBM achieved the highest accuracy in its ability to differentiate between FTD and AD, and Hippocampal atrophy is present not only in AD but also in FTD.
Abstract: Background: MRI is an important clinical tool for diagnosing dementia-like diseases such as Frontemporal Dementia (FTD). However there is a need to develop more accurate and standardized MRI analys ...
TL;DR: The aim of this study is to characterise the differences of grey matter distribution and dynamics between progressive and stable MCI subjects during a 2 year period preceding the conversion to probable Alzheimer's disease (AD).
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.
TL;DR: The patterns of regions of thinning in FTD when compared to controls and also S-MCI patients showed similar trends; thinning of the bilateral frontal poles and bilateral medial temporal lobe structures, especially the anterior part of the gingulum, the uncus, and parahippocampal gyri.
Abstract: Cortical thickness analysis has been proposed as a potential diagnostic measure in memory disorders. In this retrospective study, we compared the cortical thickness values of 24 patients with frontotemporal dementia (FTD) to those of 25 healthy controls, 45 symptomatic subjects with stable mild cognitive impairment (S-MCI), 15 subjects with progressive mild cognitive impairment (P-MCI), and 36 patients with Alzheimer's disease (AD). The patterns of regions of thinning in FTD when compared to controls and also S-MCI patients showed similar trends; thinning of the bilateral frontal poles and bilateral medial temporal lobe structures, especially the anterior part of the gingulum, the uncus, and parahippocampal gyri. Cortical thinning in FTD was also found on the boundary regions of parietal and occipital lobes. In the P-MCI group compared to FTD, the trend of thinning in small distinct areas of the parietal and occipital lobes was observed. The FTD and AD groups did not differ statistically, but we found trends toward thinning in FTD of the left cingulate gyrus, and the left occipitotemporal gyri, and in AD of the inferior parietal, occipitoparietal, and the pericalcarine regions, more in the right hemisphere. In FTD, increased slowness in the executive test (Trail-Making A) correlated with the thinner cortex, whereas the language tests showed the lower scores, the thinner cortex in the left hemisphere. Cortical thickness might be a tool for detecting subtle changes in brain atrophy in screening of dementia prior to the development of diffuse or lobar atrophies.
TL;DR: It is reported that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort, and the mRNA levels of granulin were decreased with respect to A allele in the inferior temporal cortex of neuropathologically confirmed AD patients.
Abstract: Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer's disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.
TL;DR: A similar impact of dementia and CVD on survival is found, but following diagnosis, persons with dementia, and especially women, spent half of their remaining lives in the severe disabling stages of the disease.
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.
TL;DR: This is a brief summary of experiences from Finland related to Alzheimer's disease (AD) prevention research.
Abstract: This is a brief summary of experiences from Finland related to Alzheimer's disease (AD) prevention research. The first signals that AD may have vascular modifiable risk factors came from studies on cardiovascular conditions and diabetes. Cardiovascular prevention projects such as North Karelia Project and WHO-MONICA in the 1970-1980 s were focused on younger populations, which led to the idea of looking for risk factors as far back as middle age. Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) is one of the few studies in the world focusing on late-life cognition with a large and representative population-based cohort, baseline examination at midlife, and follow-up time up to three decades. Since 1998, it has identified several modifiable risk factors for cognitive impairment/dementia, and produced the first risk score for estimating dementia risk based on midlife profiles. The CAIDE Dementia Risk Score has been used to select participants in the Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER). FINGER is an ongoing multicenter RCT involving 1,200 participants aged 60-77 years, and testing the effects of a two-year multi-domain intervention targeting several risk factors simultaneously. It started in September 2009 and will be completed at the end of 2013. The FINGER study is at the forefront of international collaborative efforts to solve the clinical and public health problems of early identification of individuals at increased risk of late-life cognitive impairment, and of developing intervention strategies to prevent or delay the onset of cognitive impairment and dementia.
TL;DR: Investigate possible associations of white matter hyperintensities (WMHs) with the metabolism of cholesterol and insulin in two subgroups of patients with memory complaints and different CSF Aβ42 and CSF tau levels to find pathogenic mechanisms of WMHS likely to be different in the two groups investigated.
TL;DR: Findings suggest that a decreasing trend in serum cholesterol measures in elderly individuals may suffice as an indication for more detailed inspection for potential signs of cognitive decline.
Abstract: Background and objective
Accumulating evidence suggests that serum lipids are associated with cognitive decline and dementias. However, majority of the existing information concerns only serum total cholesterol (TC) and data at the level of lipoprotein fractions and subclasses is limited. The aim of this study was to explore the levels and trends of main cholesterol and triglyceride measures and eight lipoprotein subclasses during normal aging and the development of mild cognitive impairment by following a group of elderly for six years.
TL;DR: Practical experiences of staff and participants in immunotherapy RCTs are investigated, finding that more open debates of practical experiences from different trial centres and sponsors are essential for optimizing trial designs and improving conditions for participants.
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.
TL;DR: The hypothesis that CSF t-t Tau or p-tau181 levels may be of direct value for the evaluation of disease severity is supported, as it shows an Alzheimer's disease-like pattern for both GM distribution and cognitive profile, compared to those with normal levels.
Abstract: The aim of this study was to investigate brain tissue volumes, grey matter (GM) distribution, and cognitive performance for cognitively impaired subjects using cerebrospinal fluid (CSF) biomarker cut-offs as grouping criteria. 41 subjects attending the Memory Clinic, Karolinska University Hospital, Huddinge, Sweden, were divided into groups based on normal or abnormal CSF levels of Aβ1-42, t-tau, and p-tau181. SIENAX algorithms were employed for brain tissue volumes estimation and voxel-based morphometry (VBM) for mapping the differences in GM patterns. VBM revealed significant lower GM volumes in temporo-parietal, occipital, and prefrontal cortices for those subjects belonging to abnormal CSF t-tau and p-tau181 groups. No differences were found between groups according to CSF Aβ1-42 cut-offs. Patients with abnormal CSF p-tau181 showed lower cognitive performance compared to those with normal levels. Patients with abnormal levels of CSF tau (but not Aβ1-42) showed an Alzheimer's disease-like pattern for both GM distribution and cognitive profile, compared to those with normal levels. These results support the hypothesis that CSF t-tau or p-tau181 levels may be of direct value for the evaluation of disease severity.