| 1. |
- Cedres, Nira, et al.
(författare)
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Association of Cerebrovascular and Alzheimer Disease Biomarkers With Cholinergic White Matter Degeneration in Cognitively Unimpaired Individuals
- 2022
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 99:15, s. e1619-e1629
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Several pathologic processes might contribute to the degeneration of the cholinergic system in aging. We aimed to determine the contribution of amyloid, tau, and cerebrovascular biomarkers toward the degeneration of cholinergic white matter (WM) projections in cognitively unimpaired individuals.Methods The contribution of amyloid and tau pathology was assessed through CSF levels of the Aβ42/40 ratio and phosphorylated tau (p-tau). CSF Aβ38 levels were also measured. Cerebrovascular pathology was assessed using automatic segmentations of WM lesions (WMLs) on MRI. Cholinergic WM projections (i.e., cingulum and external capsule pathways) were modeled using tractography based on diffusion tensor imaging data. Sex and APOE ε4 carriership were also included in the analysis as variables of interest.Results We included 203 cognitively unimpaired individuals from the H70 Gothenburg Birth Cohort Studies (all individuals aged 70 years, 51% female). WM lesion burden was the most important contributor to the degeneration of both cholinergic pathways (increase in mean square error [IncMSE] = 98.8% in the external capsule pathway and IncMSE = 93.3% in the cingulum pathway). Levels of Aβ38 and p-tau also contributed to cholinergic WM degeneration, especially in the external capsule pathway (IncMSE = 28.4% and IncMSE = 23.4%, respectively). The Aβ42/40 ratio did not contribute notably to the models (IncMSE<3.0%). APOE ε4 carriers showed poorer integrity in the cingulum pathway (IncMSE = 21.33%). Women showed poorer integrity of the external capsule pathway (IncMSE = 21.55%), which was independent of amyloid status as reflected by the nonsignificant differences in integrity when comparing amyloid-positive vs amyloid-negative women participants (T201 = −1.55; p = 0.123).Discussion In cognitively unimpaired older individuals, WMLs play a central role in the degeneration of cholinergic pathways. Our findings highlight the importance of WM lesion burden in the elderly population, which should be considered in the development of prevention programs for neurodegeneration and cognitive impairment.
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| 2. |
- Ding, Mozhu, et al.
(författare)
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Atrial fibrillation, antithrombotic treatment, and cognitive aging : A population-based study
- 2018
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 91:19, s. e1732-e1740
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo examine the association of atrial fibrillation (AF) with cognitive decline and dementia in old age, and to explore the cognitive benefit of antithrombotic treatment in patients with AF.MethodsThis population-based cohort study included 2,685 dementia-free participants from the Swedish National Study on Aging and Care in Kungsholmen, who were regularly examined from 2001-2004 to 2010-2013. AF was ascertained from clinical examination, ECG, and patient registry. Global cognitive function was assessed using the Mini-Mental State Examination. We followed the DSM-IV criteria for the diagnosis of dementia, the NINDS-AIREN (National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences) criteria for vascular dementia, and the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association) criteria for Alzheimer disease. Data were analyzed using multiple linear mixed-effects and Cox regression models.ResultsWe identified 243 participants (9.1%) with AF at baseline. During the 9-year follow-up period, 279 participants (11.4%) developed AF and 399 (14.9%) developed dementia. As a time-varying variable, AF was significantly associated with a faster annual Mini-Mental State Examination decline (beta coefficient = -0.24, 95% confidence interval [ CI]: -0.31 to -0.16) and an increased hazard ratio (HR) of all-cause dementia (HR = 1.40, 95% CI: 1.11-1.77) and vascular and mixed dementia (HR = 1.88, 95% CI: 1.09-3.23), but not Alzheimer disease (HR = 1.33, 95% CI: 0.92-1.94). Among people with either prevalent or incident AF, use of anticoagulant drugs, but not antiplatelet treatment, was associated with a 60% decreased risk of dementia (HR = 0.40, 95% CI: 0.18-0.92).Conclusion AF is associated with a faster global cognitive decline and an increased risk of dementia in older people. Use of anticoagulant drugs may reduce dementia risk in patients with AF.
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| 3. |
- Dintica, Christina S., et al.
(författare)
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Impaired olfaction is associated with cognitive decline and neurodegeneration in the brain
- 2019
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 92:7, s. e700-e709
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveWe aimed to examine whether impaired olfaction is associated with cognitive decline and indicators of neurodegeneration in the brain of dementia-free older adults.MethodsWithin the Rush Memory and Aging Project, 380 dementia-free participants (mean age = 78 years) were followed for up to 15 years, and underwent MRI scans. Olfactory function was assessed using the Brief Smell Identification Test (B-SIT) at baseline, and categorized as anosmia (B-SIT <6), hyposmia (B-SIT 6-10 in men and 6-10.25 in women), and normal (B-SIT 10.25-12 in men and 10.5-12 in women). Cognitive function was annually assessed with a battery of 21 tests, from which composite scores were derived. Structural total and regional brain volumes were estimated. Data were analyzed using linear regression and mixed-effects models.ResultsAt study entry, 138 (36.3%) had normal olfactory function, 213 (56.1%) had hyposmia, and 29 (7.6%) had anosmia. In multiadjusted mixed-effects models, hyposmia (beta = -0.03, 95% confidence interval [CI] -0.05 to -0.02) and anosmia (beta = -0.13, 95% CI -0.16 to -0.09) were associated with faster rate of cognitive decline compared to normal olfaction. On MRI, impaired olfaction (hyposmia or anosmia) was related to smaller volumes of the hippocampus (beta = -0.19, 95% CI -0.33 to -0.05), and in the entorhinal (beta = -0.16, 95% CI -0.24 to -0.08), fusiform (beta = -0.45, 95% CI -0.78 to -0.14), and middle temporal (beta = -0.38, 95% CI -0.72 to -0.01) cortices.ConclusionImpaired olfaction predicts faster cognitive decline and might indicate neurodegeneration in the brain among dementia-free older adults.
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| 4. |
- Feldman, H H, et al.
(författare)
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Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease : LEADe
- 2010
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Ingår i: Neurology. - Minneapolis ; New York : Lancet ; Ovid. - 0028-3878 .- 1526-632X. ; 74:12, s. 956-964
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD.METHODS: This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks.RESULTS: A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated.CONCLUSIONS: In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. Classification of evidence: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.
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| 5. |
- Hedström, Anna Karin, et al.
(författare)
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Organic solvents and MS susceptibility Interaction with MS risk HLA genes
- 2018
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 91:5, s. E455-E462
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Tidskriftsartikel (refereegranskat)abstract
- Objective We hypothesize that different sources of lung irritation may contribute to elicit an immune reaction in the lungs and subsequently lead to multiple sclerosis (MS) in people with a genetic susceptibility to the disease. We aimed to investigate the influence of exposure to organic solvents on MS risk, and a potential interaction between organic solvents and MS risk human leukocyte antigen (HLA) genes. Methods Using a Swedish population-based case-control study (2,042 incident cases of MS and 2,947 controls), participants with different genotypes, smoking habits, and exposures to organic solvents were compared regarding occurrence of MS, by calculating odds ratios with 95% confidence intervals using logistic regression. A potential interaction between exposure to organic solvents and MS risk HLA genes was evaluated by calculating the attributable proportion due to interaction. Results Overall, exposure to organic solvents increased the risk of MS (odds ratio 1.5, 95% confidence interval 1.2-1.8, p = 0.0004). Among both ever and never smokers, an interaction between organic solvents, carriage of HLA-DRB1*15, and absence of HLA-A*02 was observed with regard to MS risk, similar to the previously reported gene-environment interaction involving the same MS risk HLA genes and smoke exposure. Conclusion The mechanism linking both smoking and exposure to organic solvents to MS risk may involve lung inflammation with a proinflammatory profile. Their interaction with MS risk HLA genes argues for an action of these environmental factors on adaptive immunity, perhaps through activation of autoaggressive cells resident in the lungs subsequently attacking the CNS.
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| 6. |
- Hooshmand, Babak, et al.
(författare)
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Homocysteine and holotranscobalamin and the risk of Alzheimer disease : a longitudinal study
- 2010
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 75:16, s. 1408-1414
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the relation between serum levels of homocysteine (tHcy) and holotranscobalamin (holoTC), the active fraction of vitamin B12, and risk of incident Alzheimer disease (AD) in a sample of Finnish community-dwelling elderly. METHODS: A dementia-free sample of 271 subjects aged 65-79 years derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study was followed up for 7 years to detect incident AD. The association between serum tHcy and holoTC with AD was analyzed with multiple logistic regression after adjusting for several potential confounders, including common vascular risk factors. RESULTS: The odds ratios (ORs) (95% confidence interval [CI]) for AD were 1.16 (1.04-1.31) per increase of 1 μmol/L of tHcy at baseline and 0.980 (0.965-0.995) for each increase of 1 pmol/L baseline holoTC. Adjustment for several potential confounders including age, sex, education, APOE ε4 allele, body mass index, Mini-Mental State Examination, smoking, stroke, and blood pressure did not alter the associations: ORs (95% CI) for AD became 1.19 (1.01-1.39) for tHcy and 0.977 (0.958-0.997) for holoTC. Adjusting for holoTC attenuated the tHcy-AD link (OR changed from 1.16 to 1.10, 95% CI 0.96-1.25). The holoTC-AD relationship was less influenced by controlling for tHcy (OR changed from 0.980 to 0.984, 95% CI 0.968-1.000). Addition of folate did not change any of the results. CONCLUSIONS: This study suggests that both tHcy and holoTC may be involved in the development of AD. The tHcy-AD link may be partly explained by serum holoTC. The role of holoTC in AD should be further investigated.
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| 7. |
- Karalija, Nina, 1984-, et al.
(författare)
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Longitudinal Dopamine D2 Receptor Changes and Cerebrovascular Health in Aging
- 2022
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Ingår i: Neurology. - 1526-632X .- 0028-3878. ; 99, s. e1278-e1289
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Cross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline rates for DA D2-like receptors (DRD2) in aging and examine factors that may contribute to individual differences in DRD2 decline rates. METHODS: We investigated 5-year within-person changes in DRD2 availability in a sample of older adults. At both occasions, PET with 11C-raclopride and MRI were used to measure DRD2 availability in conjunction with structural and vascular brain integrity. RESULTS: Longitudinal analyses of the sample (baseline: n = 181, ages: 64-68 years, 100 men and 81 women; 5-year follow-up: n = 129, 69 men and 60 women) revealed aging-related striatal and extrastriatal DRD2 decline, along with marked individual differences in rates of change. Notably, the magnitude of striatal DRD2 decline was ∼50% of past cross-sectional estimates, suggesting that the DRD2 decline rate has been overestimated in past cross-sectional studies. Significant DRD2 reductions were also observed in select extrastriatal regions, including hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Distinct profiles of correlated DRD2 changes were found across several associative regions (ACC, dorsal striatum, and hippocampus) and in the reward circuit (nucleus accumbens and OFC). DRD2 losses in associative regions were associated with white matter lesion progression, whereas DRD2 losses in limbic regions were related to reduced cortical perfusion. DISCUSSION: These findings provide the first longitudinal evidence for individual and region-specific differences of DRD2 decline in older age and support the hypothesis that cerebrovascular factors are linked to age-related dopaminergic decline.
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| 8. |
- Kemppainen, Nina, et al.
(författare)
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Brain amyloid load and its associations with cognition and vascular risk factors in FINGER Study
- 2018
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 90:3, s. E206-E213
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate brain amyloid pathology in a dementia-risk population defined as cardiovascular risk factors, aging, and dementia risk (CAIDE) score of at least 6 but with normal cognition and to examine associations between brain amyloid load and cognitive performance and vascular risk factors.Methods A subgroup of 48 individuals from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) main study participated in brain C-11-Pittsburgh compound B (PiB)-PET imaging, brain MRI, and neuropsychological assessment at the beginning of the study. Lifestyle/vascular risk factors were determined as body mass index, blood pressure, total and low-density lipoprotein cholesterol, and glucose homeostasis model assessment. White matter lesions were visually rated from MRIs by a semiquantitative Fazekas score.Results Twenty participants (42%) had a positive PiB-PET on visual analysis. The PiB-positive group performed worse in executive functioning tests, included more participants with APOE epsilon 4 allele (50%), and showed slightly better glucose homeostasis compared to PiB-negative participants. PiB-positive and -negative participants did not differ significantly in other cognitive domain scores or other vascular risk factors. There was no significant difference in Fazekas score between the PiB groups.Conclusions The high percentage of PiB-positive participants provides evidence of a successful recruitment process of the at-risk population in the main FINGER intervention trial. The results suggest a possible association between early brain amyloid accumulation and decline in executive functions. APOE epsilon 4 was clearly associated with amyloid positivity, but no other risk factor was found to be associated with positive PiB-PET.
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| 9. |
- Li, Yuanjing, et al.
(författare)
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Association Between Behavioral, Biological, and Genetic Markers of Cardiovascular Health and MRI Markers of Brain Aging : A Cohort Study
- 2023
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 100:1, s. e38-e48
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objective The life’s simple 7 approach was proposed to define cardiovascular health (CVH) metrics. We sought to investigate the associations between behavioral, biological, and genetic markers for CVH and vascular brain aging in older adults.Methods This population-based cohort study included participants who had repeated brain MRI measures from 2001 to 2003 to 2007–2010 (i.e., count of perivascular spaces, volumes of white matter hyperintensity [WMH] and gray matter, and lacunes). At baseline, global, behavioral, and biological CVH metrics were defined and scored following the life’s simple 7 approach and categorized into unfavorable, intermediate, and favorable profiles according to tertiles. The metabolic genetic risk score was calculated by counting 15 risk alleles associated with hypertension, diabetes, or dyslipidemia. Data were analyzed using linear mixed-effects and Cox proportional hazards models, adjusting for age, sex, and education.Results The study sample consisted of 317 participants (age 60 years or older; 61.8% women). Favorable and intermediate (vs unfavorable) global CVH profiles were related to slower WMH progression, with β-coefficients (95% CI) being −0.019(-0.035–0.002) and −0.018(-0.034–0.001), respectively. Favorable and intermediate (vs unfavorable) biological CVH profiles were significantly related to slower WMH increase only in people aged 60–72 years. CVH profiles were not related to progression of other brain measures. Furthermore, a higher metabolic genetic risk score (range: 6–21) was associated with faster WMH increase (β-coefficient = 0.005; 95% CI: 0.003–0.008). There were statistical interactions of metabolic genetic risk score with global and behavioral CVH profiles on WMH accumulation. A higher metabolic genetic risk score was related to faster WMH accumulation, with β-coefficients being 0.015(0.007–0.023), 0.005(0.001–0.009), and 0.003(-0.001 to 0.006) among people with unfavorable, intermediate, and favorable global CVH profiles, respectively; the corresponding β-coefficients were 0.013(0.006–0.020), 0.006(0.003–0.009), and 0.002(-0.002 to 0.006) among people with unfavorable, intermediate, and favorable behavioral CVH profiles.Discussion Intermediate to favorable global CVH profiles in older adults are associated with slower vascular brain aging. The association of metabolic genetic risk load with accelerated vascular brain aging was evident among people with unfavorable to intermediate, but not favorable, CVH profiles. These findings highlight the importance of adhering to favorable CVH profiles, especially healthy behaviors, in vascular brain health.
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| 10. |
- Mattsson, Peter, et al.
(författare)
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Sociodemographic differences in antiepileptic drug prescriptions to adult epilepsy patients
- 2010
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 74:4, s. 295-301
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: According to the Swedish Health Care Act, patients should be provided with the health care they need, regardless of sociodemographic status. We investigated whether in Sweden sociodemographic differences are associated with access to expert health care and antiepileptic drug (AED) prescriptions in epilepsy. METHOD: Patients with epilepsy were identified in the National Patient Register. Persons >or=18 years on continuous AED treatment in 2006 were identified in the recently established Swedish Prescribed Drug Register. Data on sociodemographic variables were obtained from several other national registers. We linked data to examine whether epilepsy patients' access to neurologists and the prescription of individual AEDs are related to sex, age, educational level, area of residence, region of birth, or income. We also assessed whether AEDs are prescribed differently to patients with epilepsy by neurologists as compared to non-neurologists. RESULTS: We identified 26,124 epilepsy patients in the register who were on continuous AED treatment (effective sample). Being women, young, highly educated, having high incomes, and residing in a larger city meant being more often treated by a neurologist than by other specialists. The prescriptions of AEDs differed according to gender, age, education, place of residence, and income. Lamotrigine and levetiracetam were prescribed to a larger extent by a neurologist rather than by other specialists. CONCLUSIONS: This nationwide cross-sectional study of epilepsy patients indicates that sociodemographic characteristics are important for access to neurologists and prescriptions of individual antiepileptic drugs. Prospective studies using patient-related outcomes are needed to analyze the consequences of these differences.
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