| 1. |
- Lindholm, Beata, et al.
(author)
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The clinical significance of 10-m walk test standardizations in Parkinson’s disease
- 2018
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 265:8, s. 1829-1835
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Journal article (peer-reviewed)abstract
- Background: The 10-m walk test (10MWT) is a widely used measure of gait speed in Parkinson’s disease (PD). However, it is unclear if different standardizations of its conduct impact test results. Aim of the study: We examined the clinical significance of two aspects of the standardization of the 10MWT in mild PD: static vs. dynamic start, and a single vs. repeated trials. Implications for fall prediction were also explored. Methods: 151 people with PD (mean age and PD duration, 68 and 4 years, respectively) completed the 10MWT in comfortable gait speed with static and dynamic start (two trials each), and gait speed (m/s) was recorded. Participants then registered all prospective falls for 6 months. Results: Absolute mean differences between outcomes from the various test conditions ranged between 0.016 and 0.040 m/s (effect sizes, 0.06–0.14) with high levels of agreement (intra-class correlation coefficients, 0.932–0.987) and small standard errors of measurement (0.032–0.076 m/s). Receiver operating characteristic curves showed similar discriminate abilities for prediction of future falls across conditions (areas under curves, 0.70–0.73). Cut-off points were estimated at 1.1–1.2 m/s. Conclusions: Different 10MWT standardizations yield very similar results, suggesting that there is no practical need for an acceleration distance or repeated trials when conducting this test in mild PD.
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| 2. |
- Lindholm, Beata, et al.
(author)
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The clinical significance of 10-m walk test standardizations in Parkinson's disease
- 2018
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In: Journal of Neurology. - 0340-5354 .- 1432-1459. ; 265:8, s. 1829-1835
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Journal article (peer-reviewed)abstract
- BACKGROUND: The 10-m walk test (10MWT) is a widely used measure of gait speed in Parkinson's disease (PD). However, it is unclear if different standardizations of its conduct impact test results.AIM OF THE STUDY: We examined the clinical significance of two aspects of the standardization of the 10MWT in mild PD: static vs. dynamic start, and a single vs. repeated trials. Implications for fall prediction were also explored.METHODS: 151 people with PD (mean age and PD duration, 68 and 4 years, respectively) completed the 10MWT in comfortable gait speed with static and dynamic start (two trials each), and gait speed (m/s) was recorded. Participants then registered all prospective falls for 6 months.RESULTS: Absolute mean differences between outcomes from the various test conditions ranged between 0.016 and 0.040 m/s (effect sizes, 0.06-0.14) with high levels of agreement (intra-class correlation coefficients, 0.932-0.987) and small standard errors of measurement (0.032-0.076 m/s). Receiver operating characteristic curves showed similar discriminate abilities for prediction of future falls across conditions (areas under curves, 0.70-0.73). Cut-off points were estimated at 1.1-1.2 m/s.CONCLUSIONS: Different 10MWT standardizations yield very similar results, suggesting that there is no practical need for an acceleration distance or repeated trials when conducting this test in mild PD.
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| 3. |
- Bocancea, Diana I., et al.
(author)
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Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis
- 2023
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 146:9, s. 3719-3734
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Journal article (peer-reviewed)abstract
- Mechanisms of resilience against tau pathology in individuals across the Alzheimer’s disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We employed a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET.In this multicenter study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer’s disease-dementia with baseline [18F]flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning.We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness.In this longitudinal study of clinically impaired individuals with underlying Alzheimer’s disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.
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| 4. |
- Holm, Hannes, et al.
(author)
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Biomarkers of microvascular endothelial dysfunction predict incident dementia : a population-based prospective study
- 2017
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In: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 282:1, s. 94-101
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cerebral endothelial dysfunction occurs in a spectrum of neurodegenerative diseases. Whether biomarkers of microvascular endothelial dysfunction can predict dementia is largely unknown. We explored the longitudinal association of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal endothelin-1 (CT-proET-1) and midregional proadrenomedullin (MR-proADM) with dementia and subtypes amongst community-dwelling older adults.METHODS: A population-based cohort of 5347 individuals (men, 70%; age, 69 ± 6 years) without prevalent dementia provided plasma for determination of MR-proANP, CT-proET-1 and MR-proADM. Three-hundred-and-seventy-three patients (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) over a period of 4.6 ± 1.3 years. Relations between baseline biomarker plasma concentrations and incident dementia were assessed using multivariable Cox regression analysis.RESULTS: Higher levels of MR-proANP were significantly associated with increased risk of all-cause and vascular dementia (hazard ratio [HR] per 1 SD: 1.20, 95% confidence interval [CI], 1.07-1.36; P = 0.002, and 1.52; 1.21-1.89; P < 0.001, respectively). Risk of all-cause dementia increased across the quartiles of MR-proANP (p for linear trend = 0.004; Q4, 145-1681 pmol L(-1) vs. Q1, 22-77 pmol L(-1) : HR: 1.83; 95%CI: 1.23-2.71) and was most pronounced for vascular type (p for linear trend = 0.005: HR: 2.71; 95%CI: 1.14-6.46). Moreover, the two highest quartiles of CT-proET-1 predicted vascular dementia with a cut-off value at 68 pmol L(-1) (Q3-Q4, 68-432 pmol L(-1) vs. Q1-Q2,4-68 pmol L(-1) ; HR: 1.94; 95%CI: 1.12-3.36). Elevated levels of MR-proADM indicated no increased risk of developing dementia after adjustment for traditional risk factors.CONCLUSIONS: Elevated plasma concentration of MR-proANP is an independent predictor of all-cause and vascular dementia. Pronounced increase in CT-proET-1 indicates higher risk of vascular dementia.
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| 5. |
- Holm, Hannes, et al.
(author)
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N-Terminal Prosomatostatin and Risk of Vascular Dementia
- 2017
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In: Cerebrovascular Diseases. - : S. Karger. - 1015-9770 .- 1421-9786. ; 44:5-6, s. 259-265
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Journal article (peer-reviewed)abstract
- BACKGROUND: Increased somatostatin plasma concentration has been found in patients with vascular dementia. However, it is unknown whether or not somatostatin levels may predict dementia development in the general population. To this end, we sought to assess the association of circulating N-terminal prosomatostatin (NT-proSST) with incident dementia among community-dwelling older adults.METHODS: In the prospective population-based Malmö Preventive Project, 5,347 study participants (mean age: 69 ± 6years; 70% men) provided plasma for the determination of NT-proSST concentration. Of these, 373 participants (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) during a follow-up period of 4.6 ± 1.3 years. The association of NT-proSST with the risk of dementia and its subtypes was studied using multivariable-adjusted Cox regression models controlling for age, gender, body mass index, systolic blood pressure, antihypertensive treatment, smoking, diabetes, lipid levels and prevalent stroke.RESULTS: Higher levels of NT-proSST were significantly associated with an increased risk of vascular dementia (hazard ratio [HR] per 1 SD: 1.29; 95% CI 1.05-1.59; p = 0.016), whereas no association was observed with Alzheimer's disease (HR per 1 SD: 0.99; 95% CI 0.81-1.20; p = 0.91), all-cause dementia (HR per 1 SD: 1.04; 95% CI 0.94-1.16; p = 0.44), and mixed dementia (HR per 1 SD: 0.98; 95% CI 0.79-1.21; p = 0.84). Levels of NT-proSST above 563 pmol/L (highest quartile) conferred distinctly increased risk of vascular dementia (HR 1.66; 95% CI 1.05-2.63; p = 0.029) compared with lower values.CONCLUSIONS: Higher levels of circulating N-terminal-prosomatostatin are associated with increased incidence of vascular dementia. Our findings might be of importance for the understanding of dementia development in older adults.
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| 6. |
- Insel, Philip S., et al.
(author)
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Cognitive and functional changes associated with Aβ pathology and the progression to mild cognitive impairment
- 2016
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 48, s. 172-181
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Journal article (peer-reviewed)abstract
- Cognitively-normal people with evidence of β-amyloid (Aβ) pathology and subtle cognitive dysfunction are believed to be at high risk for progression to mild cognitive impairment due to Alzheimer's disease (AD). Clinical trials in later stages of AD typically include a coprimary endpoint to demonstrate efficacy on both cognitive and functional assessments. Recent trials focus on cognitively-normal people, but functional decline has not been explored for trial designs in this group. The goal of this study was therefore to characterize cognitive and functional decline in (1) cognitively-normal people converting to mild cognitive impairment (MCI) and (2) cognitively-normal β-amyloid-positive (Aβ+) people. Specifically, we sought to identify and compare the cognitive and functional assessments and their weighted combinations that maximize the longitudinal decline specific to these 2 groups. We studied 68 people who converted from normal cognition to MCI and 70 nonconverters, as well as 137 Aβ+ and 210 β-amyloid-negative cognitively-normal people. We used bootstrap aggregation and cross-validated mixed-models to estimate the distribution of weights applied to cognitive and functional outcomes to form composites. We also evaluated best subset optimization. Using optimized composites, we estimated statistical power for a variety of clinical trial scenarios. Overall, 55.4% of cognitively-normal to MCI converters were Aβ+. Large gains in power estimates were obtained when requiring participants to have both subtle cognitive dysfunction and Aβ pathology compared with requiring Aβ pathology alone. Additional power resulted when including functional as well as cognitive outcomes as part of the composite. Composites formed by applying equal weights to all measures provided the highest estimates of cross-validated power, although similar to both continuous weight optimization and best subset optimization. Using a composite to detect a 30% slowing of decline, 80% power was obtained for predicted Aβ+ converters with 375 completers/arm for a 30-month trial using a combination of cognitive/ functional measures. In the Aβ+ group, power to approach levels suitable for a phase III clinical trial would require considerably larger sample sizes. Composites incorporating both cognitive and functional measures may substantially increase the power of a trial in a preclinical (Aβ+) AD population with subtle evidence of cognitive dysfunction.
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| 7. |
- Janelidze, Shorena, et al.
(author)
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Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype
- 2017
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 51, s. 104-112
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Journal article (peer-reviewed)abstract
- Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF bio-markers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage. (C) 2016 The Authors. Published by Elsevier Inc.
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| 8. |
- Jansen, Willemijn J, et al.
(author)
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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
- 2018
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In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 84-95
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Journal article (peer-reviewed)abstract
- Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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| 9. |
- Movérare-Skrtic, Sofia, et al.
(author)
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Leukocyte Telomere Length (LTL) is reduced in stable mild cognitive impairment but low LTL is not associated with conversion to Alzheimer's Disease: A pilot study
- 2012
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In: Experimental Gerontology. - : Elsevier BV. - 1873-6815 .- 0531-5565. ; 47:2, s. 179-182
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Journal article (peer-reviewed)abstract
- Leukocyte telomere length (LTL) is associated with the aging process and may be related to cognitive aging. Previous studies have shown conflicting results whether LTL is affected in patients with Alzheimer's disease (AD). In this pilot study, we investigated LTL in a well-defined homogeneous mono-center population. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n=32), patients with stable MCI (n=13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n=15), and healthy controls (n=20). LTL was determined using a quantitative PCR assay. Patients with AD had similar LTL as healthy controls. Patients with stable MCI had reduced LTL both compared to AD patients (p=0.02) and controls (p=0.008). Subanalyses within the AD group showed that patients with MCI that later converted to AD had similar LTL as patients with clinical diagnosis of AD at primary evaluation and healthy controls whereas the LTL was longer compared to the stable MCI group (p=0.02). There were no correlations between LTL and the core AD biomarkers A beta(1-42), T-tau and P-tau. In conclusion, in this pilot study, patients with AD or MCI that later converted to AD had similar LTL as healthy controls. Patients with stable MCI that did not progress to dementia had reduced LTL compared to controls, which might suggest a more marked biological aging as a cause of the cognitive symptoms in this group. (C) 2011 Elsevier Inc. All rights reserved.
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| 10. |
- Nilsson, Maria H, et al.
(author)
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The effects of tau, amyloid and white matter lesions on mobility, dual tasking and balance in older people
- 2021
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In: Journals of Gerontology. Series A: Biological Sciences & Medical Sciences. - : Oxford University Press (OUP). - 1758-535X. ; 76:4, s. 683-691
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Journal article (peer-reviewed)abstract
- BACKGROUND: This study aimed to investigate whether white matter lesions (WML), β-amyloid- and tau pathologies are independently associated with mobility, dual tasking and dynamic balance performance in older non-demented individuals.METHODS: We included 299 older people (mean, SD, age: 71.8, 5.6 years) from the Swedish BioFINDER study, whereof 175 were cognitively unimpaired and 124 had mild cognitive impairment (MCI). In multivariable regression analyses, dependent variables included mobility (Timed Up & Go, TUG), dual tasking (TUG with a simultaneous subtraction task, i.e. TUG-Cog, as well as dual task cost), and balance (Figure-of-eight). The analyses were controlled for age, sex, education, diagnosis (i.e. MCI) and comorbidity (stroke, diabetes, and ischemic heart disease). Independent variables included WML volume, and measures of β-amyloid (abnormal CSF Aβ42/40 ratio) and tau pathology (CSF phosphorylated tau, p-tau).RESULTS: Multivariable regression analyses showed that an increased WML volume was independently associated with decreased mobility, i.e. TUG (standardized β=0.247; p<0.001). Tau pathology was independently associated with dual tasking both when using the raw data of TUG-Cog (β=0.224; p=0.003) and the dual task cost (β= -0.246; p=0.001). Amyloid pathology was associated with decreased balance, i.e. Figure-of-eight (β= 0.172; p=0.028). The independent effects of WML and tau pathology were mainly observed in those with MCI, which was not the case for the effects of amyloid pathology on balance.CONCLUSIONS: Common brain pathologies have different effects where WML are independently associated with mobility, tau pathology has the strongest effect on dual tasking and amyloid pathology seems to be independently associated with balance. Although these novel findings need to be confirmed in longitudinal studies, they suggest that different brain pathologies have different effects on mobility, balance and dual tasking in older non-demented individuals.
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