| 1. |
- Borland, Emma, et al.
(författare)
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Clinically Relevant Changes for Cognitive Outcomes in Preclinical and Prodromal Cognitive Stages : Implications for Clinical Alzheimer Trials
- 2022
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Ingår i: Neurology. - 0028-3878. ; 99:11, s. 1142-1153
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesIdentifying a clinically meaningful change in cognitive test score is essential when using cognition as an outcome in clinical trials. This is especially relevant because clinical trials increasingly feature novel composites of cognitive tests. Our primary objective was to establish minimal clinically important differences (MCIDs) for commonly used cognitive tests, using anchor-based and distribution-based methods, and our secondary objective was to investigate a composite cognitive measure that best predicts a minimal change in the Clinical Dementia Rating - Sum of Boxes (CDR-SB).MethodsFrom the Swedish BioFINDER cohort study, we consecutively included cognitively unimpaired (CU) individuals with and without subjective or mild cognitive impairment (MCI). We calculated MCIDs associated with a change of ≥0.5 or ≥1.0 on CDR-SB for Mini-Mental State Examination (MMSE), ADAS-Cog delayed recall 10-word list, Stroop, Letter S Fluency, Animal Fluency, Symbol Digit Modalities Test (SDMT) and Trailmaking Test (TMT) A and B, and triangulated MCIDs for clinical use for CU, MCI, and amyloid-positive CU participants. For investigating cognitive measures that best predict a change in CDR-SB of ≥0.5 or ≥1.0 point, we conducted receiver operating characteristic analyses.ResultsOur study included 451 cognitively unimpaired individuals, 90 with subjective cognitive decline and 361 without symptoms of cognitive decline (pooled mean follow-up time 32.4 months, SD 26.8, range 12-96 months), and 292 people with MCI (pooled mean follow-up time 19.2 months, SD 19.0, range 12-72 months). We identified potential triangulated MCIDs (cognitively unimpaired; MCI) on a range of cognitive test outcomes: MMSE -1.5, -1.7; ADAS delayed recall 1.4, 1.1; Stroop 5.5, 9.3; Animal Fluency: -2.8, -2.9; Letter S Fluency -2.9, -1.8; SDMT: -3.5, -3.8; TMT A 11.7, 13.0; and TMT B 24.4, 20.1. For amyloid-positive CU, we found the best predicting composite cognitive measure included gender and changes in ADAS delayed recall, MMSE, SDMT, and TMT B. This produced an AUC of 0.87 (95% CI 0.79-0.94, sensitivity 75%, specificity 88%).DiscussionOur MCIDs may be applied in clinical practice or clinical trials for identifying whether a clinically relevant change has occurred. The composite measure can be useful as a clinically relevant cognitive test outcome in preclinical AD trials.
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| 2. |
- Cullen, Nicholas, et al.
(författare)
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Association of CSF Aβ38Levels with Risk of Alzheimer Disease-Related Decline
- 2022
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Ingår i: Neurology. - 0028-3878. ; 98:9, s. 958-967
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectiveExperimental studies suggest that the balance between short and long β-amyloid (Aβ) species might modulate the toxic effects of Aβ in Alzheimer disease (AD), but clinical evidence is lacking. We studied whether Aβ38 levels in CSF relate to risk of AD dementia and cognitive decline.MethodsCSF Aβ38 levels were measured in 656 individuals across 2 clinical cohorts: the Swedish BioFINDER study and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cox regression models were used to evaluate the association between baseline Aβ38 levels and risk of AD dementia in AD biomarker-positive individuals (AD+; determined by CSF phosphorylated tau [P-tau]/Aβ42 ratio) with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Linear mixed-effects models were used to evaluate the association between baseline Aβ38 levels and cognitive decline as measured by the Mini-Mental State Examination (MMSE) in AD+ participants with SCD, MCI, or AD dementia.ResultsIn the BioFINDER cohort, high Aβ38 levels were associated with slower decline in MMSE score (β = 0.30 points per SD, p = 0.001) and with lower risk of conversion to AD dementia (hazard ratio 0.83 per SD, p = 0.03). In the ADNI cohort, higher Aβ38 levels were associated with less decline in MMSE score (β = 0.27, p = 0.01) but not risk of conversion to AD dementia (p = 0.66). Aβ38 levels in both cohorts were significantly associated with both cognitive and clinical outcomes when further adjusted for CSF P-tau or CSF Aβ42 levels.DiscussionHigher CSF Aβ38 levels are associated with lower risk of AD-related changes in 2 independent clinical cohorts. These findings suggest that γ-secretase modulators could be effective as disease-altering therapy.Trial Registration InformationClinicalTrials.gov Identifier: NCT03174938.
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| 3. |
- Gallo, Valentina, et al.
(författare)
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Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis: The EPIC cohort.
- 2013
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Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 1526-632X .- 0028-3878. ; 80:9, s. 829-838
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim of this study was to investigate for the first time the association between body fat and risk of amyotrophic lateral sclerosis (ALS) with an appropriate prospective study design. METHODS: The EPIC (European Prospective Investigation into Cancer and Nutrition) study included 518,108 individuals recruited from the general population across 10 Western European countries. At recruitment, information on lifestyle was collected and anthropometric characteristics were measured. Cox hazard models were fitted to investigate the associations between anthropometric measures and ALS mortality. RESULTS: Two hundred twenty-two ALS deaths (79 men and 143 women) occurred during the follow-up period (mean follow-up = 13 years). There was a statistically significant interaction between categories of body mass index and sex regarding ALS risk (p = 0.009): in men, a significant linear decrease of risk per unit of body mass index was observed (hazard ratio = 0.93, 95% confidence interval 0.86-0.99 per kg/m(2)); among women, the risk was more than 3-fold increased for underweight compared with normal-weight women. Among women, a significant risk reduction increasing the waist/hip ratio was also evident: women in the top quartile had less than half the risk of ALS compared with those in the bottom quartile (hazard ratio = 0.48, 95% confidence interval 0.25-0.93) with a borderline significant p value for trend across quartiles (p = 0.056). CONCLUSION: Increased prediagnostic body fat is associated with a decreased risk of ALS mortality.
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| 4. |
- Gertje, Eske Christiane, et al.
(författare)
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Associations Between CSF Markers of Inflammation, White Matter Lesions, and Cognitive Decline in Individuals Without Dementia
- 2023
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Ingår i: Neurology. - 0028-3878. ; 100:17, s. 1812-1824
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Small vessel disease (SVD) and neuroinflammation both occur in Alzheimer disease (AD) and other neurodegenerative diseases. It is unclear whether these processes are related or independent mechanisms in AD, especially in the early stages of disease. We therefore investigated the association between white matter lesions (WML; the most common manifestation of SVD) and CSF biomarkers of neuroinflammation and their effects on cognition in a population without dementia. Methods Individuals without dementia from the Swedish BioFINDER study were included. The CSF was analyzed for proinflammatory markers (interleukin [IL]-6 and IL-8), cytokines (IL-7, IL-15, and IL-16), chemokines (interferon γ-induced protein 10, monocyte chemoattractant protein 1), markers of vascular injury (soluble intercellular adhesion molecule 1, soluble vascular adhesion molecule 1), and markers of angiogenesis (placental growth factor [PlGF], soluble fms-related tyrosine kinase 1 [sFlt-1], vascular endothelial growth factors [VEGF-A and VEFG-D]), and amyloid β (Aβ)42 Aβ40, and p-tau217. WML volumes were determined at baseline and longitudinally over 6 years. Cognition was measured at baseline and follow-up over 8 years. Linear regression models were used to test associations. Results A total of 495 cognitively unimpaired (CU) elderly individuals and 247 patients with mild cognitive impairment (MCI) were included. There was significant worsening in cognition over time, measured by Mini-Mental State Examination, Clinical Dementia Rating, and modified preclinical Alzheimer composite score in CU individuals and patients with MCI, with more rapid worsening in MCI for all cognitive tests. At baseline, higher levels of PlGF (β = 0.156, p < 0.001), lower levels of sFlt-1 (β = −0.086, p = 0.003), and higher levels of IL-8 (β = 0.07, p = 0.030) were associated with more WML in CU individuals. In those with MCI, higher levels of PlGF (β = 0.172, p = 0.001), IL-16 (β = 0.125, p = 0.001), IL-8 (β = 0.096, p = 0.013), IL-6 (β = 0.088, p = 0.023), VEGF-A (β = 0.068, p = 0.028), and VEGF-D (β = 0.082, p = 0.028) were associated with more WML. PlGF was the only biomarker that was associated with WML independent of Aβ status and cognitive impairment. Longitudinal analyses of cognition showed independent effects ofCSF inflammatory markers andWMLon longitudinal cognition, especially in peoplewithout cognitive impairment at baseline. Discussion Most neuroinflammatory CSF biomarkers were associated with WML in individuals without dementia. Our findings especially highlight a role for PlGF, which was associated with WML independent of Aβ status and cognitive impairment.
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| 5. |
- Glans, Isabelle, et al.
(författare)
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Association Between Dietary Habits in Midlife With Dementia Incidence Over a 20-Year Period
- 2023
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Ingår i: Neurology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0028-3878 .- 1526-632X. ; 100:1, s. E28-E37
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesDementia cases are expected to triple during the next 30 years, highlighting the importance of finding modifiable risk factors for dementia. The aim of this study was to investigate whether adherence to conventional dietary recommendations or to a modified Mediterranean diet are associated with a subsequent lower risk of developing all-cause dementia, Alzheimer disease (AD), vascular dementia (VaD), or with future accumulation of AD-related beta-amyloid (A beta) pathology.MethodsBaseline examination in the prospective Swedish population-based Malmo Diet and Cancer Study took place in 1991-1996 with a follow-up for incident dementia until 2014. Nondemented individuals born 1923-1950 and living in Malmo were invited to participate. Thirty thousand four hundred forty-six were recruited (41% of all eligible). Twenty-eight thousand twenty-five had dietary data and were included in this study. Dietary habits were assessed with a 7-day food diary, detailed food frequency questionnaire, and 1-hour interview. Main outcomes were incident all-cause dementia, AD, or VaD determined by memory clinic physicians. Secondary outcome was A beta-accumulation measured using CSF A beta 42 (n = 738). Cox proportional hazard models were used to examine associations between diet and risk of developing dementia (adjusted for demographics, comorbidities, smoking, physical activity, and alcohol).ResultsSixty-one percent were women, and the mean (SD) age was 58.1 (7.6) years. One thousand nine hundred forty-three (6.9%) were diagnosed with dementia (median follow-up, 19.8 years). Individuals adhering to conventional dietary recommendations did not have lower risk of developing all-cause dementia (hazard ratio [HR] comparing worst with best adherence, 0.93, 95% CI 0.81-1.08), AD (HR 1.03, 0.85-1.23), or VaD (HR 0.93, 0.69-1.26). Neither did adherence to the modified Mediterranean diet lower the risk of developing all-cause dementia (HR 0.93 0.75-1.15), AD (HR 0.90, 0.68-1.19), or VaD (HR 1.00, 0.65-1.55). The results were similar when excluding participants developing dementia within 5 years or those with diabetes. No significant associations were found between diet and abnormal A beta accumulation, conventional recommendations (OR 1.28, 0.74-2.24) or modified Mediterranean diet (OR 0.85, 0.39-1.84).DiscussionIn this 20-year follow-up study, neither adherence to conventional dietary recommendations nor to modified Mediterranean diet were significantly associated with subsequent reduced risk for developing all-cause dementia, AD dementia, VaD, or AD pathology.
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| 6. |
- Hansson, Oskar, et al.
(författare)
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Blood-based NfL : A biomarker for differential diagnosis of parkinsonian disorder
- 2017
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Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 88:10, s. 930-937
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders. Methods: The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated. Results: We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73-0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81). Conclusions: Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics. Classification of evidence: This study provides Class III evidence that blood NfL levels discriminate between PD and APD.
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| 7. |
- Insel, Philip S., et al.
(författare)
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Genetic Moderation of the Association of β-Amyloid With Cognition and MRI Brain Structure in Alzheimer Disease
- 2023
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Ingår i: Neurology. - 0028-3878. ; 101:1, s. 20-29
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives: There is considerable heterogeneity in the association between increasing β-amyloid (Aβ) pathology and early cognitive dysfunction in preclinical Alzheimer disease (AD). At this stage, some individuals show no signs of cognitive dysfunction, while others show clear signs of decline. The factors explaining this heterogeneity are particularly important for understanding progression in AD but remain largely unknown. In this study, we examined an array of genetic variants that may influence the relationships among Aβ, brain structure, and cognitive performance in 2 large cohorts. Methods: In 2,953 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) study, interactions between genetic variants and 18F-Florbetapir PET standardized uptake value ratio (SUVR) to predict the Preclinical Alzheimer Cognitive Composite (PACC) were assessed. Genetic variants identified in the A4 study were evaluated in the Alzheimer Disease Neuroimaging Initiative (ADNI, N = 527) for their association with longitudinal cognition and brain atrophy in both cognitively unimpaired participants and those with mild cognitive impairment. Results: In the A4 study, 4 genetic variants significantly moderated the association between Aβ load and cognition. Minor alleles of 3 variants were associated with additional decreases in PACC scores with increasing Aβ SUVR (rs78021285, β = -2.29, SE = 0.40, pFDR = 0.02, nearest gene ARPP21; rs71567499, β = -2.16, SE = 0.38, pFDR = 0.02, nearest gene PPARD; and rs10974405, β = -1.68, SE = 0.29, pFDR = 0.02, nearest gene GLIS3). The minor allele of rs7825645 was associated with less decrease in PACC scores with increasing Aβ SUVR (β = 0.71, SE = 0.13, pFDR = 0.04, nearest gene FGF20). The genetic variant rs76366637, in linkage disequilibrium with rs78021285, was available in both the A4 and ADNI. In the A4, rs76366637 was strongly associated with reduced PACC scores with increasing Aβ SUVR (β = -1.01, SE = 0.21, t = -4.90, p < 0.001). In the ADNI, rs76366637 was associated with accelerated cognitive decline (χ2 = 15.3, p = 0.004) and atrophy over time (χ2 = 26.8, p < 0.001), with increasing Aβ SUVR. Discussion: Patterns of increased cognitive dysfunction and accelerated atrophy due to specific genetic variation may explain some of the heterogeneity in cognition in preclinical and prodromal AD. The genetic variant near ARPP21 associated with lower cognitive scores in the A4 and accelerated cognitive decline and brain atrophy in the ADNI may help to identify those at the highest risk of accelerated progression of AD.
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| 8. |
- Janelidze, Shorena, et al.
(författare)
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CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease.
- 2018
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Ingår i: Neurology. - 1526-632X .- 0028-3878. ; 91:9
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Tidskriftsartikel (refereegranskat)abstract
- To measure CSF levels of biomarkers reflecting microglia and astrocytes activation, neuroinflammation, and cerebrovascular changes and study their associations with the core biomarkers of Alzheimer disease (AD) pathology (β-amyloid [Aβ] and tau), structural imaging correlates, and clinical disease progression over time.The study included cognitively unimpaired elderly (n = 508), patients with mild cognitive impairment (MCI, n = 256), and patients with AD dementia (n = 57) from the longitudinal Swedish BioFINDER cohort. CSF samples were analyzed for YKL-40, interleukin (IL)-6, IL-7, IL-8, IL-15, IP-10, monocyte chemoattractant protein 1, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), placental growth factor, and fms-related tyrosine kinase 1 (Flt-1). MRI data were available from 677 study participants. Longitudinal clinical assessments were conducted in control individuals and patients with MCI (mean follow-up 3 years, range 1-6 years).CSF levels of YKL-40, ICAM-1, VCAM-1, IL-15, and Flt-1 were increased during the preclinical, prodromal, and dementia stages of AD. High levels of these biomarkers were associated with increased CSF levels of total tau, with the associations, especially for YKL-40, being stronger in Aβ-positive individuals. The results were similar for associations between phosphorylated tau and YKL-40, ICAM-1, and VCAM-1. High levels of the biomarkers were also associated with cortical thinning (primarily in the precuneus and superior parietal regions) and with subsequent cognitive deterioration in patients without dementia as measured with Mini-Mental State Examination (YKL-40) and Clinical Dementia Rating Sum of Boxes (YKL-40, ICAM-1, VCAM-1 and IL-15). Finally, higher levels of CSF YKL-40, ICAM-1, and Flt-1 increased risk of development of AD dementia in patients without dementia.Neuroinflammation and cerebrovascular dysfunction are early events occurring already at presymptomatic stages of AD and contribute to disease progression.
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| 9. |
- Janelidze, Shorena, et al.
(författare)
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Increased CSF biomarkers of angiogenesis in Parkinson disease
- 2015
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 85:21, s. 1834-1842
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Tidskriftsartikel (refereegranskat)abstract
- To study biomarkers of angiogenesis in Parkinson disease (PD), and how these are associated with clinical characteristics, blood-brain barrier (BBB) permeability, and cerebrovascular disease.
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| 10. |
- Kumar, Atul, et al.
(författare)
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β-Amyloid-Dependent and-Independent Genetic Pathways Regulating CSF Tau Biomarkers in Alzheimer Disease
- 2022
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Ingår i: Neurology. - 0028-3878. ; 99:5, s. 476-487
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal metabolism of β-amyloid (Aβ) and soluble phosphorylated tau (P-tau), as well as neurodegeneration, are key components of Alzheimer disease (AD), but it is unclear how these different processes are related to genetic risk factors for AD.MethodsIn the Swedish BioFINDER study, we tested associations between a priori defined polygenic risk scores (PRSs) for AD (excluding single-nucleotide polymorphism [SNP] within the APOE region in the main analysis) and biomarkers in CSF (total tau [T-tau] and P-tau181; Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-42/1-40; and neurofilament light [NfL]) in cognitively unimpaired (CU) individuals (n = 751), and in patients with mild cognitive impairment (MCI) (n = 212) and AD dementia (n = 150). Results were validated in the Alzheimer's Disease Neuroimaging Initiative data set with 777 individuals (AD = 119, MCI = 442, and CU = 216).ResultsPRSs with SNPs significant at p < 5e-03 (∼1,742 variants) were associated with higher CSF P-tau181 (β = 0.13, p = 5.6e-05) and T-tau (β = 0.12, p = 4.3e-04). The associations between PRS and tau measures were partly attenuated but remained significant after adjusting for Aβ status. Aβ pathology mediated 37% of the effect of this PRS on tau levels. Aβ-dependent and Aβ-independent subsets of the PRS were identified and characterized. There were also associations between PRSs and CSF Aβ biomarkers with nominal significance, but not when corrected for multiple comparisons. There were no associations between PRSs and CSF NfL.DiscussionGenetic pathways implicated in causing AD are related to altered levels of soluble tau through both Aβ-dependent and Aβ-independent mechanisms, which may have relevance for anti-tau drug development.
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