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Sökning: WFRF:(Stomrud Erik)

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2.
  • Engelborghs, Sebastiaan, et al. (författare)
  • Consensus guidelines for lumbar puncture in patients with neurological diseases
  • 2017
  • Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 8, s. 111-126
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain. Methods We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III). Results Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications. Discussion When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate.
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3.
  • Hägerström, Douglas, et al. (författare)
  • A new automated method for analysis of rCBF-SPECT images based on the active-shape algorithm: Normal values
  • 2012
  • Ingår i: Clinical Physiology and Functional Imaging. - 1475-0961 .- 1475-097X. ; 32, s. 114-119
  • Tidskriftsartikel (refereegranskat)abstract
    • Most nuclear medicine clinicians use only visual assessment when interpreting regional cerebral blood flow (rCBF) from single-photon emission computed tomography (SPECT) images in clinical practice. The aims of this study were to develop a new, easy to use, automated method for quantification of rCBF-SPECT and to create normal values by using the method on a normal population. We developed a 3-dimensional method based on a brain-shaped model and the active-shape algorithm. The method defines the surface shape of the brain and then projects the maximum counts 0-1·5cm deep for designated surface points. These surface projection values are divided into cortical regions representing the different lobes and presented relative to the whole cortex, cerebellum or cerebellar maximum.99mTc-hexa methyl propylene amine oxime (HMPAO) SPECT was performed on 30 healthy volunteers with a mean age of 74years (range 64-98). The ability of the active-shape algorithm to define the shape of the brain was satisfactory when visually scrutinized. The results of the quantification show rCBF values in the frontal, temporal and parietal lobes of 87-88% using cerebellum as the reference. There were no significant differences in normal rCBF values between male and female subjects and only a weak relation between rCBF and age. In conclusion, our new automated method was able to quantify rCBF-SPECT images and create normal values in ranges as expected. Further studies are needed to assess the clinical value of this method and the normal values. © 2011 The Authors. Clinical Physiology and Functional Imaging © 2011 Scandinavian Society of Clinical Physiology and Nuclear Medicine.
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4.
  • Stomrud, Erik, et al. (författare)
  • CSF biomarkers correlate with cerebral blood flow on SPECT in healthy elderly.
  • 2012
  • Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1421-9824 .- 1420-8008. ; 33:2-3, s. 156-63
  • Tidskriftsartikel (refereegranskat)abstract
    • The preclinical patterns of biological markers for Alzheimer's disease (AD) in vivo need further exploration. The aim of this study was therefore to investigate CSF biomarkers, regional cerebral blood flow (rCBF) and cognitive performance in cognitively healthy older individuals.
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5.
  • Ahmad, Shahzad, et al. (författare)
  • CDH6 and HAGH protein levels in plasma associate with Alzheimer’s disease in APOE ε4 carriers
  • 2020
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Many Alzheimer’s disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aβ) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (β = 0.638, P = 3.33 × 10−4) and HAGH (β = 0.481, P = 7.20 × 10−4), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10−3) and HAGH proteins (β = 0.506, P = 9.31 × 10−7) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10−3). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10−9). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.
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6.
  • Ahmadi, Khazar, et al. (författare)
  • Fixel-Based Analysis Reveals Tau-Related White Matter Changes in Early Stages of Alzheimer’s Disease
  • 2024
  • Ingår i: Journal of Neuroscience. - 0270-6474. ; 44:18
  • Tidskriftsartikel (refereegranskat)abstract
    • Several studies have shown white matter (WM) abnormalities in Alzheimer’s disease (AD) using diffusion tensor imaging (DTI). Nonetheless, robust characterization of WM changes has been challenging due to the methodological limitations of DTI. We applied fixel-based analyses (FBA) to examine microscopic differences in fiber density (FD) and macroscopic changes in fiber cross-section (FC) in early stages of AD (N = 393, 212 females). FBA was also compared with DTI, free-water corrected (FW)-DTI and diffusion kurtosis imaging (DKI). We further investigated the correlation of FBA and tensor-derived metrics with AD pathology and cognition. FBA metrics were decreased in the entire cingulum bundle, uncinate fasciculus and anterior thalamic radiations in Aβ-positive patients with mild cognitive impairment compared to control groups. Metrics derived from DKI, and FW-DTI showed similar alterations whereas WM degeneration detected by DTI was more widespread. Tau-PET uptake in medial temporal regions was only correlated with reduced FC mainly in the parahippocampal cingulum in Aβ-positive individuals. This tau-related WM alteration was also associated with impaired memory. Despite the spatially extensive between-group differences in DTI-metrics, the link between WM and tau aggregation was only revealed using FBA metrics implying high sensitivity but low specificity of DTI-based measures in identifying subtle tau-related WM degeneration. No relationship was found between amyloid load and any diffusion-MRI measures. Our results indicate that early tau-related WM alterations in AD are due to macrostructural changes specifically captured by FBA metrics. Thus, future studies assessing the effects of AD pathology in WM tracts should consider using FBA metrics.
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7.
  • Andersson, Emelie, et al. (författare)
  • Blood and cerebrospinal fluid neurofilament light differentially detect neurodegeneration in early Alzheimer's disease
  • 2020
  • Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 95, s. 143-153
  • Tidskriftsartikel (refereegranskat)abstract
    • Cerebrospinal fluid (CSF) neurofilament light (NfL) concentration has reproducibly been shown to reflect neurodegeneration in brain disorders, including Alzheimer's disease (AD). NfL concentration in blood correlates with the corresponding CSF levels, but few studies have directly compared the reliability of these 2 markers in sporadic AD. Herein, we measured plasma and CSF concentrations of NfL in 478 cognitively unimpaired (CU) subjects, 227 patients with mild cognitive impairment, and 113 patients with AD dementia. We found that the concentration of NfL in CSF, but not in plasma, was increased in response to Aβ pathology in CU subjects. Both CSF and plasma NfL concentrations were increased in patients with mild cognitive impairment and AD dementia. Furthermore, only NfL in CSF was associated with reduced white matter microstructure in CU subjects. Finally, in a transgenic mouse model of AD, CSF NfL increased before serum NfL in response to the development of Aβ pathology. In conclusion, NfL in CSF may be a more reliable biomarker of neurodegeneration than NfL in blood in preclinical sporadic AD.
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8.
  • Arvidsson, Ida, et al. (författare)
  • Comparing a pre-defined versus deep learning approach for extracting brain atrophy patterns to predict cognitive decline due to Alzheimer’s disease in patients with mild cognitive symptoms
  • 2024
  • Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 16:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Predicting future Alzheimer’s disease (AD)-related cognitive decline among individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) is an important task for healthcare. Structural brain imaging as measured by magnetic resonance imaging (MRI) could potentially contribute when making such predictions. It is unclear if the predictive performance of MRI can be improved using entire brain images in deep learning (DL) models compared to using pre-defined brain regions. Methods: A cohort of 332 individuals with SCD/MCI were included from the Swedish BioFINDER-1 study. The goal was to predict longitudinal SCD/MCI-to-AD dementia progression and change in Mini-Mental State Examination (MMSE) over four years. Four models were evaluated using different predictors: (1) clinical data only, including demographics, cognitive tests and APOE ε4 status, (2) clinical data plus hippocampal volume, (3) clinical data plus all regional MRI gray matter volumes (N = 68) extracted using FreeSurfer software, (4) a DL model trained using multi-task learning with MRI images, Jacobian determinant images and baseline cognition as input. A double cross-validation scheme, with five test folds and for each of those ten validation folds, was used. External evaluation was performed on part of the ADNI dataset, including 108 patients. Mann-Whitney U-test was used to determine statistically significant differences in performance, with p-values less than 0.05 considered significant. Results: In the BioFINDER cohort, 109 patients (33%) progressed to AD dementia. The performance of the clinical data model for prediction of progression to AD dementia was area under the curve (AUC) = 0.85 and four-year cognitive decline was R2 = 0.14. The performance was improved for both outcomes when adding hippocampal volume (AUC = 0.86, R2 = 0.16). Adding FreeSurfer brain regions improved prediction of four-year cognitive decline but not progression to AD (AUC = 0.83, R2 = 0.17), while the DL model worsened the performance for both outcomes (AUC = 0.84, R2 = 0.08). A sensitivity analysis showed that the Jacobian determinant image was more informative than the MRI image, but that performance was maximized when both were included. In the external evaluation cohort from ADNI, 23 patients (21%) progressed to AD dementia. The results for predicted progression to AD dementia were similar to the results for the BioFINDER test data, while the performance for the cognitive decline was deteriorated. Conclusions: The DL model did not significantly improve the prediction of clinical disease progression in AD, compared to regression models with a single pre-defined brain region.
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9.
  • Ashton, Nicholas J., et al. (författare)
  • A multicentre validation study of the diagnostic value of plasma neurofilament light
  • 2021
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-12
  • Tidskriftsartikel (refereegranskat)abstract
    • Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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10.
  • Ashton, Nicholas J., et al. (författare)
  • Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer's trial selection and disease monitoring.
  • 2022
  • Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 28:12, s. 2555-2562
  • Tidskriftsartikel (refereegranskat)abstract
    • Blood biomarkers indicative of Alzheimer's disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4-6years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer's Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.
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11.
  • Ayton, Scott, et al. (författare)
  • Acute phase markers in CSF reveal inflammatory changes in Alzheimer's disease that intersect with pathology, APOE ε4, sex and age
  • 2021
  • Ingår i: Progress in Neurobiology. - : Elsevier BV. - 0301-0082. ; 198
  • Tidskriftsartikel (refereegranskat)abstract
    • It is unknown how neuroinflammation may feature in the etiology of Alzheimer's disease (AD). We profiled acute phase response (APR) proteins (α1-antitrypsin, α1-antichymotrypsin, ceruloplasmin, complement C3, ferritin, α-fibrinogen, β-fibrinogen, γ-fibrinogen, haptoglobin, hemopexin) in CSF of 1291 subjects along the clinical and biomarker spectrum of AD to investigate the association between inflammatory changes, disease outcomes, and demographic variables. Subjects were stratified by Aβ42/t-tau as well as the following clinical diagnoses: cognitively normal (CN); subjective cognitive decline (SCD); mild cognitive impairment (MCI); and AD dementia. In separate multiple regressions (adjusting for diagnosis, age, sex, APOE-ε4) of each APR protein and a composite of all APR proteins, CSF Aβ42/t-tau status was associated with elevated ferritin, but not any other APR protein in CN and SCD subjects. Rather, the APR was elevated along with symptomatic progression (CN < SCD < MCI < AD), and this was elevation was mediated by CSF p-tau181. APOE ε4 status did not affect levels of any APR proteins in CSF, while these were elevated in males and with increased age. The performance of the APR in predicting clinical diagnosis was influenced by APOE ε4 status, sex, and age. These data provide new insight into inflammatory changes in AD and how this intersects with pathology changes and patient demographics.
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12.
  • Ayton, Scott, et al. (författare)
  • CSF ferritin in the clinicopathological progression of Alzheimer's disease and associations with APOE and inflammation biomarkers
  • 2023
  • Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 94:3, s. 211-219
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: A putative role for iron in driving Alzheimer's disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aβ42/t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Methods: Ferritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF samples from BioFINDER (n=1239; 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aβ42/t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort. Results: In both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%-40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-. Conclusions: CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.
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13.
  • Ayton, Scott, et al. (författare)
  • The Neuroinflammatory Acute Phase Response in Parkinsonian-Related Disorders
  • 2022
  • Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 37:5, s. 993-1003
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Neuroinflammation is implicated in the pathophysiology of Parkinson's disease (PD) and related conditions, yet prior clinical biomarker data report mixed findings. Objectives: The aim was to measure a panel of neuroinflammatory acute phase response (APR) proteins in the cerebrospinal fluid (CSF) of participants with PD and related disorders. Methods: Eleven APR proteins were measured in the CSF of 867 participants from the BioFINDER cohort who were healthy (612) or had a diagnosis of PD (155), multiple system atrophy (MSA) (26), progressive supranuclear palsy (PSP) (22), dementia with Lewy bodies (DLB) (23), or Parkinson’s disease with dementia (PDD) (29). Results: CSF APR proteins were mostly unchanged in PD, with only haptoglobin and α1-antitrypsin significantly elevated compared to controls. These proteins were variably increased in the other disorders. Certain protein components yielded unique signatures according to diagnosis: ferritin and transthyretin were selectively elevated in MSA and discriminated these patients from all others. Haptoglobin was selectively increased in PSP, discriminating this disease from MSA when used in combination with ferritin and transthyretin. This panel of proteins did not correlate well with severity of motor impairment in any disease category, but several (particularly ceruloplasmin and ferritin) were associated with memory performance (Mini-Mental State Examination) in patients with DLB and PDD. Conclusions: These findings provide new insights into inflammatory changes in PD and related disorders while also introducing biomarkers of potential clinical diagnostic utility.
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14.
  • Barthélemy, Nicolas R., et al. (författare)
  • CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease
  • 2023
  • Ingår i: Nature Aging. - : Springer Science and Business Media LLC. - 2662-8465. ; 3:4, s. 391-401
  • Tidskriftsartikel (refereegranskat)abstract
    • Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman’s ρ = 0.69) than Aβ42/Aβ40 (ρ = −0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD.
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15.
  • Barthélemy, Nicolas R, et al. (författare)
  • Highly Accurate Blood Test for Alzheimer's Disease Comparable or Superior to Clinical CSF Tests
  • Ingår i: Nature Medicine. - 1546-170X.
  • Tidskriftsartikel (refereegranskat)abstract
    • With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. We evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n=1,422) and the US Knight ADRC cohort (n=337). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aβ42/40 and p-tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology, respectively, using PET imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aβ PET status, with an area-under-the-curve (AUC) for both between 0.95-0.97. Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95-0.98. In cognitively impaired sub-cohorts (BioFINDER-2: n=720; Knight ADRC: n=50), plasma %p-tau217 had an accuracy, positive predictive value and negative predictive value of 89-90% for Aβ PET and 87-88% for tau-PET status, which was clinically equivalent to CSF tests, further improving to 95% using a two cut-off approach. Blood plasma %p-tau217 demonstrated performance clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments.
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16.
  • Baumeister, Hannah, et al. (författare)
  • A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings
  • Ingår i: Brain : a journal of neurology. - 1460-2156. ; 147:7, s. 2400-2413
  • Tidskriftsartikel (refereegranskat)abstract
    • Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.
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17.
  • Berron, David, et al. (författare)
  • Early stages of tau pathology and its associations with functional connectivity, atrophy and memory
  • 2021
  • Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2771-2783
  • Tidskriftsartikel (refereegranskat)abstract
    • In Alzheimer's disease, post-mortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with Brodmann area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior-medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance. We included 215 amyloid-β- cognitively unimpaired, 81 amyloid-β+ cognitively unimpaired and 87 amyloid-β+ individuals with mild cognitive impairment, who each underwent 18F-RO948 tau and 18F-flutemetamol amyloid PET imaging, structural T1-MRI and memory assessments as part of the Swedish BioFINDER-2 study. First, event-based modelling revealed that the entorhinal cortex and Brodmann area 35 show the earliest signs of tau accumulation followed by the anterior and posterior hippocampus, Brodmann area 36 and the parahippocampal cortex. In later stages, tau accumulation became abnormal in neocortical temporal and finally parietal brain regions. Second, in cognitively unimpaired individuals, increased tau load was related to local atrophy in the entorhinal cortex, Brodmann area 35 and the anterior hippocampus and tau load in several anterior medial temporal lobe subregions was associated with distant atrophy of the posterior hippocampus. Tau load, but not atrophy, in these regions was associated with lower memory performance. Further, tau-related reductions in functional connectivity in critical networks between the medial temporal lobe and regions in the posterior-medial system were associated with this early memory impairment. Finally, in patients with mild cognitive impairment, the association of tau load in the hippocampus with memory performance was partially mediated by posterior hippocampal atrophy. In summary, our findings highlight the progression of tau pathology across medial temporal lobe subregions and its disease stage-specific association with memory performance. While tau pathology might affect memory performance in cognitively unimpaired individuals via reduced functional connectivity in critical medial temporal lobe-cortical networks, memory impairment in mild cognitively impaired patients is associated with posterior hippocampal atrophy.
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18.
  • Berron, David, et al. (författare)
  • Hippocampal subregional thinning related to tau pathology in early stages of Alzheimer’s disease
  • 2022
  • Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Subregions in the medial temporal lobe (MTL) are affected early by Alzheimer’s disease (AD) pathology and subject to grey matter atrophy. Measuring the earliest AD-related atrophy in the hippocampus is challenging as region-of-interest (ROI) analyses of hippocampal subregional volumes collapse across voxels within anatomical subregions. PET imaging studies, however, report accumulation of tau pathology between anatomical subregions in the earliest disease stages (Berron et al., 2021) fitting reports from the neuropathological literature (Lace et al., 2019; Ravikumar et al., 2021). Thus, sensitive in vivo methods of point-wise structural measures are needed in order to detect the earliest hippocampal thinning in AD along the anterior-posterior as well as the medial-lateral hippocampal axis. Method: Here we analyzed data from 76 amyloid-beta negative (Ab-) cognitively normal (CN), 46 Ab+ CN individuals and 25 Ab+ patients with mild cognitive impairment (MCI) from the BioFINDER-2 study, who underwent 7 Tesla T2-weighted structural magnetic resonance imaging, tau positron emission tomography imaging (using 18F-RO-948) and cognitive assessments. First, we segmented hippocampal subfields and extrahippocampal subregions. Second, we calculated point-wise hippocampal thickness estimates (Diers et al.) of hippocampal subfields subiculum, cornu ammonis (CA)1, CA2 and CA3 on the level of the hippocampal body. Thirdly, we extracted local tau-PET SUVR from Area 35 (A35), entorhinal cortex and amygdala. Finally, we assessed relationships between hippocampal local thickness and tau accumulation as well as cognitive performance. Result: Our analyses revealed earliest hippocampal thinning associated with tau accumulation in an area spanning the boundary of subiculum and CA1 at the level of the anterior hippocampal body. Ab+ MCI patients showed more posterior thinning in comparison to Ab- CU participants. Median thickness in an ROI comprising vertices with A35 tau-related thinning (A35-TauThinning-ROI) was significantly lower in MCI Ab+ and tended to be lower in CU Ab+ compared to CU Ab-. Higher median thickness in the hippocampal A35-TauThinning-ROI, but not whole CA1 nor subiculum thickness, was associated with better 10-Word-Delayed-Recall and higher PACC scores. Conclusion: Our results suggest that tau-related thinning of hippocampal subregions can be observed already in early disease stages. Tau-related point-wise thickness measures were more sensitive compared to volumetric measures of anatomical subregions.
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19.
  • Binette, Alexa Pichet, et al. (författare)
  • Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer
  • 2022
  • Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Method: We included 327 participants from the Swedish BioFINDER-2 cohort with cerebrospinal fluid (CSF) p-tau217, Aβ-PET, longitudinal tau-PET, and longitudinal cognition. The main groups of interest were Aβ-positive non-demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p-tau217 and regional Aβ-PET were associated with tau-PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p-tau217 between Aβ-PET and tau-PET change. Second, we investigated how soluble p-tau217 and tau-PET change related to change in cognition, and mediation between these variables. Result: In early AD stages (non-demented participants), increased concentration of soluble p-tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau-PET rate of change), beyond the effect of regional Aβ-PET and baseline tau-PET (Figure 2A-C). Further, averaged across all regions, soluble p-tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p-tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p-tau levels have plateaued, soluble p-tau217 was not associated with accumulation of tau aggregates beyond baseline tau-PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p-tau217 (Figure 4B-C). Conclusion: Soluble p-tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD.
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20.
  • Blennow, Kaj, 1958, et al. (författare)
  • Predicting clinical decline and conversion to Alzheimer's disease or dementia using novel Elecsys Aβ(1-42), pTau and tTau CSF immunoassays.
  • 2019
  • Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • We evaluated the performance of CSF biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients with cognitive symptoms. CSF samples from patients in two multicentre longitudinal studies (ADNI, n=619; BioFINDER, n=431) were analysed. Aβ(1-42), tTau and pTau CSF concentrations were measured using Elecsys CSF immunoassays, and tTau/Aβ(1-42) and pTau/Aβ(1-42) ratios calculated. Patients were classified as biomarker (BM)-positive or BM-negative at baseline. Ability of biomarkers to predict risk of clinical decline and conversion to AD/dementia was assessed using pre-established cut-offs for Aβ(1-42) and ratios; tTau and pTau cut-offs were determined. BM-positive patients showed greater clinical decline than BM-negative patients, demonstrated by greater decreases in MMSE scores (all biomarkers: -2.10 to -0.70). Risk of conversion to AD/dementia was higher in BM-positive patients (HR: 1.67to11.48). Performance of Tau/Aβ(1-42) ratios was superior to single biomarkers, and consistent even when using cut-offs derived in a different cohort. Optimal pTau and tTau cut-offs were approximately 27pg/mL and 300pg/mL in both BioFINDER and ADNI. Elecsys pTau/Aβ(1-42) and tTau/Aβ(1-42) are robust biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients, and may support AD diagnosis in clinical practice.
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21.
  • Blennow, Kaj, 1958, et al. (författare)
  • Second-generation Elecsys cerebrospinal fluid immunoassays aid diagnosis of early Alzheimer's disease.
  • 2023
  • Ingår i: Clinical chemistry and laboratory medicine. - : Walter de Gruyter GmbH. - 1437-4331 .- 1434-6621. ; 61:2, s. 234-244
  • Tidskriftsartikel (refereegranskat)abstract
    • Timely diagnosis of Alzheimer's disease (AD) is critical for appropriate treatment/patient management. Cerebrospinal fluid (CSF) biomarker analysis is often used to aid diagnosis. We assessed analytical performance of second-generation (Gen II) Elecsys® CSF immunoassays (Roche Diagnostics International Ltd), and adjusted existing cut-offs, to evaluate their potential utility in clinical routine.Analytical performance was assessed using CSF samples measured with Elecsys CSF Gen II immunoassays on cobas e analyzers. Aβ42 Gen I/Gen II immunoassay method comparisons were performed (Passing-Bablok regression). Cut-off values were adjusted using estimated bias in biomarker levels between BioFINDER protocol aliquots/Gen I immunoassays and Gen II protocol aliquots/immunoassays. Distribution of Gen II immunoassay values was evaluated in AD, mild cognitive impairment (MCI), and cognitively normal cohorts; percentage observations outside the measuring range were derived.The Gen II immunoassays demonstrated good analytical performance, including repeatability, intermediate precision, lot-to-lot agreement (Pearson's r:≥0.999), and platform agreement (Pearson's r:≥0.995). Aβ42 Gen I/Gen II immunoassay measurements were strongly correlated (Pearson's r: 0.985-0.999). Aβ42 Gen II immunoassay cut-offs were adjusted to 1,030 and 800ng/L, and pTau181/Aβ42 ratio cut-offs to 0.023 and 0.029, for Gen II and I protocols, respectively. No observations were below the lower limit of the measuring range; above the upper limit, there were none from the AD cohort, and 2.6 and 6.8% from the MCI and cognitively normal cohorts, respectively.Our findings suggest that the Gen II immunoassays have potential utility in clinical routine to aid diagnosis of AD.
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22.
  • Boada, Mercè, et al. (författare)
  • Complementary pre-screening strategies to uncover hidden prodromal and mild Alzheimer's disease : Results from the MOPEAD project
  • 2022
  • Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:6, s. 1119-1127
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: The Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project was conceived to explore innovative complementary strategies to uncover hidden prodromal and mild Alzheimer's disease (AD) dementia cases and to raise awareness both in the general public and among health professionals about the importance of early diagnosis. Methods: Four different strategies or RUNs were used: (a) a web-based (WB) prescreening tool, (2) an open house initiative (OHI), (3) a primary care–based protocol for early detection of cognitive decline (PC), and (4) a tertiary care–based pre-screening at diabetologist clinics (DC). Results: A total of 1129 patients at high risk of having prodromal AD or dementia were identified of 2847 pre-screened individuals (39.7%). The corresponding proportion for the different initiatives were 36.8% (WB), 35.6% (OHI), 44.4% (PC), and 58.3% (DC). Conclusion: These four complementary pre-screening strategies were useful for identifying individuals at high risk of having prodromal or mild AD.
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23.
  • Borland, Emma, et al. (författare)
  • Clinically Relevant Changes for Cognitive Outcomes in Preclinical and Prodromal Cognitive Stages : Implications for Clinical Alzheimer Trials
  • 2022
  • Ingår i: Neurology. - 0028-3878. ; 99:11, s. 1142-1153
  • 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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24.
  • Borland, Emma, et al. (författare)
  • The age-related effect on cognitive performance in cognitively healthy elderly is mainly caused by underlying AD pathology or cerebrovascular lesions : implications for cutoffs regarding cognitive impairment
  • 2020
  • Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: As research in treatments for neurocognitive diseases progresses, there is an increasing need to identify cognitive decline in the earliest stages of disease for initiation of treatment in addition to determining the efficacy of treatment. For early identification, accurate cognitive tests cutoff values for cognitive impairment are essential. METHODS: We conducted a study on 297 cognitively healthy elderly people from the BioFINDER study and created subgroups excluding people with signs of underlying neuropathology, i.e., abnormal cerebrospinal fluid [CSF] β-amyloid or phosphorylated tau, CSF neurofilament light (neurodegeneration), or cerebrovascular pathology. We compared cognitive test results between groups and examined the age effect on cognitive test results. RESULTS: In our subcohort without any measurable pathology (n = 120), participants achieved better test scores and significantly stricter cutoffs for cognitive impairment for almost all the examined tests. The age effect in this subcohort disappeared for all cognitive tests, apart from some attention/executive tests, predominantly explained by the exclusion of cerebrovascular pathology. CONCLUSION: Our study illustrates a new approach to establish normative data that could be useful to identify earlier cognitive changes in preclinical dementias. Future studies need to investigate if there is a genuine effect of healthy aging on cognitive tests or if this age effect is a proxy for higher prevalence of preclinical neurodegenerative diseases.
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25.
  • Boström, Fredrik, et al. (författare)
  • CSF Mg and Ca as diagnostic markers for dementia with Lewy bodies.
  • 2008
  • Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 30:8, s. 1265-1271
  • Tidskriftsartikel (refereegranskat)abstract
    • Accumulating evidence implicates a role for altered metal homeostasis in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). However, few investigations have addressed this issue in dementia with Lewy bodies (DLB). The aim of the present study was to investigate metal concentrations in cerebrospinal fluid (CSF) and plasma from patients with DLB and other neurodegenerative disorders. To that end, CSF and plasma samples were collected from 29 patients with DLB, 174 patients with AD, 90 patients with AD with minor vascular components, and 51 healthy volunteers. Total concentrations of Mg, Ca, Mn, Fe, Cu, Zn, Rb, Sr, and Cs were determined using mass spectrometry. Patients with DLB had elevated Ca and Mg levels in CSF and Mg levels in plasma as compared to all other groups (p<0.001). Furthermore, a combination of CSF-Mg and CSF-Ca could distinguish DLB from AD with a sensitivity of 93% and a specificity of 85%. Cu levels in both CSF and plasma tended to be higher in DLB compared to the other groups, but these trends failed to reach significance after correction for multiple comparisons. Mn, Fe, Zn, Rb, and Sr concentration in CSF or plasma were similar in all groups. The observed elevations of CSF-Mg, CSF-Ca and CSF-Cu may contribute to or be associated with the neurodegenerative process in DLB. Furthermore, determination of CSF-Mg and CSF-Ca concentration may be a valuable tool in distinguishing DLB from AD.
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26.
  • Brum, Wagner S., et al. (författare)
  • A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases
  • 2023
  • Ingår i: Nature Aging. - 2662-8465. ; 3:9, s. 1079-1090
  • Tidskriftsartikel (refereegranskat)abstract
    • Cost-effective strategies for identifying amyloid-beta (A beta) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-A beta immunotherapies for Alzheimer's disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining A beta-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE epsilon 4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of A beta-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF A beta 42/A beta 40 testing, whereas step 1 alone determined A beta-status for low-and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting A beta-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings.
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27.
  • Buchhave, Peder, et al. (författare)
  • Cube copying test in combination with rCBF or CSF A beta(42) predicts development of Alzheimer's disease
  • 2008
  • Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 25:6, s. 544-552
  • Tidskriftsartikel (refereegranskat)abstract
    • <i>Background/Aim: </i>The aim was to identify subjects with incipient Alzheimer’s disease (AD) among patients with mild cognitive impairment (MCI) using brief cognitive tests. <i>Methods: </i>A total of 147 MCI patients were followed for 4–6 years and the incidence of AD was 11.6%/year. At baseline, the cube copying test, clock drawing test, MMSE and measurements of regional cerebral blood flow (rCBF) and cerebrospinal fluid (CSF) β-amyloid<sub>1–42</sub> (Aβ<sub>42</sub>) were performed. <i>Results: </i>The cube copying test, but not the clock drawing test, could predict AD among MCI patients with an area under the receiver operating characteristic curve of 0.64 (p < 0.01). The relative risk for future AD was increased in MCI subjects with impaired cube copying test (sex- and age-adjusted hazard ratio = 1.8, p < 0.05) and the incidence of AD was 18.2% in this subgroup. Combining the cube copying test with either rCBF or CSF Aβ<sub>42</sub> had additive effects on the risk assessment for future development of AD. MCI patients achieving high scores on both MMSE and cube copying test had a very low risk of developing AD (incidence of AD = 1.6%). <i>Conclusion: </i>In conclusion, combinations of the cube copying test with MMSE, rCBF and CSF Aβ<sub>42</sub> measurements can identify subgroups of MCI subjects with either substantially reduced or increased risk for future development of AD.
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28.
  • Buchhave, Peder, et al. (författare)
  • Longitudinal study of CSF biomarkers in patients with Alzheimer's disease.
  • 2009
  • Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 16:Suppl 3, s. 337-337
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The CSF biomarkers tau and Abeta42 can identify patients with AD, even during the preclinical stages. However, previous studies on longitudinal changes of tau and Abeta42 in individual patients with AD and elderly controls report somewhat inconsistent results. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the levels of tau and Abeta42 at baseline and after 1 year in 100 patients with AD. In a second cohort of 45 AD patients we measured the CSF biomarkers at baseline and after 2 years. Moreover, in 34 healthy elderly controls the CSF biomarkers were followed for 4 years. The baseline levels of tau were increased with >60% in AD patients compared to controls (p<0.001), while baseline Abeta42 levels were decreased with >50% (p<0.001). In the AD group followed for 2 years, tau increased with 16% compared to the baseline levels (p<0.05). However, the levels of tau were stable over 4 years in the controls. The levels of Abeta42 did not change significantly over time in any of the groups. In the patients with AD, tau was moderately associated with worse cognitive performance already at baseline (p<0.05). CONCLUSIONS/SIGNIFICANCE: Tau and Abeta42 in CSF seem to reflect the underlying disease state in both early and late stages of AD. The slight increase in tau over time observed in the patients with AD is modest when compared to the relatively large difference in absolute tau levels between AD patients and controls. Therefore, these markers maintain their usefulness as state markers over time and might serve as surrogate markers for treatment efficacy in clinical trials.
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29.
  • Cicognola, Claudia, et al. (författare)
  • Associations of CSF PDGFRβ With Aging, Blood-Brain Barrier Damage, Neuroinflammation, and Alzheimer Disease Pathologic Changes
  • 2023
  • Ingår i: Neurology. - 1526-632X. ; 101:1, s. 30-39
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND OBJECTIVES: Injured pericytes in the neurovascular unit release platelet-derived growth factor β (PDGFRβ) into the cerebrospinal fluid (CSF). However, it is not clear how pericyte injury contributes to Alzheimer's disease (AD)-related changes and blood brain barrier (BBB) damage. We aimed to test if CSF PDGFRβ was associated with different AD- and age-associated pathological changes leading to dementia.METHODS: PDGFRβ was measured in the CSF of 771 cognitively unimpaired (CU, n=408), mild cognitive impairment (MCI, n=175) and dementia subjects (n=188) from the Swedish BioFINDER-2 cohort. We then checked association Aβ-PET and tau-PET SUVR, APOE ε4 genotype and MRI measurements of cortical thickness, white matter lesions (WML) and cerebral blood flow (CBF). We also analysed the role of CSF PDGFRβ in the relationship between aging, BBB dysfunction (measured by CSF/plasma albumin ratio, QAlb) and neuroinflammation (i.e., CSF levels of YKL-40 and glial fibrillary acidic protein [GFAP], preferentially expressed in reactive astrocytes). RESULTS: The cohort had a mean age of 67 years (CU=62.8, MCI=69.9, dementia=70.4) and 50.1% were male (CU=46.6%, MCI=53.7%, dementia=54.3%). Higher CSF PDGFRβ concentrations were related to higher age (b=19.1, β=0.5, 95% CI=16-22.2, p<0.001), increased CSF neuroinflammatory markers of glial activation YKL-40 (b=3.4, β=0.5, 95% CI=2.8-3.9, p<0.001) and GFAP (b=27.4, β=0.4, 95% CI=20.9-33.9, p<0.001), and worse BBB integrity measured by QAlb (b=37.4, β=0.2, 95% CI=24.9-49.9, p<0.001). Age was also associated with worse BBB integrity, and this was partly mediated by PDGFRβ and neuroinflammatory markers (16-33% of total effect). However, PDGFRβ showed no associations with APOE ε4 genotype, PET imaging of Aβ and tau pathology or MRI measures of brain atrophy and white matter lesions (p>0.05).DISCUSSION: In summary, pericyte damage, reflected by CSF PDGFRβ, may be involved in age-related BBB disruption together with neuroinflammation, but is not related to Alzheimer-related pathological changes.
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30.
  • Coomans, Emma M., et al. (författare)
  • Interactions between vascular burden and amyloid-β pathology on trajectories of tau accumulation
  • 2024
  • Ingår i: Brain. - 0006-8950. ; 147:3, s. 949-960
  • Tidskriftsartikel (refereegranskat)abstract
    • Cerebrovascular pathology often co-exists with Alzheimer’s disease pathology and can contribute to Alzheimer’s disease-related clinical progression. However, the degree to which vascular burden contributes to Alzheimer’s disease pathological progression is still unclear. This study aimed to investigate interactions between vascular burden and amyloid-β pathology on both baseline tau tangle load and longitudinal tau accumulation. We included 1229 participants from the Swedish BioFINDER-2 Study, including cognitively unimpaired and impaired participants with and without biomarker-confirmed amyloid-β pathology. All underwent baseline tau-PET (18F-RO948), and a subset (n = 677) underwent longitudinal tau-PET after 2.5 ± 1.0 years. Tau-PET uptake was computed for a temporal meta-region-of-interest. We focused on four main vascular imaging features and risk factors: microbleeds; white matter lesion volume; stroke-related events (infarcts, lacunes and haemorrhages); and the Framingham Heart Study Cardiovascular Disease risk score. To validate our in vivo results, we examined 1610 autopsy cases from an Arizona-based neuropathology cohort on three main vascular pathological features: cerebral amyloid angiopathy; white matter rarefaction; and infarcts. For the in vivo cohort, primary analyses included age-, sex- and APOE ε4-corrected linear mixed models between tau-PET (outcome) and interactions between time, amyloid-β and each vascular feature (predictors). For the neuropathology cohort, age-, sex- and APOE ε4-corrected linear models between tau tangle density (outcome) and an interaction between plaque density and each vascular feature (predictors) were performed. In cognitively unimpaired individuals, we observed a significant interaction between microbleeds and amyloid-β pathology on greater baseline tau load (β = 0.68, P < 0.001) and longitudinal tau accumulation (β = 0.11, P < 0.001). For white matter lesion volume, we did not observe a significant independent interaction effect with amyloid-β on tau after accounting for microbleeds. In cognitively unimpaired individuals, we further found that stroke-related events showed a significant negative interaction with amyloid-β on longitudinal tau (β = −0.08, P < 0.001). In cognitively impaired individuals, there were no significant interaction effects between cerebrovascular and amyloid-β pathology at all. In the neuropathology dataset, the in vivo observed interaction effects between cerebral amyloid angiopathy and plaque density (β = 0.38, P < 0.001) and between infarcts and plaque density (β = −0.11, P = 0.005) on tau tangle density were replicated. To conclude, we demonstrated that cerebrovascular pathology—in the presence of amyloid-β pathology—modifies tau accumulation in early stages of Alzheimer’s disease. More specifically, the co-occurrence of microbleeds and amyloid-β pathology was associated with greater accumulation of tau aggregates during early disease stages. This opens the possibility that interventions targeting microbleeds may attenuate the rate of tau accumulation in Alzheimer’s disease.
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31.
  • Cullen, Nicholas, et al. (författare)
  • Association of CSF Aβ38Levels with Risk of Alzheimer Disease-Related Decline
  • 2022
  • Ingår i: Neurology. - 0028-3878. ; 98:9, s. 958-967
  • 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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32.
  • Cullen, Nicholas C., et al. (författare)
  • Accelerated inflammatory aging in Alzheimer’s disease and its relation to amyloid, tau, and cognition
  • 2021
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • It is unclear how pathological aging of the inflammatory system relates to Alzheimer’s disease (AD). We tested whether age-related inflammatory changes in cerebrospinal fluid (CSF) and plasma exist across different stages of AD, and whether such changes related to AD pathology. Linear regression was first used model chronological age in amyloid-β negative, cognitively unimpaired individuals (Aβ− CU; n = 312) based on a collection of 73 inflammatory proteins measured in both CSF and plasma. Fitted models were then applied on protein levels from Aβ+ individuals with mild cognitive impairment (Aβ+ MCI; n = 150) or Alzheimer’s disease dementia (Aβ+ AD; n = 139) to test whether the age predicted from proteins alone (“inflammatory age”) differed significantly from true chronological age. Aβ− individuals with subjective cognitive decline (Aβ− SCD; n = 125) or MCI (Aβ− MCI; n = 104) were used as an independent contrast group. The difference between inflammatory age and chronological age (InflammAGE score) was then assessed in relation to core AD biomarkers of amyloid, tau, and cognition. Both CSF and plasma inflammatory proteins were significantly associated with age in Aβ− CU individuals, with CSF-based proteins predicting chronological age better than plasma-based counterparts. Meanwhile, the Aβ− SCD and validation Aβ− CU groups were not characterized by significant inflammatory aging, while there was increased inflammatory aging in Aβ− MCI patients for CSF but not plasma inflammatory markers. Both CSF and plasma inflammatory changes were seen in the Aβ+ MCI and Aβ+ AD groups, with varying degrees of change compared to Aβ− CU and Aβ− SCD groups. Finally, CSF inflammatory changes were highly correlated with amyloid, tau, general neurodegeneration, and cognition, while plasma changes were mostly associated with amyloid and cognition. Inflammatory pathways change during aging and are specifically altered in AD, tracking closely with pathological hallmarks. These results have implications for tracking AD progression and for suggesting possible pathways for drug targeting.
  •  
33.
  • Cullen, Nicholas C., et al. (författare)
  • Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations
  • 2021
  • Ingår i: Nature Aging. - : Springer Science and Business Media LLC. - 2662-8465. ; 1, s. 114-123
  • Tidskriftsartikel (refereegranskat)abstract
    • We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI) using plasma biomarkers of β-amyloid (Aβ), tau and neurodegeneration. A total of 573 patients with MCI from the Swedish BioFINDER study and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included in the study. The primary outcomes were longitudinal cognition and conversion to Alzheimer’s disease (AD) dementia. A model combining tau phosphorylated at threonine 181 (P-tau181) and neurofilament light (NfL), but not Aβ42/Aβ40, had the best prognosis performance of all models (area under the curve = 0.88 for 4-year conversion to AD in BioFINDER, validated in ADNI), was stronger than a basic model of age, sex, education and baseline cognition, and performed similarly to cerebrospinal fluid biomarkers. A publicly available online tool for individualized prognosis in MCI based on our combined plasma biomarker models is introduced. Combination of plasma biomarkers may be of high value to identify individuals with MCI who will progress to AD dementia in clinical trials and in clinical practice.
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34.
  • Cullen, Nicholas C., et al. (författare)
  • Plasma amyloid-β42/40 and apolipoprotein E for amyloid PET pre-screening in secondary prevention trials of Alzheimer's disease
  • 2023
  • Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 5:2
  • Tidskriftsartikel (refereegranskat)abstract
    • The extent to which newly developed blood-based biomarkers could reduce screening costs in secondary prevention trials of Alzheimer's disease is mostly unexplored. We collected plasma amyloid-β42/40, apolipoprotein E ϵ4 status and amyloid PET at baseline in 181 cognitively unimpaired participants [the age of 72.9 (5.3) years; 61.9% female; education of 11.9 (3.4) years] from the Swedish BioFINDER-1 study. We tested whether a model predicting amyloid PET status from plasma amyloid-β42/40, apolipoprotein E status and age (combined) reduced cost of recruiting amyloid PET + cognitively unimpaired participants into a theoretical trial. We found that the percentage of cognitively unimpaired participants with an amyloid PET + scan rose from 29% in an unscreened population to 64% [(49, 79); P < 0.0001] when using the biomarker model to screen for high risk for amyloid PET + status. In simulations, plasma screening also resulted in a 54% reduction of the total number of amyloid PET scans required and reduced total recruitment costs by 43% [(31, 56), P < 0.001] compared to no pre-screening when assuming a 16× PET-to-plasma cost ratio. Total savings remained significant when the PET-to-plasma cost ratio was assumed to be 8× or 4×. This suggests that a simple plasma biomarker model could lower recruitment costs in Alzheimer's trials requiring amyloid PET positivity for inclusion.
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35.
  • Cullen, Nicholas C., et al. (författare)
  • Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations
  • 2021
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Plasma biomarkers of amyloid, tau, and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. We therefore tested if plasma measurements of amyloid-β (Aβ)42/40, phospho-tau217 (P-tau217), and neurofilament light (NfL) together predict clinical deterioration in 435 CU individuals followed for an average of 4.8 ± 1.7 years in the BioFINDER study. A combination of all three plasma biomarkers and basic demographics best predicted change in cognition (Pre-Alzheimer’s Clinical Composite; R2 = 0.14, 95% CI [0.12–0.17]; P < 0.0001) and subsequent AD dementia (AUC = 0.82, 95% CI [0.77–0.91], P < 0.0001). In a simulated clinical trial, a screening algorithm combining all three plasma biomarkers would reduce the required sample size by 70% (95% CI [54–81]; P < 0.001) with cognition as trial endpoint, and by 63% (95% CI [53–70], P < 0.001) with subsequent AD dementia as trial endpoint. Plasma ATN biomarkers show usefulness in cognitively unimpaired populations and could make large clinical trials more feasible and cost-effective.
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36.
  • Cullen, Nicholas C., et al. (författare)
  • Test-retest variability of plasma biomarkers in Alzheimer's disease and its effects on clinical prediction models
  • 2023
  • Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:3, s. 797-806
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION The effect of random error on the performance of blood-based biomarkers for Alzheimer's disease (AD) must be determined before clinical implementation. METHODS We measured test-retest variability of plasma amyloid beta (A beta)42/A beta 40, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau (p-tau)217 and simulated effects of this variability on biomarker performance when predicting either cerebrospinal fluid (CSF) A beta status or conversion to AD dementia in 399 non-demented participants with cognitive symptoms. RESULTS Clinical performance was highest when combining all biomarkers. Among single-biomarkers, p-tau217 performed best. Test-retest variability ranged from 4.1% (A beta 42/A beta 40) to 25% (GFAP). This variability reduced the performance of the biomarkers (approximate to Delta AUC [area under the curve] -1% to -4%) with the least effects on models with p-tau217. The percent of individuals with unstable predicted outcomes was lowest for the multi-biomarker combination (14%). DISCUSSION Clinical prediction models combining plasma biomarkers-particularly p-tau217-exhibit high performance and are less effected by random error. Individuals with unstable predicted outcomes ("gray zone") should be recommended for further tests.
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37.
  • Ferreira, Daniel, et al. (författare)
  • The interactive effect of demographic and clinical factors on hippocampal volume : A multicohort study on 1958 cognitively normal individuals
  • 2017
  • Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 27:6, s. 653-667
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer's disease is characterized by hippocampal atrophy. Other factors also influence the hippocampal volume, but their interactive effect has not been investigated before in cognitively healthy individuals. The aim of this study is to evaluate the interactive effect of key demographic and clinical factors on hippocampal volume, in contrast to previous studies frequently investigating these factors in a separate manner. Also, to investigate how comparable the control groups from ADNI, AIBL, and AddNeuroMed are with five population-based cohorts. In this study, 1958 participants were included (100 AddNeuroMed, 226 ADNI, 155 AIBL, 59 BRC, 295 GENIC, 279 BioFiNDER, 398 PIVUS, and 446 SNAC-K). ANOVA and random forest were used for testing between-cohort differences in demographic-clinical variables. Multiple regression was used to study the influence of demographic-clinical variables on hippocampal volume. ANCOVA was used to analyze whether between-cohort differences in demographic-clinical variables explained between-cohort differences in hippocampal volume. Age and global brain atrophy were the most important variables in explaining variability in hippocampal volume. These variables were not only important themselves but also in interaction with gender, education, MMSE, and total intracranial volume. AddNeuroMed, ADNI, and AIBL differed from the population-based cohorts in several demographic-clinical variables that had a significant effect on hippocampal volume. Variability in hippocampal volume in individuals with normal cognition is high. Differences that previously tended to be related to disease mechanisms could also be partly explained by demographic and clinical factors independent from the disease. Furthermore, cognitively normal individuals especially from ADNI and AIBL are not representative of the general population. These findings may have important implications for future research and clinical trials, translating imaging biomarkers to the general population, and validating current diagnostic criteria for Alzheimer's disease and predementia stages.
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38.
  • Gertje, Eske Christiane, et al. (författare)
  • Associations Between CSF Markers of Inflammation, White Matter Lesions, and Cognitive Decline in Individuals Without Dementia
  • 2023
  • Ingår i: Neurology. - 0028-3878. ; 100:17, s. 1812-1824
  • 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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39.
  • Glans, Isabelle, et al. (författare)
  • Association Between Dietary Habits in Midlife With Dementia Incidence Over a 20-Year Period
  • 2023
  • Ingår i: Neurology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0028-3878 .- 1526-632X. ; 100:1, s. E28-E37
  • 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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40.
  • Glans, Isabelle, et al. (författare)
  • Associations of modifiable and non-modifiable risk factors with cognitive functions – a prospective, population-based, 17 years follow-up study of 3,229 individuals
  • 2024
  • Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 16:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Although several cardiovascular, demographic, genetic and lifestyle factors have been associated with cognitive function, little is known about what type of cognitive impairment they are associated with. The aim was to examine the associations between different risk factors and future memory and attention/executive functions, and their interaction with APOE genotype. Methods: Participants from a large, prospective, population-based, Swedish study were included (n = 3,229). Linear regression models were used to examine baseline hypertension, body mass index (BMI), long-term glucose levels (HbA1c), different lipid levels, physical activity, alcohol consumption, smoking, education, APOE genotype, age and sex. All models were adjusted for follow-up time and basic demographics, and, in a second step, all significant predictors were included to examine independent effects. Follow-up outcomes were memory and attention/executive functions. Results: The mean age at baseline was 56.1 (SD 5.7) years and 59.7% were women. The mean follow-up time was 17.4 (range 14.3–20.8) years. When examining independent effects, APOE ε4 genotype(p < 0.01), and higher HbA1c(p < 0.001), were associated with future low memory function. Higher BMI (p < 0.05), and HbA1c(p < 0.05), lower high-density lipoprotein cholesterol (HDL-C)(p < 0.05)and stroke(p < 0.001) were associated with future low attention/executive function. The strongest factors associated with both better memory and attention/executive functions were higher education and alcohol consumption. Further, significant interaction effects between predictors and APOE genotype were found. For memory function, the protective effects of education were greater among ɛ4-carriers(p < 0.05). For attention/executive function, the protective effects of alcohol were greater among ɛ2 or ɛ4-carriers(p < 0.05). Also, attention/executive function was lower among ɛ4-carriers with higher BMI(p < 0.05) and ɛ2-carriers with higher HbA1c-levels(p < 0.05). Conclusions: Targeting cardiovascular risk factors in mid-life could have greater effect on future attention/executive functions rather than memory, whereas targeting diabetes could be beneficial for multiple cognitive domains. In addition, effects of different risk factors may vary depending on the APOE genotype. The varied cognitive profiles suggest that different mechanisms and brain regions are affected by the individual risk factors. Having detailed knowledge about the specific cognitive effects of different risk factors might be beneficial in preventive health counseling.
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41.
  • Groot, Colin, et al. (författare)
  • A biomarker profile of elevated CSF p-tau with normal tau PET is associated with increased tau accumulation rates on PET in early Alzheimer’s disease
  • 2022
  • Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Different tau biomarkers become abnormal at different stages of Alzheimer’s disease (AD), with CSF p-tau typically being elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we selected a group of amyloid-β-positive (A+) individuals with elevated CSF p-tau levels but negative tau-PET scans and assessed longitudinal changes in tau-PET, cortical thickness and cognitive decline. Method: Individuals without dementia (i.e., cognitively unimpaired (CU) or mild cognitive impairment, n=231) were selected from the BioFINDER-2 study. These subjects were categorized into biomarker groups based on Gaussian mixture modelling to determine cut-offs for abnormal CSF Aβ42/40 (A; <0.078), CSF p-tau217 (P; >110 pg/ml) and [18F]RO948 tau-PET SUVR within a temporal meta-ROI (T; SUVR >1.40). Resulting groups were: A+P-T- (concordant, n=30), A+P+T- (discordant, n=48) and A+P+T+ (concordant, n=18). We additionally used 135 A- CU individuals (A- CU) as a reference group (Tables 1 and 2). Differences in annual change in regional tau-PET SUVR, cortical thickness and cognition between the A+P+T- group and the other groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures) education. Result: Longitudinal change in tau-PET was faster in the A+P+T- group than in the A- CU and A+P-T- groups across medial temporal and neocortical regions, with the medial temporal increases being more pronounced. The A+P+T- group showed slower rate of increases in tau-PET compared to the A+P+T+ group, primarily in neocortical regions (Figures 1 and 2). We did not detect differences in yearly change in cortical thickness (Figure 3) or in cognitive decline (Figure 3) between the A+P+T- and A+P-T- groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups. Conclusion: These findings suggest that the A+P+T- biomarker profile is associated with early tau accumulation, and with relative sparing of cortical thinning and cognitive decline compared to A+P+T+ individuals. Therefore, the A+P+T- group represents an interesting target-group for early anti-tau interventions and for examining the emergence of tau aggregates in early AD.
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42.
  • Groot, Colin, et al. (författare)
  • Phospho-tau with subthreshold tau-PET predicts increased tau accumulation rates in amyloid-positive individuals
  • 2023
  • Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 146:4, s. 1580-1591
  • Tidskriftsartikel (refereegranskat)abstract
    • Different tau biomarkers become abnormal at different stages of Alzheimer's disease, with CSF phospho-tau typically becoming elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in Tau-PET, cortical thickness and cognitive decline in amyloid-β-positive (A+) individuals with elevated CSF P-tau levels (P+) but subthreshold Tau-PET retention (T-). To this end, individuals without dementia (i.e., cognitively unimpaired or mild cognitive impairment, N = 231) were selected from the BioFINDER-2 study. Amyloid-β-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF P-tau217 and [18F]RO948 (Tau) PET, yielding groups of tau-concordant-negative (A + P-T-; n = 30), tau-discordant (i.e., A + P+T-; n = 48) and tau-concordant-positive (A + P+T+; n = 18) individuals. In addition, 135 amyloid-β-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional Tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was ∼2 years. Longitudinal increase in Tau-PET was faster in the A + P+T- group than in the control and A + P-T- groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A + P+T- group showed a slower rate of increases in tau-PET compared to the A + P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A + P+T- and A + P-T- groups. The A + P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A + P+T- biomarker profile in persons without dementia is associated with an isolated effect on increased Tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring effects of interventions with disease modifying agents on tau accumulation in early Alzheimer's disease, and for examining the emergence of tau aggregates in Alzheimer's disease. Further, we suggest to update the AT(N) criteria for Alzheimer's disease biomarker classification to APT(N).
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43.
  • Gustavsson, Anders, et al. (författare)
  • Health utility in preclinical and prodromal Alzheimer's disease for establishing the value of new disease-modifying treatments—EQ-5D data from the Swedish BioFINDER study
  • 2021
  • Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:11, s. 1832-1842
  • Tidskriftsartikel (refereegranskat)abstract
    • Quality of life and health utility are important outcomes for patients with Alzheimer's disease (AD) and central for demonstrating the value of new treatments. Estimates in biomarker-confirmed AD populations are missing, potentially delaying payer approval of treatment. We examined whether health utility, assessed with the EuroQoL-5 3-level version (EQ-5D-3L), differed between individuals with a positive or negative amyloid beta (Aβ) biomarker in patients with mild cognitive impairment (MCI) and cognitively unimpaired (CU) participants from the Swedish BioFINDER study (n = 578). Participants with prodromal AD (Aβ-positive MCI) reported better health utility (n = 79, mean = 0.81, 95% confidence interval [CI] 0.77–0.85) than Aβ-negative MCI (mean = 0.71, 95% CI 0.64–0.78), but worse than controls (Aβ-negative CU, mean = 0.87, 95% CI 0.86–0.89). Health utility in preclinical AD (Aβ-positive CU; mean = 0.86, 95% CI 0.83–0.89) was similar to controls. This relatively good health utility in prodromal AD suggests a larger value of delaying progression to dementia than previously anticipated and a great value of delaying clinical progression in preclinical AD.
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44.
  • Gustavsson, Anna-Märta, et al. (författare)
  • Cerebral Microbleeds and White Matter Hyperintensities in Cognitively Healthy Elderly : A Cross-Sectional Cohort Study Evaluating the Effect of Arterial Stiffness
  • 2015
  • Ingår i: Central and Eastern European Migration Review. - : S. Karger. - 1664-5456 .- 2053-8871. ; 5:2, s. 41-51
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Arterial stiffness reflects the ageing processes in the vascular system, and studies have shown an association between reduced cognitive function and cerebral small vessel disease. Small vessel disease can be visualized as white matter hyperintensities (WMH) and lacunar infarcts but also as cerebral microbleeds on brain magnetic resonance imaging (MRI). We aimed to investigate if arterial stiffness influences the presence of microbleeds, WMH and cognitive function in a population of cognitively healthy elderly.METHODS: The study population is part of the Swedish BioFinder study and consisted of 208 individuals without any symptoms of cognitive impairment, who scored >27 points on the Mini-Mental State Examination. The participants (mean age, 72 years; 59% women) underwent MRI of the brain with visual rating of microbleeds and WMH. Arterial stiffness was measured with carotid-femoral pulse wave velocity (cfPWV). Eight cognitive tests covering different cognitive domains were performed.RESULTS: Microbleeds were detected in 12% and WMH in 31% of the participants. Mean (±standard deviation, SD) cfPWV was 10.0 (±2.0) m/s. There was no association between the presence of microbleeds and arterial stiffness. There was a positive association between arterial stiffness and WMH independent of age or sex (odds ratio, 1.58; 95% confidence interval, 1.04-2.40, p < 0.05), but the effect was attenuated when further adjustments for several cardiovascular risk factors were performed (p > 0.05). Cognitive performance was not associated with microbleeds, but individuals with WMH performed slightly worse than those without WMH on the Symbol Digit Modalities Test (mean ± SD, 35 ± 7.8 vs. 39 ± 8.1, p < 0.05). Linear regression revealed no direct associations between arterial stiffness and the results of the cognitive tests.CONCLUSIONS: Arterial stiffness was not associated with the presence of cerebral microbleeds or cognitive function in cognitively healthy elderly. However, arterial stiffness was related to the presence of WMH, but the association was attenuated when multiple adjustments were made. There was a weak negative association between WMH and performance in one specific test of attention. Longitudinal follow-up studies are needed to further assess the associations.
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45.
  • Gustavsson, Anna Märta, et al. (författare)
  • Midlife Atherosclerosis and Development of Alzheimer or Vascular Dementia
  • 2020
  • Ingår i: Annals of Neurology. - : John Wiley & Sons. - 0364-5134 .- 1531-8249. ; 87:1, s. 52-62
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To investigate whether midlife atherosclerosis is associated with different dementia subtypes and related underlying pathologies.METHODS: Participants comprised the cardiovascular cohort of the Swedish prospective population-based Malmö Diet and Cancer Study (N = 6,103). Carotid plaques and intima media thickness (IMT) were measured at baseline (1991-1994). Dementia incidence until 2014 was obtained from national registers. Diagnoses were reviewed and validated in medical records. In a cognitively unimpaired subcohort (n = 330), β-amyloid42 and tau were quantified in cerebrospinal fluid (CSF), and white matter hyperintensity volume, lacunar infarcts, and cerebral microbleeds were estimated on magnetic resonance imaging (2009-2015).RESULTS: During 20 years of follow-up, 462 individuals developed dementia (mean age at baseline = 57.5 ± 5.9 years, 58% women). Higher IMT in midlife was associated with an increased hazard ratio (HR) of all-cause dementia (adjusted HR = 1.14 [95% confidence interval (CI) = 1.03-1.26]) and vascular dementia (adjusted HR = 1.32 [95% CI = 1.10-1.57]) but not Alzheimer disease (AD) dementia (adjusted HR = 0.95 [95% CI = 0.77-1.17]). Carotid plaques were associated with vascular dementia when assessed as a 3-graded score (adjusted HR = 1.90 [95% CI = 1.07-3.38]). In the cognitively unimpaired subcohort (53.8 ± 4.6 years at baseline, 60% women), higher IMT in midlife was associated with development of small vessel disease (adjusted odds ratio [OR] = 1.47 [95% CI = 1.05-2.06]) but not significantly with abnormal CSF AD biomarkers (adjusted OR = 1.28 [95% CI = 0.87-1.90] for Aβ42 and 1.35 [95% CI = 0.86-2.13] for Aβ42 /p-tau). Carotid plaques revealed no significant association with any of the underlying brain pathologies.INTERPRETATION: Our findings support an association between midlife atherosclerosis and development of vascular dementia and cerebral small vessel disease but not between atherosclerosis and subsequent AD dementia or AD pathology. ANN NEUROL 2019.
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46.
  • Hahn, Andreas, et al. (författare)
  • Association Between Earliest Amyloid Uptake and Functional Connectivity in Cognitively Unimpaired Elderly
  • 2019
  • Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1460-2199 .- 1047-3211. ; 29, s. 2173-2182
  • Tidskriftsartikel (refereegranskat)abstract
    • Alterations in cognitive performance have been noted in nondemented subjects with elevated accumulation of amyloid-β (Aβ) fibrils. However, it is not yet understood whether brain function is already influenced by Aβ deposition during the very earliest stages of the disease. We therefore investigated associations between [18F]Flutemetamol PET, resting-state functional connectivity, gray and white matter structure and cognitive performance in 133 cognitively normal elderly that exhibited normal global Aβ PET levels. [18F]Flutemetamol uptake in regions known to accumulate Aβ fibrils early in preclinical AD (i.e., mainly certain parts of the default-mode network) was positively associated with dynamic but not static functional connectivity (r = 0.77). Dynamic functional connectivity was further related to better cognitive performance (r = 0.21-0.72). No significant associations were found for Aβ uptake with gray matter volume or white matter diffusivity. The findings demonstrate that the earliest accumulation of Aβ fibrils is associated with increased functional connectivity, which occurs before any structural alterations. The enhanced functional connectivity may reflect a compensatory mechanism to maintain high cognitive performance in the presence of increasing amyloid accumulation during the earliest phases of AD.
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47.
  • Hall, Sara, et al. (författare)
  • Plasma Phospho-Tau Identifies Alzheimer's Co-Pathology in Patients with Lewy Body Disease
  • 2021
  • Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:3, s. 767-771
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Alzheimer's disease co-pathology is common in dementia with Lewy bodies and Parkinson's disease with dementia (Lewy body disease) and can reliably be detected with positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers. Recently developed blood biomarkers are more accessible and less expensive alternatives. Objective: To investigate if plasma phospho-tau217 and phospho-tau181 can detect Alzheimer's pathology in Lewy body disease with dementia. Methods: In this cross-sectional study we investigated plasma phospho-tau217 and phospho-tau181 in 35 patients with Lewy body disease with dementia. Patients underwent tau-PET imaging (18F-RO948). Results: Plasma phospho-tau217 correlated with plasma phospho-tau181, CSF phospho-tau217 (rs = 0.68, P < 0.001), and negatively with CSF β-amyloid42/40 (rs = −0.52, P = 0.001). Plasma phospho-tau217 and phospho-tau181 correlated with tau-PET signal in the temporal cortex (rs > 0.56, P < 0.001) and predicted abnormal tau-PET status and β-amyloid status (area under the curve > 0.78 and > 0.81, respectively). Conclusion: Plasma phospho-tau might be a useful marker for Alzheimer's co-pathology in Lewy body disease with dementia.
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48.
  • Hansson, Oskar, et al. (författare)
  • CSF biomarkers of Alzheimer's disease concord with amyloid-β PET and predict clinical progression : A study of fully automated immunoassays in BioFINDER and ADNI cohorts
  • 2018
  • Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:11, s. 1470-1481
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: We studied whether fully automated Elecsys cerebrospinal fluid (CSF) immunoassay results were concordant with positron emission tomography (PET) and predicted clinical progression, even with cutoffs established in an independent cohort. Methods: Cutoffs for Elecsys amyloid-β1–42 (Aβ), total tau/Aβ(1–42), and phosphorylated tau/Aβ(1–42) were defined against [18F]flutemetamol PET in Swedish BioFINDER (n = 277) and validated against [18F]florbetapir PET in Alzheimer's Disease Neuroimaging Initiative (n = 646). Clinical progression in patients with mild cognitive impairment (n = 619) was studied. Results: CSF total tau/Aβ(1–42) and phosphorylated tau/Aβ(1–42) ratios were highly concordant with PET classification in BioFINDER (overall percent agreement: 90%; area under the curve: 94%). The CSF biomarker statuses established by predefined cutoffs were highly concordant with PET classification in Alzheimer's Disease Neuroimaging Initiative (overall percent agreement: 89%–90%; area under the curves: 96%) and predicted greater 2-year clinical decline in patients with mild cognitive impairment. Strikingly, tau/Aβ ratios were as accurate as semiquantitative PET image assessment in predicting visual read–based outcomes. Discussion: Elecsys CSF biomarker assays may provide reliable alternatives to PET in Alzheimer's disease diagnosis.
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49.
  • Hansson, Oskar, et al. (författare)
  • Evaluation of Plasma A beta as Predictor of Alzheimer's Disease in Older Individuals Without Dementia: A Population-Based Study
  • 2012
  • Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 28:1, s. 231-238
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyloid-beta (A beta) pathology is a major component in the mechanisms behind Alzheimer's disease (AD). Measurement of A beta(42) in cerebrospinal fluid predicts cognitive decline in patients with mild cognitive impairment and identifies AD in patients with dementia. However, studies on A beta in plasma are contradictory. In this prospective population-based study, plasma A beta(42) and A beta(40) were measured at baseline in 730 adults aged 70 years or older and without dementia. After five years, plasma levels were analyzed again and participants were assessed for development of dementia. During follow-up, 53 individuals (7%) developed dementia of which 37 (5%) were classified as AD. No difference in baseline plasma A beta(42), A beta(40), or A beta(42)/A beta(40) ratio levels were observed between converters to dementia or AD compared to the cognitively stable individuals. However, individuals with plasma A beta(40) levels above the median level for the group at baseline had an increased risk of developing dementia and AD during the follow-up, even after adjustment for age, gender, APOE genotype, and educational level (odds ratio = 2.2, 95% confidence interval = 1.0-4.7, p < 0.05). Neither plasma A beta(42) nor the A beta(42)/A beta(40) ratio influenced the risk of developing dementia or AD. Moreover, A beta(42) and A beta(40) levels increased over the 5 years, whereas the A beta(42)/A beta(40) ratio decreased (p < 0.001). In conclusion, this study suggests that measurement of plasma A beta should not be used clinically to predict dementia or AD. However, plasma A beta(40) may possibly be regarded as a moderate risk marker comparable to other risk markers for AD such as first-degree family history of dementia.
  •  
50.
  • Hansson, Oskar, et al. (författare)
  • Pre-analytical protocol for measuring Alzheimer's disease biomarkers in fresh CSF
  • 2020
  • Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: We aimed to establish a standardized, routine-use pre-analytical protocol for measuring Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF). Methods: The effect of pre-analytical factors (sample collection/handling/storage/transportation) on biomarker levels was assessed using freshly collected CSF. Tube type/sterilization was assessed using previously frozen samples. A low-bind false-bottom tube (FBT, Sarstedt) was used for all experiments, except tube types/sterilization experiments. Biomarkers were measured using Elecsys CSF assays. Results: Amyloid beta (Aβ)1-42 levels varied by tube type, using a low-bind FBT reduced variation. Aβ1-42 levels were higher with no mixing versus roller/inversion mixing. Aβ1-42 levels were lower with horizontal versus upright transportation; this was resolved by maximal tube filling and storage at 2°C to 8°C. Aβ1-40 levels were less strongly affected. Phospho-tau and total-tau levels were largely unaffected. Discussion: We propose an easy-to-use, standardized, routine-use pre-analytical protocol, using low-bind FBTs, for measuring AD CSF biomarkers in clinical practice.
  •  
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