| 1. |
- Palmqvist, Sebastian, et al.
(author)
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Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease
- 2015
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In: Neurology. - : Lippincott Williams & Wilkins. - 1526-632X .- 0028-3878. ; 85:14, s. 1240-1249
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Journal article (peer-reviewed)abstract
- Objective:To compare the diagnostic accuracy of CSF biomarkers and amyloid PET for diagnosing early-stage Alzheimer disease (AD).Methods:From the prospective, longitudinal BioFINDER study, we included 122 healthy elderly and 34 patients with mild cognitive impairment who developed AD dementia within 3 years (MCI-AD). -Amyloid (A) deposition in 9 brain regions was examined with [F-18]-flutemetamol PET. CSF was analyzed with INNOTEST and EUROIMMUN ELISAs. The results were replicated in 146 controls and 64 patients with MCI-AD from the Alzheimer's Disease Neuroimaging Initiative study.Results:The best CSF measures for identifying MCI-AD were A42/total tau (t-tau) and A42/hyperphosphorylated tau (p-tau) (area under the curve [AUC] 0.93-0.94). The best PET measures performed similarly (AUC 0.92-0.93; anterior cingulate, posterior cingulate/precuneus, and global neocortical uptake). CSF A42/t-tau and A42/p-tau performed better than CSF A42 and A42/40 (AUC difference 0.03-0.12, p < 0.05). Using nonoptimized cutoffs, CSF A42/t-tau had the highest accuracy of all CSF/PET biomarkers (sensitivity 97%, specificity 83%). The combination of CSF and PET was not better than using either biomarker separately.Conclusions:Amyloid PET and CSF biomarkers can identify early AD with high accuracy. There were no differences between the best CSF and PET measures and no improvement when combining them. Regional PET measures were not better than assessing the global A deposition. The results were replicated in an independent cohort using another CSF assay and PET tracer. The choice between CSF and amyloid PET biomarkers for identifying early AD can be based on availability, costs, and doctor/patient preferences since both have equally high diagnostic accuracy.Classification of evidence:This study provides Class III evidence that amyloid PET and CSF biomarkers identify early-stage AD equally accurately.
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| 2. |
- Mattsson, Niklas, et al.
(author)
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18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease
- 2017
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In: EMBO Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 9, s. 1212-1223
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Journal article (peer-reviewed)abstract
- To elucidate the relationship between cerebrospinal fluid (CSF) total-tau (T-tau) and phosphorylated tau (P-tau) with the tau PET ligand 18F-AV-1451 in Alzheimer's disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T-tau and P-tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of 18F-AV-1451, and mainly in demented AD patients. 18F-AV-1451, but not CSF T-tau or P-tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal 18F-AV-1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though 18F-AV-1451 retention was always increased at this disease stage. We conclude that CSF T-tau and P-tau mainly behave as biomarkers of "disease state", since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, 18F-AV-1451 is a biomarker of "disease stage", since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.
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| 3. |
- Sandberg, Jacob, et al.
(author)
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Relating Experienced To Recalled breathlessness Observational (RETRO) study : A prospective study using a mobile phone application
- 2019
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In: BMJ Open Respiratory Research. - : BMJ Publishing Group. - 2052-4439. ; 6:1
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Journal article (peer-reviewed)abstract
- Background: Breathlessness, the subjective sensation of breathing discomfort, is common and appears in the daily life of people with cardiorespiratory diseases. Physicians often rely on patient's history based on symptom recall. The relation between recalled and experienced breathlessness is still poorly understood. This paper presents the protocol for a study primarily aimed at evaluating the relationship between experienced breathlessness and (1) recalled breathlessness and (2) predicted future breathlessness. Methods: A mobile phone application will be used to collect data during daily life. Medically stable participants, ≥18 years of age with mean daily breathlessness of Numerical Rating Scale (NRS) 3/10 and able to use a mobile phone with internet will rate their breathlessness intensity on a 0-10 NRS prompted the user several times daily for 1 week. Participants will recall their breathlessness each day and week. Multivariable random effects regression models will be used for statistical analyses. Results: Results of the study will be submitted for publication in peer-reviewed journals and presented at relevant conferences. Discussion: This protocol describes a study aimed at investigating previously unknown areas of the experience and recall of breathlessness using a new method of data collection. © 2019 Author(s).
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| 4. |
- Borland, Emma, et al.
(author)
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The Montreal Cognitive Assessment : Normative Data from a Large Swedish Population-Based Cohort
- 2017
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 59:3, s. 893-901
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Journal article (peer-reviewed)abstract
- Background: The Montreal Cognitive Assessment (MoCA) has a high sensitivity for detecting cognitive dysfunction. Swedish normative data does not exist and international norms are often derived from populations where cognitive impairment has not been screened for and not been thoroughly assessed to exclude subjects with dementia or mild cognitive impairment. Objective: To establish norms for MoCA and develop a regression-based norm calculator based on a large, well-examined cohort. Methods: MoCA was administered on 860 randomly selected elderly people from a population-based cohort from the EPIC study. Cognitive dysfunction was screened for and further assessed at a memory clinic. After excluding cognitively impaired participants, normative data was derived from 758 people, aged 65-85. Results: MoCA cut-offs (-1 to -2 standard deviations) for cognitive impairment ranged from <25 to <21 for the lowest educated and <26 to <24 for the highest educated, depending on age group. Significant predictors for MoCA score were age, sex and level of education. Conclusion: We present detailed normative MoCA data and cut-offs according to the DSM-5 criteria for cognitive impairment based on a large population-based cohort of elderly individuals, screened and thoroughly investigated to rule out cognitive impairment. Level of education, sex, and age should be taken in account when evaluating MoCA score, which is facilitated by our online regression-based calculator that provide percentile and z-score for a subject's MoCA score.
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| 5. |
- Petrazzuoli, Ferdinando, et al.
(author)
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Brief Cognitive Tests Used in Primary Care Cannot Accurately Differentiate Mild Cognitive Impairment from Subjective Cognitive Decline
- 2020
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 75:4, s. 1191-1201
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Journal article (peer-reviewed)abstract
- Background: Differentiating mild cognitive impairment (MCI) from subjective cognitive decline (SCD) is important because of the higher progression rate to dementia for MCI and when considering future disease-modifying drugs that will have treatment indications at the MCI stage. Objective: We examined if the two most widely-used cognitive tests, the Mini-Mental State Examination (MMSE) and clock-drawing test (CDT), and a test of attention/executive function (AQT) accurately can differentiate MCI from SCD. Methods: We included 466 consecutively recruited non-demented patients with cognitive complaints from the BioFINDER study who had been referred to memory clinics, predominantly from primary care. They were classified as MCI (n = 258) or SCD (n = 208) after thorough neuropsychological assessments. The accuracy of MMSE, CDT, and AQT for identifying MCI was examined both in training and validation samples and in the whole population. Results: As a single test, MMSE had the highest accuracy (sensitivity 73%, specificity 60%). The best combination of two tests was MMSE < 27 points or AQT > 91 seconds (sensitivity 56%, specificity 78%), but in logistic regression models, their AUC (0.76) was not significantly better than MMSE alone (AUC 0.75). CDT and AQT performed significantly worse (AUC 0.71; p < 0.001-0.05); otherwise no differences were seen between any combination of two or three tests. Conclusion: Neither single nor combinations of tests could differentiate MCI from SCD with adequately high accuracy. There is a great need to further develop, validate, and implement accurate screening-tests for primary care to improve accurate identification of MCI among individuals that seek medical care due to cognitive symptoms.
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| 6. |
- Wuestefeld, Anika, et al.
(author)
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Age-related and amyloid-beta-independent tau deposition and its downstream effects
- 2023
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In: Brain : a journal of neurology. - 1460-2156. ; 146:8, s. 3192-3205
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Journal article (peer-reviewed)abstract
- Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology.
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| 7. |
- Ashton, Nicholas J., et al.
(author)
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A multicentre validation study of the diagnostic value of plasma neurofilament light
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-12
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Journal article (peer-reviewed)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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| 8. |
- Petrazzuoli, Ferdinando, et al.
(author)
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Unburdening dementia a basic social process grounded theory - based on a primary care physician survey from 25 countries
- 2020
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In: Scandinavian Journal of Primary Health Care. - : Taylor & Francis Group. - 0281-3432 .- 1502-7724. ; 38:3, s. 253-264
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Journal article (peer-reviewed)abstract
- Objective To explore dementia management from a primary care physician perspective. Design One-page seven-item multiple choice questionnaire; free text space for every item; final narrative question of a dementia case story. Inductive explorative grounded theory analysis. Derived results in cluster analyses. Appropriateness of dementia drugs assessed by tertiary care specialist. Setting Twenty-five European General Practice Research Network member countries. Subjects Four hundred and forty-five key informant primary care physician respondents of which 106 presented 155 case stories. Main outcome measures Processes and typologies of dementia management. Proportion of case stories with drug treatment and treatment according to guidelines. Results Unburdeningdementia - a basic social process - explained physicians' dementia management according to a grounded theory analysis using both qualitative and quantitative data. Unburdening starts withRecognizingthe dementia burden byBurden IdentificationandBurden Assessmentfollowed byBurden Relief. Drugs to relieve the dementia burden were reported for 130 of 155 patients; acetylcholinesterase inhibitors or memantine treatment in 89 of 155 patients - 60% appropriate according to guidelines and 40% outside of guidelines. More Central and Northern primary care physicians were allowed to prescribe, and more were engaged in dementia management than Eastern and Mediterranean physicians according to cluster analyses. Physicians typically identified and assessed the dementia burden and then tried to relieve it, commonly by drug prescriptions, but also by community health and home help services, mentioned in more than half of the case stories. Conclusions Primary care physician dementia management was explained by anUnburdeningprocess with the goal to relieve the dementia burden, mainly by drugs often prescribed outside of guideline indications. Implications:Unique data about dementia management by European primary care physicians to inform appropriate stakeholders.
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| 9. |
- Petrazzuoli, Ferdinando, et al.
(author)
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A Quick Test of Cognitive Speed : norm-referenced criteria for 121 Italian adults aged 45 to 90 years
- 2014
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In: International psychogeriatrics. - : Cambridge University Press. - 1041-6102 .- 1741-203X. ; 26:9, s. 1493-1500
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Journal article (peer-reviewed)abstract
- Background: A Quick Test of Cognitive Speed (AQT) is a brief test that can identify cognitive impairment. AQT has been validated in Arabic, English, Greek, Japanese, Norwegian, Spanish, and Swedish. The aim of this study was to develop Italian criterion-referenced norms for AQT. Methods: AQT consists of three test plates where the patient shall rapidly name (1) the color of 40 blue, red, yellow, or black squares (AQT color), (2) the form of 40 black figures (circles, squares, triangles, or rectangles; AQT form), (3) the color and form of 40 figures (consisting of previous colors and forms; AQT color-form). The AQT test was administered to 121 Italian cognitively healthy primary care patients (age range: 45-90 years). Their mean Mini-Mental State Examination (MMSE) score was 28.8 +/- 0.9 points (range 26-30 points). AQT naming times in seconds were used for developing preliminary criterion cut-off times for different age groups. Results: Age was found to have a significant moderate positive correlation with AQT naming times color (r = 0.65, p < 0.001), form (r = 0.53, p < 0.001), color-form (r = 0.63, p < 0.001) and a moderate negative correlation with MMSE score (r = -0.44, p < 0.001) and AQT naming times differed significantly between younger (45-55 years old), older (56-70 years old), and the oldest (71-90 years old) participants. Years of education correlated positively but weakly with MMSE score (r = 0.27, p = 0.003) and negatively but weakly with AQT color (r = -0.16, p = ns), form (r = -0.24, p = 0.007), and color-form (r = -0.19, p = 0.005). We established preliminary cut-off times for the AQT test based on +1 and +2 standard deviations according to the approach in other languages and settings. Conclusions: This is the first Italian normative AQT study. Future studies of AQT - a test useful for dementia screening in primary care - will eventually refine cut-off times for normality balancing sensitivity and specificity in cognitive diagnostics.
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| 10. |
- Ahmadi, Khazar, et al.
(author)
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Gray matter hypoperfusion is a late pathological event in the course of Alzheimer's disease
- 2023
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In: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - 1559-7016. ; 43:4, s. 565-580
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Journal article (peer-reviewed)abstract
- Several studies have shown decreased cerebral blood flow (CBF) in Alzheimer's disease (AD). However, the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, PET, and CSF biomarkers, we investigated the associations between gray matter (GM)-CBF and the key mechanisms in AD including amyloid-β (Aβ) and tau pathology, synaptic and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in temporo-occipito-parietal cortex in the Aβ-positive cognitively impaired compared to both Aβ-negative and Aβ-positive cognitively unimpaired individuals. In participants along the AD spectrum, GM-CBF was associated with tau, synaptic and axonal dysfunction, but not Aβ in similar cortical regions. Axonal degeneration was further associated with hypoperfusion in cognitively unimpaired individuals. Disease progression modeling revealed that GM-CBF disruption Followed the abnormality of biomarkers of Aβ, tau and brain atrophy. These findings indicate that tau tangles and neurodegeneration are more closely connected with GM-CBF changes than Aβ pathology. Although subjected to the sensitivity of the employed neuroimaging techniques and the modeling approach, these findings suggest that hypoperfusion might not be an early event associated with the build-up of Aβ in preclinical phase of AD.
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