Background Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma... Show moreBackground Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. Methods Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 +/- 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 +/- 7.9; 45% female), AD patients (n = 57; age = 65.5 +/- 8.0; 39% female), and non-demented controls (n = 148; 61.3 +/- 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 +/- 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 +/- 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 +/- 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. Results Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. Conclusions We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts. Show less
Vermunt, L.; Otte, M.; Verberk, I.M.W.; Killestein, J.; Lemstra, A.W.; Flier, W.M. van der; ... ; Teunissen, C.E. 2022
Interpretation of axonal damage biomarker Neurofilament Light chain (NfL) concentrations is difficult due to the lack of age-specific and disease-specific reference values. We here developed an... Show moreInterpretation of axonal damage biomarker Neurofilament Light chain (NfL) concentrations is difficult due to the lack of age-specific and disease-specific reference values. We here developed an interactive interface to support interpretation of NfL results in human body fluids. We used NfL values of 1698 individuals without a neurological disorder, aged 19-85 years, and patients with MS and dementias. Percentile regression estimates per diagnosis populate interactive graphs, alongside NfL background information (available on: https:// mybiomarkers.shinyapps.io/Neurofilament). This accessible interface provides reference for interpretation of the individual patient results for clinicians. It showcases an adaptable method to support interpretation of age-dependent biomarkers in neurology. Show less
Wubben, N.; Haaksma, M.; Ramakers, I.H.G.B.; Flier, W.M. van der; Verhey, F.R.J.; Rikkert, M.G.M.O.; Melis, R.J.F. 2022
Objectives: To explain the heterogeneity in dementia disease trajectory, we studied the influence of changing patient characteristics on disease course by comparing the association of dementia... Show moreObjectives: To explain the heterogeneity in dementia disease trajectory, we studied the influence of changing patient characteristics on disease course by comparing the association of dementia progression with baseline comorbidity and frailty, and with time-varying comorbidity and frailty.Methods: We used individual growth models to study baseline and time-varying associations in newly diagnosed dementia patients (n = 331) followed for 3 years. We measured cognition using the Mini-Mental State Examination (MMSE), daily functioning using the Disability Assessment for Dementia (DAD), frailty using the Fried criteria and comorbidity using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G).Results: Although baseline comorbidity and frailty were associated with decreased daily functioning at diagnosis, their effects clearly diminished over time. In contrast, when incorporating comorbidity and frailty as time-varying covariates, comorbidity was associated with lower daily functioning, and frailty with both lower cognition and daily functioning. Being frail was associated with a 0.9-point lower MMSE score (p = 0.03) and a 14.9-point lower DAD score (p < 0.01). A 1-point increase in CIRS-G score was associated with a 1.1-point lower DAD score (p < 0.01).Conclusions: Time-varying comorbidity and frailty were more consistently associated with dementia disease course than baseline comorbidity and frailty. Therefore, modeling only baseline predictors is insufficient for understanding the course of dementia in a changing patient context. Show less
Poos, J.M.; Ham, C.J.M. van der; Leeuwis, A.E.; Pijnenburg, Y.; Flier, W.M. van der; Postma, A. 2021
Background: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular... Show moreBackground: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function.Objective: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function.Methods: 160 outpatient clinic patients (68.8 +/- 8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker).Results: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p-values interaction terms > 0.05).Conclusion: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns. Show less
Amier, R.P.; Marcks, N.; Hooghiemstra, A.M.; Nijveldt, R.; Buchem, M.A. van; Roos, A. de; ... ; Heart-Brain Connection Consortium 2021
OBJECTIVES This study sought to investigate the extent of hypertensive exposure as assessed by cardiovascular magnetic resonance imaging (MRI) in relation to cerebral small vessel disease (CSVD)... Show moreOBJECTIVES This study sought to investigate the extent of hypertensive exposure as assessed by cardiovascular magnetic resonance imaging (MRI) in relation to cerebral small vessel disease (CSVD) and cognitive impairment, with the aim of understanding the role of hypertension in the early stages of deteriorating brain health.BACKGROUND Preserving brain health into advanced age is one of the great challenges of modern medicine. Hypertension is thought to induce vascular brain injury through exposure of the cerebral microcirculation to increased pressure/pulsatility. Cardiovascular MRI provides markers of (subclinical) hypertensive exposure, such as aortic stiffness by puke wave velocity (PWV), left ventricular (LV) mass index (LVMi), and concentricity by mass-to-volume ratio.METHODS A total of 559 participants from the Heart-Brain Connection Study (431 patients with manifest cardiovascular disease and 128 control participants), age 67.8 +/- 8.8 years, underwent 3.0-T heart-brain MRI and extensive neuropsychological testing. Aortic PWV, LVMi, and LV mass-to-volume ratio were evaluated in relation to presence of CSVD and cognitive impairment. Effect modification by patient group was investigated by interaction terms; results are reported pooled or stratified accordingly.RESULTS Aortic PWV (odds ratio [OR]: 1.17; 95% confidence interval [CI]: 1.05 to 1.30 in patient groups only), LVMi (in carotid occlusive disease, OR: 5.69; 95% CI: 1.63 to 19.87; in other groups, OR: 1.30; 95% CI: 1.05 to 1.62]) and LV mass-to-volume ratio (OR: 1.81; 95% CI: 1.46 to 2.24) were associated with CSVD. Aortic PWV (OR: 1.07; 95% CI: 1.02 to 1.13) and LV mass-to-volume ratio (OR: 1.27; 95% CI: 1.07 to 1.51) were also associated with cognitive impairment. Relations were independent of sociodemographic and cardiac index and mostly persisted after correction for systolic blood pressure or medical history of hypertension. Causal mediation analysis showed significant mediation by presence of CSVD in the relation between hypertensive exposure markers and cognitive impairment.CONCLUSIONS The extent of hypertensive exposure is associated with CSVD and cognitive impairment beyond clinical brood pressure or medical history. The mediating role of CSVD suggests that hypertension may lead to cognitive impairment through the occurrence of CSVD. (C) 2021 Published by Elsevier on behalf of the American College of Cardiology Foundation. Show less
Bron, E.E.; Klein, S.; Papma, J.M.; Jiskoot, L.C.; Venkatraghavan, V.; Linders, J.; ... ; Lugt, A. van der 2021
This work validates the generalizability of MRI-based classification of Alzheimer's disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD... Show moreThis work validates the generalizability of MRI-based classification of Alzheimer's disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI). We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive preprocessing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross validation in the Alzheimer's Disease Neuroimaging Initiative (ADNI; 334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non converters) and in the independent Health-RI Parelsnoer Neurodegenerative Diseases Biobank data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia. AD-CN classification based on modulated GM maps resulted in a similar area-under-the-curve (AUC) for SVM (0.940; 95%CI: 0.924-0.955) and CNN (0.933; 95%CI: 0.918-0.948). Application to conversion prediction in MCI yielded significantly higher performance for SVM (AUC = 0.756; 95%CI: 0.720-0.788) than for CNN (AUC = 0.742; 95%CI: 0.709-0.776) (p < 0.01 for McNemar's test). In external validation, performance was slightly decreased. For AD-CN, it again gave similar AUCs for SVM (0.896; 95%CI: 0.855-0.932) and CNN (0.876; 95%CI: 0.836-0.913). For prediction in MCI, performances decreased for both SVM (AUC = 0.665; 95%CI: 0.576-0.760) and CNN (AUC = 0.702; 95%CI: 0.624-0.786). Both with SVM and CNN, classification based on modulated GM maps significantly outperformed classification based on minimally processed images (p = 0.01). Deep and conventional classifiers performed equally well for AD classification and their performance decreased only slightly when applied to the external cohort. We expect that this work on external validation contributes towards translation of machine learning to clinical practice. Show less
Objectiv(e): To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms. Methods: Data from two large cohort studies, the Dutch Parelsnoer Institute -... Show moreObjectiv(e): To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms. Methods: Data from two large cohort studies, the Dutch Parelsnoer Institute - Neurodegenerative Diseases and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (N= 650), mild cognitive impairment (N = 887), and Alzheimer's disease dementia (N = 626). Cerebrospinal fluid (CSF) levels of A beta(42), t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses. Results: Alzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF A beta(42), higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF A beta(42) and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning. Conclusion: The association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning. Show less
Pool, R.; Hagenbeek, F.A.; Hendriks, A.M.; Dongen, J. van; Willemsen, G.; Geus, E. de; ... ; Duijn, C.M. van 2020
Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term 'metabolomics' refers to the comprehensive study of these molecules. The... Show moreMetabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term 'metabolomics' refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented. Show less
Pool, R.; Hagenbeek, F.A.; Hendriks, A.M.; Dongen, J. van; Willemsen, G.; Geus, E. de; ... ; BBMRI Metabol Consortium 2020
Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term 'metabolomics' refers to the comprehensive study of these molecules. The... Show moreMetabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term 'metabolomics' refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented. Show less
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... Show moreMany 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 (A beta) 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 (beta =0.638, P=3.33x10(-4)) and HAGH (beta =0.481, P=7.20x10(-4)), were significantly elevated in APOE epsilon 4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (beta =1.365, P=3.97x10(-3)) and HAGH proteins (beta =0.506, P=9.31x10(-7)) when comparing cases and controls in APOE epsilon 4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE epsilon 4 stratum (P<1x10(-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=1.92x10(-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. Show less
Hagenbeek, F.A.; Pool, R.; Dongen, J. van; Draisma, H.M.; Hottenga, J.J.; Willemsen, G.; ... ; Abdel Abdellaoui 2020
Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-019-13770-6, published online 7 January 2020.The original version of the Supplementary Information associated with this Article... Show moreCorrection to: Nature Communicationshttps://doi.org/10.1038/s41467-019-13770-6, published online 7 January 2020.The original version of the Supplementary Information associated with this Article included an incorrect Supplementary Data 1 file, in which additional delimiters were included in the first column for a number of rows, resulting in column shifts for some of these rows. The HTML has been updated to include a corrected version of Supplementary Data 1; the original incorrect version of Supplementary Data 1 can be found as Supplementary Information associated with this Correction. Show less
Background To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive... Show moreBackground To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI), we investigated whether a single dose of a monoaminergic drug (methylphenidate) improves executive functioning and whether a single dose of a cholinergic drug (galantamine) improves memory in VCI patients. Methods STREAM-VCI is a single-center, double-blind, three-way crossover trial. We included 30 VCI patients (Mini-Mental State Examination (MMSE) >= 16 and Clinical Dementia Rating score 0.5-1.0) with cerebrovascular pathology on MRI. All patients received single doses of methylphenidate (10 mg), galantamine (16 mg), and placebo in random order on three separate study visits. We used the NeuroCart (R), a computerized test battery, to assess drug-sensitive cognitive effects. Predefined main outcomes, measured directly after a single dose of a study drug, were (i) change in performance on the adaptive tracker for executive functioning and (ii) performance on the Visual Verbal Learning Test-15 (VVLT-15) for memory, compared to placebo. We performed mixed model analysis of variance. Results The study population had a mean age of 67 +/- 8 years and MMSE 26 +/- 3, and 9 (30%) were female. Methylphenidate improved performance on the adaptive tracker more than placebo (mean difference 1.40%; 95% confidence interval [CI] 0.56-2.25; p = 0.002). In addition, methylphenidate led to better memory performance on the VVLT-15 compared to placebo (mean difference in recalled words 0.59; 95% CI 0.03-1.15; p = 0.04). Galantamine did not improve performance on the adaptive tracker and led to worse performance on delayed recall of the VVLT-15 (mean difference - 0.84; 95% CI - 1.65, - 0.03; p = 0.04). Methylphenidate was well tolerated while galantamine produced gastrointestinal side effects in a considerable number of patients. Conclusions In this proof-of-principle study, methylphenidate is well tolerated and improves executive functioning and immediate recall in patients with VCI. Galantamine did not improve memory or executive dysfunction. Results might be influenced by the considerable amount of side effects seen. Show less
Hagenbeek, F.A.; Pool, R.; Dongen, J. van; Draisma, H.H.M.; Hottenga, J.J.; Willemsen, G.; ... ; BBMRI Metabolomics Consortium 2020
Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability... Show moreMetabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify > 800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h(total)(2)), and the proportion of heritability captured by known metabolite loci (h(Metabolite-hits)(2)) for 309 lipids and 52 organic acids. Our study reveals significant differences in h(Metabolite-hits)(2) among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation have higher h(Metabolite-hits)(2) estimates than phosphatidylcholines with low degrees of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes. Show less
Heinen, R.; Groeneveld, O.N.; Barkhof, F.; Bresser, J. de; Exalto, L.G.; Kuijf, H.J.; ... ; TRACE-VCI Study Grp 2020
IntroductionIt is unknown whether different types of small vessel disease (SVD), differentially relate to brain atrophy and if co-occurring Alzheimer's disease pathology affects this relation... Show moreIntroductionIt is unknown whether different types of small vessel disease (SVD), differentially relate to brain atrophy and if co-occurring Alzheimer's disease pathology affects this relation.MethodsIn 725 memory clinic patients with SVD (mean age 67 +/- 8 years, 48% female) we compared brain volumes of those with moderate/severe white matter hyperintensities (WMHs; n = 326), lacunes (n = 132) and cerebral microbleeds (n = 321) to a reference group with mild WMHs (n = 197), also considering cerebrospinal fluid (CSF) amyloid status in a subset of patients (n = 488).ResultsWMHs and lacunes, but not cerebral microbleeds, were associated with smaller gray matter (GM) volumes. In analyses stratified by CSF amyloid status, WMHs and lacunes were associated with smaller total brain and GM volumes only in amyloid-negative patients. SVD-related atrophy was most evident in frontal (cortical) GM, again predominantly in amyloid-negative patients.DiscussionAmyloid status modifies the differential relation between SVD lesion type and brain atrophy in memory clinic patients. Show less
Groeneveld, O.N.; Moneti, C.; Heinen, R.; Bresser, J. de; Kuijf, H.J.; Exalto, L.G.; ... ; TRACE-VCI Study Grp 2019
Background The development of novel diagnostics enables increasingly earlier diagnosis of Alzheimer's disease (AD). Timely diagnosis may benefit patients by reducing their uncertainty regarding the... Show moreBackground The development of novel diagnostics enables increasingly earlier diagnosis of Alzheimer's disease (AD). Timely diagnosis may benefit patients by reducing their uncertainty regarding the cause of symptoms, yet does not always provide patients with the desired certainty. Objective To examine, using both quantitative and qualitative methods, uncertainty communicated by memory clinic clinicians in post-diagnostic testing consultations with patients and their caregivers. Methods First, we identified all uncertainty expressions of 22 clinicians in audiotaped post-diagnostic testing consultations with 78 patients. Second, we statistically explored relationships between patient/clinician characteristics and uncertainty expressions. Third, the transcribed uncertainty expressions were qualitatively analysed, determining the topic to which they pertained, their source and initiator/elicitor (clinicians/patients/caregivers). Results Within 57/78 (73%) consultations, clinicians expressed in total 115 uncertainties, of which 37% elicited by the patient or caregiver. No apparent relationships were found between patient/clinician characteristics and whether or not, and how often clinicians expressed uncertainty. Uncertainty expressions pertained to ten different topics, most frequently patient's diagnosis and symptom progression. Expressed uncertainty was mostly related to the unpredictability of the future and limits to available knowledge. Discussion and conclusions The majority of clinicians openly discussed the limits of scientific knowledge and diagnostic testing with patients and caregivers in the dementia context. Noticeably, clinicians did not discuss uncertainty in about one quarter of consultations. More evidence is needed on the beneficial and/or harmful effects on patients of discussing uncertainty with them. This knowledge can be used to support clinicians to optimally convey uncertainty and facilitate patients' uncertainty management. Show less
