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
Klaassens, B.L.; Gerven, J.M.A. van; Klaassen, E.S.; Grond, J. van der; Rombouts, S.A.R.B. 2019
Disruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness... Show moreDisruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness of these systems in AD we measured the effects of a single-dose of the selective serotonin reuptake inhibitor citalopram and acetylcholinesterase inhibitor galantamine in 12 patients with AD and 12 age-matched controls on functional brain connectivity with resting state functional magnetic resonance imaging. In this randomized, double blind, placebo-controlled crossover study, functional magnetic resonance images were repeatedly obtained before and after dosing, resulting in a dataset of 432 scans. Connectivity maps of ten functional networks were extracted using a dual regression method and drug vs. placebo effects were compared between groups with a multivariate analysis with signals coming from cerebrospinal fluid and white matter as covariates at the subject level, and baseline and heart rate measurements as confound regressors in the higher-level analysis (at p < 0.05, corrected). A galantamine induced difference between groups was observed for the cerebellar network. Connectivity within the cerebellar network and between this network and the thalamus decreased after galantamine vs. placebo in AD patients, but not in controls. For citalopram, voxelwise network connectivity did not show significant group x treatment interaction effects. However, we found default mode network connectivity with the precuneus and posterior cingulate cortex to be increased in AD patients, which could not be detected within the control group. Further, in contrast to the AD patients, control subjects showed a consistent reduction in mean connectivity with all networks after administration of citalopram. Since AD has previously been characterized by reduced connectivity between the default mode network and the precuneus and posterior cingulate cortex, the effects of citalopram on the default mode network suggest a restoring potential of selective serotonin reuptake inhibitors in AD. The results of this study also confirm a change in cerebellar connections in AD, which is possibly related to cholinergic decline. Show less
Klaassens, B.L.; Gerven, J.M.A. van; Klaassen, E.S.; Grond, J. van der; Rombouts, S.A.R.B. 2019
Dementie is een verwoestende ziekte waar wereldwijd miljoenen mensen aan leiden. De meest voorkomende oorzaak van dementie is de ziekte van Alzheimer. Voor het ontwikkelen van effectieve... Show moreDementie is een verwoestende ziekte waar wereldwijd miljoenen mensen aan leiden. De meest voorkomende oorzaak van dementie is de ziekte van Alzheimer. Voor het ontwikkelen van effectieve behandelingen is het belangrijk om dementie in een vroeg stadium te detecteren. Traditioneel alzheimeronderzoek is voornamelijk gericht op groepsverschillen tussen patiënten en controles. Recent onderzoek is deels verschoven naar individuele classificatie met machine learning. In dit proefschrift onderzoeken we het gebruik van magnetic resonance imaging (MRI) voor automatische detectie van de ziekte van Alzheimer, en vroege detectie van cognitieve achteruitgang. In dit proefschrift laten we zien dat het combineren van MRI modaliteiten de classificatie kan verbeteren. Ook laten we zien dat diffusie MRI een goede maat is om alzheimer te diagnosticeren. Bij toepassing van dezelfde methoden op een groep presymptomatische gendragers die amyloïdangiopathie zullen ontwikkelen vonden we geen verschillen tussen de gendragers en controles. Tevens waren we niet in staat om cognitieve achteruitgang na 4 jaar te voorspellen in een groep ouderen met verhoogd risico op achteruitgang. Met MRI kunnen betrouwbare individuele uitspraken gedaan kan worden over patiënten, maar het is met de huidige methoden niet gevoelig voor vroege detectie van cognitieve achteruitgang. Show less
Lee, S.J. van der; Conway, O.J.; Jansen, I.; Carrasquillo, M.M.; Kleineidam, L.; Akker, E. van den; ... ; GIFT Genetic Invest 2019
Self-perceived word-finding difficulties are common in aging individuals as well as in Alzheimer's Disease (AD). Language and speech deficits are difficult to objectify with neuropsychological... Show moreSelf-perceived word-finding difficulties are common in aging individuals as well as in Alzheimer's Disease (AD). Language and speech deficits are difficult to objectify with neuropsychological assessments. We therefore aimed to investigate whether amyloid, an early AD pathological hallmark, is associated with speech-derived semantic complexity. We included 63 individuals with subjective cognitive decline (age 64 ± 8, MMSE 29 ± 1), with amyloid status (positron emission tomography [PET] scans n = 59, or Aβ1-42 cerebrospinal fluid [CSF] n = 4). Spontaneous speech was recorded using three open-ended tasks (description of cookie theft picture, abstract painting and a regular Sunday), transcribed verbatim and subsequently, linguistic parameters were extracted using T-scan computational software, including specific words (content words, frequent, concrete and abstract nouns, and fillers), lexical complexity (lemma frequency, Type-Token-Ratio) and syntactic complexity (Developmental Level scale). Nineteen individuals (30%) had high levels of amyloid burden, and there were no differences between groups on conventional neuropsychological tests. Using multinomial regression with lin- guistic parameters (in tertiles), we found that high amyloid burden is associated with fewer concrete nouns (ORmiddle (95%CI): 7.6 (1.4–41.2), ORlowest: 6.7 (1.2–37.1)) and content words (ORlowest: 6.3 (1.0–38.1). In addition, we found an interaction for education between high amyloid burden and more abstract nouns. In conclusion, high amyloid burden was modestly associated with fewer specific words, but not with syntactic complexity, lexical complexity or conventional neuropsychological tests, suggesting that subtle spontaneous speech deficits might occur in preclinical AD. Show less
Gong, N.J.; Dibb, R.; Bulk, M.; Weerd, L. van der; Liu, C.L. 2019
The human social brain is complex. Current knowledge fails to define the neurobiological processes underlying social behaviour involving the (patho-) physiological mechanisms that link system-level... Show moreThe human social brain is complex. Current knowledge fails to define the neurobiological processes underlying social behaviour involving the (patho-) physiological mechanisms that link system-level phenomena to the multiple hierarchies of brain function. Unfortunately, such a high complexity may also be associated with a high susceptibility to several pathogenic interventions. Consistently, social deficits sometimes represent the first signs of a number of neuropsychiatric disorders including schizophrenia (SCZ), Alzheimer's disease (AD) and major depressive disorder (MDD) which leads to a progressive social dysfunction. In the present review we summarize present knowledge linking neurobiological substrates sustaining social functioning, social dysfunction and social withdrawal in major psychiatric disorders. Interestingly, AD, SCZ, and MDD affect the social brain in similar ways. Thus, social dysfunction and its most evident clinical expression (i.e., social withdrawal) may represent an innovative transdiagnostic domain, with the potential of being an independent entity in terms of biological roots, with the perspective of targeted interventions. Show less
Bilderbeck, A.C.; Penninx, B.W.J.H.; Arango, C.; Wee, N. van der; Kahn, R.; Winter-van Rossum, I.; ... ; Dawson, G.R. 2019
Trans-diagnostic, domain- or symptom-focused approaches have been heralded as advancing psychiatric research, but relatively few clinical research programmes have been undertaken to leverage their... Show moreTrans-diagnostic, domain- or symptom-focused approaches have been heralded as advancing psychiatric research, but relatively few clinical research programmes have been undertaken to leverage their potential. In this manuscript we describe the approach and protocol for an exploratory study, PRISM (Psychiatric Ratings using Intermediate Stratified Markers), that will be conducted to explore the biomarkers in schizophrenia (SZ) and Alzheimer's Disease (AD) that may be related to a common symptom, social withdrawal. Patient participants (N = 72 SZ and N = 72 AD study completers), will complete a series of fMRI, EEG, and behavioural paradigms, as well as contributing blood-derived (e.g. epigenetic) and smartphone data related to social behaviour. Self- as well as caregiver- and researcher-reported assessments will be provided to characterise social withdrawal. Normative data will also be collected from a group of healthy controls (N = 48 study completers), half of whom will be matched in terms of age and gender distribution to the SZ and AD group, respectively. Thus we will explore both differentiation and cross-diagnostic overlap in the biomarkers associated with different levels of social withdrawal in SZ and AD. In this way we aim to provide a deeper understanding of the biological underpinnings of symptomatology common to both disorders, and provide insights into novel treatment targets and future drug development approaches. Show less
Objectives: The predictive value of frailty and comorbidity, in addition to more readily available information, is not widely studied. We determined the incremental predictive value of frailty and... Show moreObjectives: The predictive value of frailty and comorbidity, in addition to more readily available information, is not widely studied. We determined the incremental predictive value of frailty and comorbidity for mortality and institutionalization across both short and long prediction periods in persons with dementia.Design: Longitudinal clinical cohort study with a follow-up of institutionalization and mortality occurrence across 7 years after baseline.Setting and Participants: 331 newly diagnosed dementia patients, originating from 3 Alzheimer centers (Amsterdam, Maastricht, and Nijmegen) in the Netherlands, contributed to the Clinical Course of Cognition and Comorbidity (4C) Study.Measures: We measured comorbidity burden using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) and constructed a Frailty Index (FI) based on 35 items. Time-to-death and time-to-institutionalization from dementia diagnosis onward were verified through linkage to the Dutch population registry.Results: After 7 years, 131 patients were institutionalized and 160 patients had died. Compared with a previously developed prediction model for survival in dementia, our Cox regression model showed a significant improvement in model concordance (U) after the addition of baseline CIRS-G or FI when examining mortality across 3 years (FI: U = 0.178, P = .005, CIRS-G: U = 0.180, P = .012), but not for mortality across 6 years (FI: U = 0.068, P = .176, CIRS-G: U = 0.084, P = .119). In a competing risk regression model for time-to-institutionalization, baseline CIRS-G and FI did not improve the prediction across any of the periods.Conclusions: Characteristics such as frailty and comorbidity change over time and therefore their predictive value is likely maximized in the short term. These results call for a shift in our approach to prognostic modeling for chronic diseases, focusing on yearly predictions rather than a single prediction across multiple years. Our findings underline the importance of considering possible fluctuations in predictors over time by performing regular longitudinal assessments in future studies as well as in clinical practice. (C) 2018 AMDA - The Society for Post-Acute and Long-Term Care Medicine. Show less
