| 1. |
- Coenen, Mirthe, et al.
(författare)
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Spatial distributions of white matter hyperintensities on brain MRI: A pooled analysis of individual participant data from 11 memory clinic cohorts
- 2023
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Ingår i: NeuroImage. Clinical. - 2213-1582. ; 40
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. METHODS: Individual participant data (N=3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. RESULTS: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. DISCUSSION: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.
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| 2. |
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| 3. |
- Eikelboom, Willem S., et al.
(författare)
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Biweekly fluctuations of neuropsychiatric symptoms according to the Neuropsychiatric Inventory : Erratic symptoms or scores?
- 2022
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Ingår i: International Journal of Geriatric Psychiatry. - : Wiley. - 0885-6230 .- 1099-1166. ; 37:7
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: This study investigates the stability of neuropsychiatric symptoms (NPS) assessed biweekly using the Neuropsychiatric Inventory (NPI) in a memory clinic population during a 6 week period. Methods: Twenty-three spousal caregivers (mean [SD] age = 69.7 [8.8], 82.6% female) of 23 patients (43.5% had dementia) completed all assessments. The NPI was assessed four times during 6 weeks. We examined whether NPI domains were present during all four assessments, studied within-person variation for each NPI domain, and calculated Spearman's correlations between subsequent time-points. Furthermore, we associated repeated NPI assessments with repeated measures of caregiver burden to examine the clinical impact of changes in NPI scores over time. Results: The course of NPS was highly irregular according to the NPI, with only 35.8% of the NPI domains that were present at baseline persisted during all 6 weeks. We observed large within-person variation in the presence of individual NPI domains (61.3%, range 37.5%–83.9%) and inconsistent correlations between NPI assessments (e.g., range rs = 0.20–0.57 for agitation, range rs = 0.29–0.59 for anxiety). Higher NPI total scores were related to higher caregiver burden (rs = 0.60, p < 0.001), but changes in NPI total scores were unrelated to changes in caregiver burden (rs = 0.16, p = 0.20). Conclusions: We observed strong fluctuations in NPI scores within very short time windows raising the question whether this represents erratic symptoms and/or scores. Further studies are needed to investigate the origins of these fluctuations.
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| 4. |
- Eikelboom, Willem S., et al.
(författare)
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Early recognition and treatment of neuropsychiatric symptoms to improve quality of life in early Alzheimer's disease : Protocol of the BEAT-IT study
- 2019
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuropsychiatric symptoms (NPS) are very common in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and are associated with various disadvantageous clinical outcomes including a negative impact on quality of life, caregiver burden, and accelerated disease progression. Despite growing evidence of the efficacy of (non)pharmacological interventions to reduce these symptoms, NPS remain underrecognized and undertreated in memory clinics. The BEhavioural symptoms in Alzheimer's disease Towards early Identification and Treatment (BEAT-IT) study is developed to (1) investigate the neurobiological etiology of NPS in AD and (2) study the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) approach to structure and standardize the current care of NPS in AD. By means of the DICE method, we aim to improve the quality of life of AD patients with NPS and their caregivers who visit the memory clinic. This paper describes the protocol for the intervention study that incorporates the latter aim. Methods: We aim to enroll a total of 150 community-dwelling patients with MCI or AD and their caregivers in two waves. First, we will recruit a control group who will receive care as usual. Next, the second wave of participants will undergo the DICE method. This approach consists of the following steps: (1) describe the context in which NPS occur, (2) investigate the possible causes, (3) create and implement a treatment plan, and (4) evaluate whether these interventions are effective. Primary outcomes are the quality of life of patients and their caregivers. Secondary outcomes include NPS change, caregiver burden, caregivers' confidence managing NPS, psychotropic medication use, the experiences of patients and caregivers who underwent the DICE method, and the cost-effectiveness of the intervention. Conclusions: This paper describes the protocol of an intervention study that is part of the BEAT-IT study and aims to improve current recognition and treatment of NPS in AD by structuring and standardizing the detection and treatment of NPS in AD using the DICE approach. Trial registration: The trial was registered on the Netherlands Trial Registry (NTR7459); registered 6 September 2018.
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| 5. |
- Eikelboom, Willem S., et al.
(författare)
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Effects of the DICE Method to Improve Timely Recognition and Treatment of Neuropsychiatric Symptoms in Early Alzheimer's Disease at the Memory Clinic : The BEAT-IT Study
- 2023
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 93:4, s. 1407-1423
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD) and are associated with negative outcomes. However, NPS are currently underrecognized at the memory clinic and non-pharmacological interventions are scarcely implemented. Objective: To evaluate the effectiveness of the Describe, Investigate, Create, Evaluate (DICE) method™ to improve the care for NPS in AD at the memory clinic. Methods: We enrolled sixty community-dwelling people with mild cognitive impairment or AD dementia and NPS across six Dutch memory clinics with their caregivers. The first wave underwent care as usual (n = 36) and the second wave underwent the DICE method (n = 24). Outcomes were quality of life (QoL), caregiver burden, NPS severity, NPS-related distress, competence managing NPS, and psychotropic drug use. Reliable change index was calculated to identify responders to the intervention. A cost-effectiveness analysis was performed and semi-structured interviews with a subsample of the intervention group (n = 12). Results: The DICE method did not improve any outcomes over time compared to care as usual. Half of the participants of the intervention group (52%) were identified as responders and showed more NPS and NPS-related distress at baseline compared to non-responders. Interviews revealed substantial heterogeneity among participants regarding NPS-related distress, caregiver burden, and availability of social support. The intervention did not lead to significant gains in quality-adjusted life years and well-being years nor clear savings in health care and societal costs. Conclusion: The DICE method showed no benefits at group-level, but individuals with high levels of NPS and NPS-related distress may benefit from this intervention.
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| 6. |
- Eikelboom, Willem S., et al.
(författare)
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Evaluating the DICE method to improve early recognition and treatment of neuropsychiatric symptoms in early Alzheimer’s disease
- 2022
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S8
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Tidskriftsartikel (refereegranskat)abstract
- Background: While neuropsychiatric symptoms (NPS) are common in early Alzheimer’s disease (AD), they are currently underdiagnosed and undertreated in the memory clinic. Therefore, we evaluated the effectiveness of the Describe, Investigate, Create, Evaluate (DICE™) approach to structure and standardize the care for NPS in AD in the memory clinic. Method: A total of 60 community-dwelling patients with MCI, AD dementia, or AD/VaD dementia were enrolled with their caregivers in two waves (Table-1). The first wave (n = 36) received care as usual and served as a control group, while the second wave of patients (n = 24, of which n = 20 have currently completed the study) underwent the DICE method. We applied the DICE method during two visits in which NPS were assessed, underlying causes were examined, and patients and caregivers were instructed on management strategies to deal with NPS, which were evaluated after one month. Outcomes were assessed after three and six months. Primary outcomes were quality of life of patients (QoL-AD) and caregivers (Carerqol-7D). Secondary outcomes included caregiver burden (Perseverance time), NPS prevalence and severity (NPI-Q & BEHAVE-AD), NPS-related distress (NPI-Q), competence managing NPS (additional NPI-Q item), and psychotropic drug use. We used linear mixed models to examine differences in outcomes at group-level and reliable change index to examine which participants in the intervention group showed reliable improvement in the primary outcomes. Result: We found no significant differences between the two groups in change in quality of life or any of the secondary outcomes (all p>0.05, Table-2). A proportion of the intervention group showed reliable improvement in quality of life of patients (n = 6/20) and caregivers (n = 7/20). At baseline, these patients tended to show higher NPS burden and their caregivers reported more NPS-related distress and lower feelings of competence while managing NPS compared to participants that did no show reliable improvement. Conclusion: This Stage 2 efficacy study shows no benefits of the DICE method on in early AD at group-level, but suggest that particular participants might benefit from this approach. Data will be re-analyzed when all intervention group participants have completed the study and will be extended with qualitative data investigating NPS-related knowledge and management styles of participants.
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| 7. |
- Eikelboom, Willem S., et al.
(författare)
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Neuropsychiatric and Cognitive Symptoms Across the Alzheimer Disease Clinical Spectrum: Cross-sectional and Longitudinal Associations
- 2021
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Ingår i: Neurology. - 1526-632X. ; 97:13, s. 1276-1287
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: To investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of β-amyloid-positive (A+) individuals across the Alzheimer disease (AD) clinical spectrum. METHODS: In this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia and were A+. We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across 5 cognitive domains and with the Mini-Mental State Examination (MMSE). We examined trajectories including model-based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time points (subsample n = 520, mean 1.8 [SD 0.7] years follow-up). RESULTS: We included 1,524 A+ individuals from the Amsterdam Dementia Cohort with A+ SCD (n = 113), A+ MCI (n = 321), or A+ AD dementia (n = 1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed a uniform gradual decline; while in contrast, large intraindividual heterogeneity of NPS was observed over time across all AD groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β = -0.18 to -0.11, false discovery rate [FDR]-adjusted p < 0.05), while there were no cross-sectional relationships in SCD and MCI (range β = -0.32 to 0.36, all FDR-adjusted p > 0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β = -0.13 to 0.44, all FDR-adjusted p > 0.05). DISCUSSION: NPS and cognitive symptoms are both prevalent across the AD clinical spectrum, but show a different evolution during the course of the disease.
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| 8. |
- Eikelboom, Willem S., et al.
(författare)
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Neuropsychiatric Symptoms Complicating the Diagnosis of Alzheimer's Disease : A Case Report
- 2018
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 66:4, s. 1363-1369
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Tidskriftsartikel (refereegranskat)abstract
- Neuropsychiatric symptoms (NPS) are increasingly recognized as a core element of Alzheimer's disease (AD); however, clinicians still consider AD primarily as a cognitive disorder. We describe a case in which the underrecognition of NPS as part of AD resulted in substantial delay of an AD diagnosis, a wrong psychiatric diagnosis, and the organization of inappropriate care. The aim of this paper is to acknowledge NPS as an (early) manifestation of AD and to suggest features that may point toward underlying AD in older adults with late-life behavioral changes.
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| 9. |
- Eikelboom, Willem S., et al.
(författare)
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Sex differences in neuropsychiatric symptoms in Alzheimer’s disease dementia : a meta-analysis
- 2022
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
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Forskningsöversikt (refereegranskat)abstract
- Background: Neuropsychiatric symptoms (NPS) are common in individuals with Alzheimer’s disease (AD) dementia, but substantial heterogeneity exists in the manifestation of NPS. Sex differences may explain this clinical variability. We aimed to investigate the sex differences in the prevalence and severity of NPS in AD dementia. Methods: Literature searches were conducted in Embase, MEDLINE/PubMed, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, PsycINFO, and Google Scholar from inception to February 2021. Study selection, data extraction, and quality assessment were conducted in duplicate. Effect sizes were calculated as odds ratios (OR) for NPS prevalence and Hedges’ g for NPS severity. Data were pooled using random-effects models. Sources of heterogeneity were examined using meta-regression analyses. Results: Sixty-two studies were eligible representing 21,554 patients (61.2% females). The majority of the included studies had an overall rating of fair quality (71.0%), with ten studies of good quality (16.1%) and eight studies of poor quality (12.9%). There was no sex difference in the presence of any NPS (k = 4, OR = 1.35 [95% confidence interval 0.78, 2.35]) and overall NPS severity (k = 13, g = 0.04 [− 0.04, 0.12]). Regarding specific symptoms, female sex was associated with more prevalent depressive symptoms (k = 20, OR = 1.60 [1.28, 1.98]), psychotic symptoms (general psychosis k = 4, OR = 1.62 [1.12, 2.33]; delusions k = 12, OR = 1.56 [1.28, 1.89]), and aberrant motor behavior (k = 6, OR = 1.47 [1.09, 1.98]). In addition, female sex was related to more severe depressive symptoms (k = 16, g = 0.24 [0.14, 0.34]), delusions (k = 10, g = 0.19 [0.04, 0.34]), and aberrant motor behavior (k = 9, g = 0.17 [0.08, 0.26]), while apathy was more severe among males compared to females (k = 11, g = − 0.10 [− 0.18, − 0.01]). There was no association between sex and the prevalence and severity of agitation, anxiety, disinhibition, eating behavior, euphoria, hallucinations, irritability, and sleep disturbances. Meta-regression analyses revealed no consistent association between the effect sizes across studies and method of NPS assessment and demographic and clinical characteristics. Discussion: Female sex was associated with a higher prevalence and greater severity of several specific NPS, while male sex was associated with more severe apathy. While more research is needed into factors underlying these sex differences, our findings may guide tailored treatment approaches of NPS in AD dementia.
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| 10. |
- Eikelboom, Willem S., et al.
(författare)
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The recognition and management of neuropsychiatric symptoms in early Alzheimer's disease : a qualitative study among Dutch memory clinic physicians
- 2022
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Ingår i: Psychogeriatrics. - : Wiley. - 1346-3500 .- 1479-8301. ; 22:5, s. 707-717
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Tidskriftsartikel (refereegranskat)abstract
- Background: Timely recognition and treatment of neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) dementia may improve quality of life, reduce caregiver burden, and delay disease progression. However, management of NPS in early AD dementia remains challenging. To date, little is known about the specific challenges for memory clinic-based physicians. The aims of this qualitative study were to obtain insights regarding the recognition and treatment of NPS in AD dementia in the memory clinic, to identify challenges experienced by physicians while managing NPS, and to examine the attitudes of memory clinic physicians on the role of the memory clinic in the care for NPS in early AD dementia. Methods: Semi-structured interviews were conducted with 13 physicians working at a memory clinic in the Netherlands (n = 7 neurologist, n = 6 geriatrician, 46% female). The data were analyzed by two independent researchers using thematic analysis. Results: We observed large variation among Dutch memory clinic physicians regarding care practices, expertise, and attitudes on the role of the memory clinic considering NPS in AD dementia. The most prominent challenges that memory clinic physicians experienced while managing NPS included that the outpatient setting complicates the recognition and treatment of NPS, a lack of experience, knowledge, and/or resources to adequately apply non-pharmacological interventions, and a lack of consensus among physicians on the role of the memory clinic in NPS recognition and management. Conclusions: We identified challenges that need to be addressed to improve the early recognition and adequate management of NPS in AD dementia at the memory clinic.
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| 11. |
- Eikelboom, Willem S., et al.
(författare)
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The reporting of neuropsychiatric symptoms in electronic health records of individuals with Alzheimer’s disease : a natural language processing study
- 2023
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Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuropsychiatric symptoms (NPS) are prevalent in the early clinical stages of Alzheimer’s disease (AD) according to proxy-based instruments. Little is known about which NPS clinicians report and whether their judgment aligns with proxy-based instruments. We used natural language processing (NLP) to classify NPS in electronic health records (EHRs) to estimate the reporting of NPS in symptomatic AD at the memory clinic according to clinicians. Next, we compared NPS as reported in EHRs and NPS reported by caregivers on the Neuropsychiatric Inventory (NPI). Methods: Two academic memory clinic cohorts were used: the Amsterdam UMC (n = 3001) and the Erasmus MC (n = 646). Patients included in these cohorts had MCI, AD dementia, or mixed AD/VaD dementia. Ten trained clinicians annotated 13 types of NPS in a randomly selected training set of n = 500 EHRs from the Amsterdam UMC cohort and in a test set of n = 250 EHRs from the Erasmus MC cohort. For each NPS, a generalized linear classifier was trained and internally and externally validated. Prevalence estimates of NPS were adjusted for the imperfect sensitivity and specificity of each classifier. Intra-individual comparison of the NPS classified in EHRs and NPS reported on the NPI were conducted in a subsample (59%). Results: Internal validation performance of the classifiers was excellent (AUC range: 0.81–0.91), but external validation performance decreased (AUC range: 0.51–0.93). NPS were prevalent in EHRs from the Amsterdam UMC, especially apathy (adjusted prevalence = 69.4%), anxiety (adjusted prevalence = 53.7%), aberrant motor behavior (adjusted prevalence = 47.5%), irritability (adjusted prevalence = 42.6%), and depression (adjusted prevalence = 38.5%). The ranking of NPS was similar for EHRs from the Erasmus MC, although not all classifiers obtained valid prevalence estimates due to low specificity. In both cohorts, there was minimal agreement between NPS classified in the EHRs and NPS reported on the NPI (all kappa coefficients < 0.28), with substantially more reports of NPS in EHRs than on NPI assessments. Conclusions: NLP classifiers performed well in detecting a wide range of NPS in EHRs of patients with symptomatic AD visiting the memory clinic and showed that clinicians frequently reported NPS in these EHRs. Clinicians generally reported more NPS in EHRs than caregivers reported on the NPI.
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| 12. |
- Jansen, Iris E, et al.
(författare)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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| 13. |
- Le Guen, Yann, et al.
(författare)
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Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 1091-6490 .- 0027-8424. ; 120:36
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Tidskriftsartikel (refereegranskat)abstract
- Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
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| 14. |
- Meeter, Lieke H.H., et al.
(författare)
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Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia
- 2019
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:9, s. 997-1004
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Tidskriftsartikel (refereegranskat)abstract
- Background: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. Methods: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). Results: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs=-0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs=-0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. Conclusion: CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities.
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| 15. |
- Ossenkoppele, Rik, et al.
(författare)
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Research Criteria for the Behavioral Variant of Alzheimer Disease : A Systematic Review and Meta-analysis
- 2022
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 79:1, s. 48-60
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Forskningsöversikt (refereegranskat)abstract
- Importance: The behavioral variant of Alzheimer disease (bvAD) is characterized by early and predominant behavioral deficits caused by AD pathology. This AD phenotype is insufficiently understood and lacks standardized clinical criteria, limiting reliability and reproducibility of diagnosis and scientific reporting. Objective: To perform a systematic review and meta-analysis of the bvAD literature and use the outcomes to propose research criteria for this syndrome. Data Sources: A systematic literature search in PubMed/MEDLINE and Web of Science databases (from inception through April 7, 2021) was performed in duplicate. Study Selection: Studies reporting on behavioral, neuropsychological, or neuroimaging features in bvAD and, when available, providing comparisons with typical amnestic-predominant AD (tAD) or behavioral variant frontotemporal dementia (bvFTD). Data Extraction and Synthesis: This analysis involved random-effects meta-analyses on group-level study results of clinical data and systematic review of the neuroimaging literature. The study was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Main Outcomes and Measures: Behavioral symptoms (neuropsychiatric symptoms and bvFTD core clinical criteria), cognitive function (global cognition, episodic memory, and executive functioning), and neuroimaging features (structural magnetic resonance imaging, [18F]fluorodeoxyglucose-positron emission tomography, perfusion single-photon emission computed tomography, amyloid positron emission tomography, and tau positron emission tomography). Results: The search led to the assessment of 83 studies, including 13 suitable for meta-analysis. Data were collected for 591 patients with bvAD. There was moderate to substantial heterogeneity and moderate risk of bias across studies. Cases with bvAD showed more severe behavioral symptoms than tAD (standardized mean difference [SMD], 1.16 [95% CI, 0.74-1.59]; P <.001) and a trend toward less severe behavioral symptoms compared with bvFTD (SMD, -0.22 [95% CI, -0.47 to 0.04]; P =.10). Meta-analyses of cognitive data indicated worse executive performance in bvAD vs tAD (SMD, -1.03 [95% CI, -1.74 to -0.32]; P =.008) but not compared with bvFTD (SMD, -0.61 [95% CI, -1.75 to 0.53]; P =.29). Cases with bvAD showed a nonsignificant difference of worse memory performance compared with bvFTD (SMD, -1.31 [95% CI, -2.75 to 0.14]; P =.08) but did not differ from tAD (SMD, 0.43 [95% CI, -0.46 to 1.33]; P =.34). The neuroimaging literature revealed 2 distinct bvAD neuroimaging phenotypes: an AD-like pattern with relative frontal sparing and a relatively more bvFTD-like pattern characterized by additional anterior involvement, with the AD-like pattern being more prevalent. Conclusions and Relevance: These data indicate that bvAD is clinically most similar to bvFTD, while it shares most pathophysiological features with tAD. Based on these insights, we propose research criteria for bvAD aimed at improving the consistency and reliability of future research and aiding the clinical assessment of this AD phenotype..
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| 16. |
- Singleton, Ellen H., et al.
(författare)
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Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer disease
- 2020
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer’s disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. Methods: We retrospectively included 150 participants, including 29 bvAD, 28 “typical” amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [18F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. Results: bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvADbvFTD, area under the curve [AUC] range 0.85–0.91, all p < 0.001). The top-3 for bvAD vs. tAD were amygdalar volume (bvAD>tAD), MRI anterior-DMN-ratios (bvAD
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| 17. |
- Singleton, Ellen H., et al.
(författare)
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Social cognition deficits and biometric signatures in the behavioural variant of Alzheimer’s disease
- 2023
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 146:5, s. 2163-2174
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Tidskriftsartikel (refereegranskat)abstract
- The behavioural variant of Alzheimer’s disease (bvAD) is characterized by early predominant behavioural changes, mimicking the behavioural variant of frontotemporal dementia (bvFTD), which is characterized by social cognition deficits and altered biometric responses to socioemotional cues. These functions remain understudied in bvAD. We investigated multiple social cognition components (i.e. emotion recognition, empathy, social norms and moral reasoning), using the Ekman 60 faces test, Interpersonal Reactivity Index, empathy eliciting videos, Social Norms Questionnaire and moral dilemmas, while measuring eye movements and galvanic skin response. We compared 12 patients with bvAD with patients with bvFTD (n = 14), typical Alzheimer’s disease (tAD, n = 13) and individuals with subjective cognitive decline (SCD, n = 13), using ANCOVAs and age- and sex-adjusted post hoc testing. Patients with bvAD (40.1 ± 8.6) showed lower scores on the Ekman 60 faces test compared to individuals with SCD (49.7 ± 5.0, P < 0.001), and patients with tAD (46.2 ± 5.3, P = 0.05) and higher scores compared to patients with bvFTD (32.4 ± 7.3, P = 0.002). Eye-tracking during the Ekman 60 faces test revealed no differences in dwell time on the eyes (all P > 0.05), but patients with bvAD (18.7 ± 9.5%) and bvFTD (19.4 ± 14.3%) spent significantly less dwell time on the mouth than individuals with SCD (30.7 ± 11.6%, P < 0.01) and patients with tAD (32.7 ± 12.1%, P < 0.01). Patients with bvAD (11.3 ± 4.6) exhibited lower scores on the Interpersonal Reactivity Index compared with individuals with SCD (15.6 ± 3.1, P = 0.05) and similar scores to patients with bvFTD (8.7 ± 5.6, P = 0.19) and tAD (13.0 ± 3.2, P = 0.43). The galvanic skin response to empathy eliciting videos did not differ between groups (all P > 0.05). Patients with bvAD (16.0 ± 1.6) and bvFTD (15.2 ± 2.2) showed lower scores on the Social Norms Questionnaire than patients with tAD (17.8 ± 2.1, P < 0.05) and individuals with SCD (18.3 ± 1.4, P < 0.05). No group differences were observed in scores on moral dilemmas (all P > 0.05), while only patients with bvFTD (0.9 ± 1.1) showed a lower galvanic skin response during personal dilemmas compared with SCD (3.4 ± 3.3 peaks per min, P = 0.01). Concluding, patients with bvAD showed a similar although milder social cognition profile and a similar eye-tracking signature to patients with bvFTD and greater social cognition impairments and divergent eye movement patterns compared with patients with tAD. Our results suggest reduced attention to salient facial features in these phenotypes, potentially contributing to their emotion recognition deficits.
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| 18. |
- Singleton, Ellen, et al.
(författare)
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Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer's disease
- 2021
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 92:8, s. 872-880
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The clinical phenotype of the rare behavioural variant of Alzheimer's disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination. Methods: For the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a 'typical' memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7). Results: Individual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05). Conclusions: Both in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.
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| 19. |
- van der Ende, Emma L, et al.
(författare)
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Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study.
- 2022
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Ingår i: Journal of neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Neuroinflammation is emerging as an important pathological process in frontotemporal dementia (FTD), but biomarkers are lacking. We aimed to determine the value of complement proteins, which are key components of innate immunity, as biomarkers in cerebrospinal fluid (CSF) and plasma of presymptomatic and symptomatic genetic FTD mutation carriers.We measured the complement proteins C1q and C3b in CSF by ELISAs in 224 presymptomatic and symptomatic GRN, C9orf72 or MAPT mutation carriers and non-carriers participating in the Genetic Frontotemporal Dementia Initiative (GENFI), a multicentre cohort study. Next, we used multiplex immunoassays to measure a panel of 14 complement proteins in plasma of 431 GENFI participants. We correlated complement protein levels with corresponding clinical and neuroimaging data, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP).CSF C1q and C3b, as well as plasma C2 and C3, were elevated in symptomatic mutation carriers compared to presymptomatic carriers and non-carriers. In genetic subgroup analyses, these differences remained statistically significant for C9orf72 mutation carriers. In presymptomatic carriers, several complement proteins correlated negatively with grey matter volume of FTD-related regions and positively with NfL and GFAP. In symptomatic carriers, correlations were additionally observed with disease duration and with Mini Mental State Examination and Clinical Dementia Rating scale® plus NACC Frontotemporal lobar degeneration sum of boxes scores.Elevated levels of CSF C1q and C3b, as well as plasma C2 and C3, demonstrate the presence of complement activation in the symptomatic stage of genetic FTD. Intriguingly, correlations with several disease measures in presymptomatic carriers suggest that complement protein levels might increase before symptom onset. Although the overlap between groups precludes their use as diagnostic markers, further research is needed to determine their potential to monitor dysregulation of the complement system in FTD.
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