| 61. |
|
|
| 62. |
- Singleton, E. H., et al.
(författare)
-
The behavioral variant of Alzheimer’s disease does not show a selective loss of Von Economo and phylogenetically related neurons in the anterior cingulate cortex
- 2022
-
Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer’s disease (bvAD) remain unclear. A selective loss of Von Economo neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD. Methods: VENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n = 9) and compared to typical AD (tAD, n = 6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n = 18) and controls (n = 13) using ANCOVAs adjusted for age and Bonferroni corrected. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss. Results: The number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0 ± 15.3, GABRQ-ir pyramidal: 260.4 ± 87.1) and tAD (VENs: 32.0 ± 18.1, p = 1.00, GABRQ-ir pyramidal: 349.8 ± 109.6, p = 0.38) and controls (VENs: 33.5 ± 20.3, p = 1.00, GABRQ-ir pyramidal: 339.4 ± 95.9, p = 0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.5 ± 82.658, p = 0.01) and no significant differences in number of VENs (bvFTD: 10.9 ± 13.8, p = 0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5. Discussion: VENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.
|
|
| 63. |
- Smith, Gustav, et al.
(författare)
-
The Impact of Ancestry and Common Genetic Variants on QT Interval in African Americans.
- 2012
-
Ingår i: Circulation: Cardiovascular Genetics. - 1942-325X. ; 5:6, s. 647-655
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: -Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death (SCD) and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. METHODS AND RESULTS: -First, individual estimates of African and European ancestry were inferred from genome-wide single nucleotide polymorphism (SNP) data in seven population-based cohorts of African Americans (n=12 097) and regressed on measured QT interval from electrocardiograms. Second, imputation was performed for 2.8 million SNPs and a genome-wide association (GWA) study of QT interval performed in ten cohorts (n=13 105). There was no evidence of association between genetic ancestry and QT interval (p=0.94). Genome-wide significant associations (p<2.5x10(-8)) were identified with SNPs at two loci, upstream of the genes NOS1AP (rs12143842, p=2x10(-15)) and ATP1B1 (rs1320976, p=2x10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low p-values (p<10(-5)) were observed for SNPs at several other loci previously identified in GWA studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF and PLN. CONCLUSIONS: -We observed no difference in duration of cardiac repolarization with global genetic indices of African ancestry. In addition, our GWA study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include African Americans.
|
|
| 64. |
|
|
| 65. |
- Dewan, Ramita, et al.
(författare)
-
Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
- 2021
-
Ingår i: Neuron. - : Elsevier BV. - 1097-4199 .- 0896-6273. ; 109:3
-
Tidskriftsartikel (refereegranskat)abstract
- We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
|
|
| 66. |
- Eikelboom, Willem S., et al.
(författare)
-
Early recognition and treatment of neuropsychiatric symptoms to improve quality of life in early Alzheimer's disease : Protocol of the BEAT-IT study
- 2019
-
Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11:1
-
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.
|
|
| 67. |
- Eikelboom, Willem S., et al.
(författare)
-
The reporting of neuropsychiatric symptoms in electronic health records of individuals with Alzheimer’s disease : a natural language processing study
- 2023
-
Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 15:1
-
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.
|
|
| 68. |
|
|
| 69. |
- Khan, Tauseef A., et al.
(författare)
-
Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke : Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals
- 2013
-
Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 42:2, s. 475-492
-
Tidskriftsartikel (refereegranskat)abstract
- Background At the APOE gene, encoding apolipoprotein E, genotypes of the epsilon 2/epsilon 3/epsilon 4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk. Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT). Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84-1.43) for epsilon 2/epsilon 2; 0.85 (95% CrI: 0.78-0.92) for epsilon 2/epsilon 3; 1.05 (95% CrI: 0.89-1.24) for epsilon 2/epsilon 4; 1.05 (95% CrI: 0.99-1.12) for epsilon 3/epsilon 4; and 1.12 (95% CrI: 0.94-1.33) for epsilon 4/epsilon 4 using the epsilon 3/epsilon 3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 x 10(-152)), apolipoprotein B (P-trend: 8.7 x 10(-06)) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 x 10(-26)) and HDL-C (P-trend: 1.6 x 10(-12)). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear. Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE epsilon 2/epsilon 2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
|
|
| 70. |
|
|
