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1.
Cogn Behav Neurol ; 34(4): 275-287, 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34851865

RESUMO

BACKGROUND: Individuals with the behavioral variant of frontotemporal dementia (bvFTD) exhibit various levels of abulia, disinhibition, impaired judgment, and decline in executive function. Empirical evidence has shown that individuals with bvFTD also often exhibit difficulty using honorific speech, which expresses respect to another party or addressee. OBJECTIVE: To analyze differences in the ability to use honorific speech among individuals with bvFTD, individuals with dementia of the Alzheimer type (AD dementia), and individuals with normal cognition (NC). METHOD: A total of 53 native Korean speakers (13 bvFTD, 20 AD dementia, and 20 NC) completed an experimental honorific speech task (HST) that involved both expressive and receptive tasks. We analyzed the number of correct responses and error patterns separately for an expressive task and for a receptive task. RESULTS: The bvFTD group had significantly fewer correct responses on the HST compared with the AD dementia and NC groups. The bvFTD group exhibited more misjudgment errors in identifying nonhonorific speech as honorific speech in the expressive task, and significantly longer response times in the receptive task, than the AD dementia and NC groups. Significant associations were identified between HST scores and cortical atrophy in the temporal and frontotemporal lobes. CONCLUSION: A decline in the ability to use honorific speech may be a diagnosable behavioral and psychiatric symptom for bvFTD in Korean-speaking individuals. This decline in individuals with bvFTD could be attributed to multiple factors, including social manners (politeness) and impaired social language use ability (pragmatics).

2.
Front Neurol ; 12: 762251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34950100

RESUMO

Objective: We investigated the mediation effects of subcortical volume change in the relationship of amyloid beta (Aß) and lacune with cognitive function in patients with mild cognitive impairment (MCI). Methods: We prospectively recruited 101 patients with MCI who were followed up with neuropsychological tests, MRI, or Pittsburgh compound B (PiB) PET for 3 years. The mediation effect of subcortical structure on the association of PiB or lacunes with cognitive function was analyzed using mixed effects models. Results: Volume changes in the amygdala and hippocampus partially mediated the effect of PiB changes on memory function (direct effect = -0.168/-0.175, indirect effect = -0.081/-0.077 for amygdala/hippocampus) and completely mediated the effect of PiB changes on clinical dementia rating scale sum of the box (CDR-SOB) (indirect effect = 0.082/0.116 for amygdala/hippocampus). Volume changes in the thalamus completely mediated the effect of lacune on memory, frontal executive functions, and CDR-SOB (indirect effect = -0.037, -0.056, and 0.047, respectively). Conclusions: Our findings provide a better understanding of the distinct role of subcortical structures in the mediation of the relationships of amyloid or vascular changes with a decline in specific cognitive domains.

3.
J Alzheimers Dis ; 2021 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-34958024

RESUMO

BACKGROUND: Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) commonly coexist. OBJECTIVE: We aimed to characterize an overlapping syndrome of AD and NPH that presents with gait disturbance, ventriculomegaly on magnetic resonance imaging, and significant amyloid deposition on positron emission tomography (PET). METHODS: Of 114 patients who underwent cerebrospinal fluid (CSF) drainage for a possible diagnosis of NPH between 2015 and 2020 in Samsung Medical Center, we identified 24 patients (21.1%) with the NPH patients with amyloid deposition on PET, which we referred to as hydrocephalic AD in this study. We compared their clinical and imaging findings with those of 123 typical AD without hydrocephalic signs/symptoms. We also investigated the frequency and potential predictors of the tap test response in hydrocephalic AD. RESULTS: Evans' index was 0.36±0.03, and a disproportionately enlarged subarachnoid space was present in 54.2% of the hydrocephalic AD patients. The mean age (75.2±7.3 years) and the APOE4 frequency (68.2%) did not differ from those of AD controls. However, the hydrocephalic AD patients showed better memory and language performance, and a thinner cingulate cortex. About 42% of the hydrocephalic AD patients responded to the tap test, of whom seven underwent shunt surgery. Cognition did not improve, whereas gait improved after shunt surgery in all. CONCLUSION: Hydrocephalic AD has different neuropsychological and imaging characteristics from typical AD. Future studies are warranted to further investigate the effect of CSF removal on their clinical course and to elucidate the pathophysiological interaction between amyloid and NPH.

4.
BMC Musculoskelet Disord ; 22(1): 869, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34641837

RESUMO

BACKGROUND: Interosseous ligament vertical segment (IOLV) and calcaneofibular ligament (CFL) have been reported to be important in stabilizing the subtalar joint. Unlike CFL, there is not much information regarding the comparison of MRI results with surgical evaluation of IOLV and the comparison between 2D and 3D MRI on IOLV evaluation. The feasibility of MRI in IOLV evaluation has yet to be reported. The purpose of this study was to evaluate the validity and reliability of MRI in IOLV tear detection via correlation with arthroscopic results. We also compared the diagnostic performance of 2D and 3D MR images. METHODS: In this retrospective study, 52 patients who underwent subtalar arthroscopy after ankle MRI were enrolled. Arthroscopic results confirmed IOLV tear in 25 cases and intact IOLV in 27 cases. Two radiologists independently evaluated the IOLV tears using only conventional 2D images, followed by isotropic 3D images, and comparison with arthroscopic results. RESULTS: Only the 2D sequences interpreted by two readers showed a sensitivity of 64.0-96.0%, a specificity of 29.6-44.4%, a positive predictive value of 51.6-56.4%, and a negative predictive value of 57.1-88.9%. Addition of isotropic 3D sequences changed the sensitivity to 60.0-80.0%, specificity to 63.0-77.8%, positive predictive value to 64.3-76.9%, and negative predictive value to 66.7-80.8%. The overall diagnostic performance of isotropic 3D sequences (AUC values: 0.679-0.816) was higher than that of 2D sequences (AUC values: 0.568-0.647). Inter-observer and intra-observer agreement between the two readers was moderate-to-good for both 2D and 3D sequences. The diagnostic accuracy in 19 patients with tarsal sinus fat obliteration tended to increase from 26.3-42.1% to 57.9-73.7% with isotropic 3D sequences compared with 2D sequences. CONCLUSIONS: Isotropic 3D MRI was feasible for the assessment of IOLV tear prior to subtalar arthroscopy. Additional 3D sequences showed higher diagnostic accuracy compared with conventional 2D sequences in IOLV evaluation. Isotropic 3D sequences may be more valuable in detecting IOLV tear in case of tarsal sinus fat obliteration.


Assuntos
Artroscopia , Imageamento por Ressonância Magnética , Estudos de Viabilidade , Humanos , Ligamentos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
5.
Eur J Neurol ; 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34716964

RESUMO

BACKGROUND AND PURPOSE: Subcortical vascular cognitive impairment (SVCI) is characterized by the presence of cerebral small vessel disease (CSVD) markers. Some SVCI patients also show Alzheimer's disease and cerebral amyloid angiopathy markers. However, the effects of these imaging markers on long-term clinical outcomes have not yet been established. The present study, therefore, aimed to determine how these imaging markers influence functional disability and/or mortality. METHODS: We recruited 194 participants with SVCI from the memory clinic and followed them up. All participants underwent brain magnetic resonance imaging at baseline, and 177 (91.2%) participants underwent beta-amyloid (Aß) positron emission tomography. We examined the occurrence of ischemic or hemorrhagic strokes. We also evaluated functional disability and mortality using the modified Rankin scale. To determine the effects of imaging markers on functional disability or mortality, we used Fine and Gray competing regression or Cox regression analysis. RESULTS: During a 8.6-year follow-up period, 46 of 194 patients (23.7%) experienced a stroke, 110 patients (56.7%) developed functional disabilities and 75 (38.6%) died. Aß positivity (subdistribution hazard ratio [SHR] = 2.73), greater white matter hyperintensity (WMH) volume (SHR = 3.11) and ≥3 microbleeds (SHR = 2.29) at baseline were independent predictors of functional disability regardless of the occurrence of stroke. Greater WMH volume (hazard ratio = 2.07) was an independent predictor of mortality. CONCLUSIONS: Our findings suggest that diverse imaging markers may predict long-term functional disability and mortality in patients with SVCI, which in turn may provide clinicians with a more insightful understanding of the long-term outcomes of SVCI.

6.
Cells ; 10(10)2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34685508

RESUMO

Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that protects against brain injury. However, little is known about the effect of Ex-4 on kainic acid (KA)-induced seizures and hippocampal cell death. Therefore, this study evaluated the neuroprotective effects of Ex-4 pretreatment in a mouse model of KA-induced seizures. Three days before KA treatment, mice were intraperitoneally injected with Ex-4. We found that Ex-4 pretreatment reversed KA-induced reduction of GLP-1R expression in the hippocampus and attenuated KA-induced seizure score, hippocampal neuronal death, and neuroinflammation. Ex-4 pretreatment also dramatically reduced hippocampal lipocalin-2 protein in KA-treated mice. Furthermore, immunohistochemical studies showed that Ex-4 pretreatment significantly alleviated blood-brain barrier leakage. Finally, Ex-4 pretreatment stimulated hippocampal expression of phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), a known target of GLP-1/GLP-1R signaling. These findings indicate that Ex-4 pretreatment may protect against KA-induced neuronal damage by regulating GLP-1R/CREB-mediated signaling pathways.

7.
Alzheimers Res Ther ; 13(1): 179, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686209

RESUMO

BACKGROUND: We assessed the feasibility of plasma Aß42/Aß40 determined using a novel liquid chromatography-mass spectrometry method (LC-MS) as a useful biomarker of PET status in a Korean cohort from the DPUK Study. METHODS: A total of 580 participants belonging to six groups, Alzheimer's disease dementia (ADD, n = 134), amnestic mild cognitive impairment (aMCI, n = 212), old controls (OC, n = 149), young controls (YC, n = 15), subcortical vascular cognitive impairment (SVCI, n = 58), and cerebral amyloid angiopathy (CAA, n = 12), were included in this study. Plasma Aß40 and Aß42 were quantitated using a new antibody-free, LC-MS, which drastically reduced the sample preparation time and cost. We performed receiver operating characteristic (ROC) analysis to develop the cutoff of Aß42/Aß40 and investigated its performance predicting centiloid-based PET positivity (PET+). RESULTS: Plasma Aß42/Aß40 were lower for PET+ individuals in ADD, aMCI, OC, and SVCI (p < 0.001), but not in CAA (p = 0.133). In the group of YC, OC, aMCI, and ADD groups, plasma Aß42/Aß40 predicted PET+ with an area under the ROC curve (AUC) of 0.814 at a cutoff of 0.2576. When adding age, APOE4, and diagnosis, the AUC significantly improved to 0.912. CONCLUSION: Plasma Aß42/Aß40, as measured by this novel LC-MS method, showed good discriminating performance based on PET positivity.


Assuntos
Doença de Alzheimer , Espectrometria de Massas em Tandem , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides , Biomarcadores , Cromatografia Líquida de Alta Pressão , Humanos , Fragmentos de Peptídeos , República da Coreia
8.
J Alzheimers Dis ; 84(2): 633-645, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34569949

RESUMO

BACKGROUND: Primary progressive aphasia (PPA) is associated with amyloid-ß (Aß) pathology. However, clinical feature of PPA based on Aß positivity remains unclear. OBJECTIVE: We aimed to assess the prevalence of Aß positivity in patients with PPA and compare the clinical characteristics of patients with Aß-positive (A+) and Aß-negative (A-) PPA. Further, we applied Aß and tau classification system (AT system) in patients with PPA for whom additional information of in vivo tau biomarker was available. METHODS: We recruited 110 patients with PPA (41 semantic [svPPA], 27 non-fluent [nfvPPA], 32 logopenic [lvPPA], and 10 unclassified [ucPPA]) who underwent Aß-PET imaging at multi centers. The extent of language impairment and cortical atrophy were compared between the A+ and A-PPA subgroups using general linear models. RESULTS: The prevalence of Aß positivity was highest in patients with lvPPA (81.3%), followed by ucPPA (60.0%), nfvPPA (18.5%), and svPPA (9.8%). The A+ PPA subgroup manifested cortical atrophy mainly in the left superior temporal/inferior parietal regions and had lower repetition scores compared to the A-PPA subgroup. Further, we observed that more than 90% (13/14) of the patients with A+ PPA had tau deposition. CONCLUSION: Our findings will help clinicians understand the patterns of language impairment and cortical atrophy in patients with PPA based on Aß deposition. Considering that most of the A+ PPA patents are tau positive, understanding the influence of Alzheimer's disease biomarkers on PPA might provide an opportunity for these patients to participate in clinical trials aimed for treating atypical Alzheimer's disease.

9.
Alzheimers Res Ther ; 13(1): 154, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521461

RESUMO

BACKGROUNDS: Alzheimer's disease is the most common cause of dementia, and currently, there is no disease-modifying treatment. Favorable functional outcomes and reduction of amyloid levels were observed following transplantation of mesenchymal stem cells (MSCs) in animal studies. OBJECTIVES: We conducted a phase I clinical trial in nine patients with mild-to-moderate Alzheimer's disease dementia to evaluate the safety and dose-limiting toxicity of three repeated intracerebroventricular injections of human umbilical cord blood-derived MSCs (hUCB-MSCs). METHODS: We recruited nine mild-to-moderate Alzheimer's disease dementia patients from Samsung Medical Center, Seoul, Republic of Korea. Four weeks prior to MSC administration, the Ommaya reservoir was implanted into the right lateral ventricle of the patients. Three patients received a low dose (1.0 × 107 cells/2 mL), and six patients received a high dose (3.0 × 107 cells/2 mL) of hUCB-MSCs. Three repeated injections of MSCs were performed (4-week intervals) in all nine patients. These patients were followed up to 12 weeks after the first hUCB-MSC injection and an additional 36 months in the extended observation study. RESULTS: After hUCB-MSC injection, the most common adverse event was fever (n = 9) followed by headache (n = 7), nausea (n = 5), and vomiting (n = 4), which all subsided within 36 h. There were three serious adverse events in two participants that were considered to have arisen from the investigational product. Fever in a low dose participant and nausea with vomiting in another low dose participant each required extended hospitalization by a day. There were no dose-limiting toxicities. Five participants completed the 36-month extended observation study, and no further serious adverse events were observed. CONCLUSIONS: Three repeated administrations of hUCB-MSCs into the lateral ventricle via an Ommaya reservoir were feasible, relatively and sufficiently safe, and well-tolerated. Currently, we are undergoing an extended follow-up study for those who participated in a phase IIa trial where upon completion, we hope to gain a deeper understanding of the clinical efficacy of MSC AD therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02054208. Registered on 4 February 2014. ClinicalTrials.gov NCT03172117. Registered on 1 June 2017.


Assuntos
Doença de Alzheimer , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Doença de Alzheimer/terapia , Animais , Sangue Fetal , Seguimentos , Humanos
10.
J Alzheimers Dis ; 83(3): 1025-1031, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34366354

RESUMO

Atypical psychological symptoms frequently occur in early-onset Alzheimer's disease (EOAD), which makes it difficult to differentiate it from other psychiatric disorders. We report the case of a 28-year-old woman with EOAD, carrying a presenilin-1 mutation (S170P), who was initially misdiagnosed with schizophrenia because of prominent psychiatric symptoms in the first 1-2 years of the disease. Amyloid-ß positron emission tomography (PET) showed remarkably high tracer uptake in the striatum and thalamus. Tau PET showed widespread cortical uptake and relatively low uptake in the subcortical and medial temporal regions. Our case advocates for considering EOAD diagnosis for young patients with psychiatric and atypical cognitive symptoms.

11.
Sci Rep ; 11(1): 17255, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446742

RESUMO

We investigated the effect of education on the edge efficiency in resting state functional networks (RSFNs) in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease dementia (ADD). We collected the data of 57 early aMCI, 141 late aMCI, 173 mild ADD, and 39 moderate-to-severe ADD patients. We used years of education as a proxy for cognitive reserve. We measured edge efficiency for each edge in RSFNs, and performed simple slope analyses to discover their associations with education level among the four groups. In the late aMCI, a sub-network that had hub nodes in the right middle frontal gyrus and the right posterior cingulate gyrus, showed a positive association between RSFN edge efficiency and education (threshold = 2.5, p = 0.0478). There was no negative effect of education on the RSFN edge efficiency. In the early aMCI, mild ADD, and moderate-to-severe ADD, there were no sub-networks showing positive or negative correlation between education and RSFN edge efficiency. There was a positive effect of higher education on RSFN edge efficiency in the late aMCI, but not in the early aMCI or ADD. This indicates that in late aMCI, those who have higher education level have greater ability to resist collapsed functional network.


Assuntos
Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Demência/fisiopatologia , Escolaridade , Rede Nervosa/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Cognição/fisiologia , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Modelos Neurológicos , Testes Neuropsicológicos/estatística & dados numéricos
12.
Artigo em Inglês | MEDLINE | ID: mdl-34328533

RESUMO

PURPOSE: In this study, we used machine learning to develop a new method derived from a ligand-independent amyloid (Aß) positron emission tomography (PET) classifier to harmonise different Aß ligands. METHODS: We obtained 107 paired 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) PET images at the Samsung Medical Centre. To apply the method to FMM ligand, we transferred the previously developed FBB PET classifier to test similar features from the FMM PET images for application to FMM, which in turn developed a ligand-independent Aß PET classifier. We explored the concordance rates of our classifier in detecting cortical and striatal Aß positivity. We investigated the correlation of machine learning-based cortical tracer uptake (ML-CTU) values quantified by the classifier between FBB and FMM. RESULTS: This classifier achieved high classification accuracy (area under the curve = 0.958) even with different Aß PET ligands. In addition, the concordance rate of FBB and FMM using the classifier (87.5%) was good to excellent, which seemed to be higher than that in visual assessment (82.7%) and lower than that in standardised uptake value ratio cut-off categorisation (93.3%). FBB and FMM ML-CTU values were highly correlated with each other (R = 0.903). CONCLUSION: Our findings suggested that our novel classifier may harmonise FBB and FMM ligands in the clinical setting which in turn facilitate the biomarker-guided diagnosis and trials of anti-Aß treatment in the research field.

13.
Neuroimage Clin ; 30: 102685, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34215155

RESUMO

OBJECTIVE: Neuropsychological test-specific neural substrates in subcortical vascular cognitive impairment (SVCI) are expected to differ from those in Alzheimer's disease-related cognitive impairment (ADCI) but the details are unclear. To determine neural substrates related to cerebral small vessel disease, we investigated the correlations between cognitive dysfunctions measured by standardized neuropsychological tests and cortical thickness in a large sample of participants with amyloid negative (Aß (-)) SVCI. METHODS: One hundred ninety-eight participants with Aß (-) SVCI were recruited from the memory clinic between November 2007 to August 2018. To acquire neural substrates, we performed linear regression using the scores of each neuropsychological test as a predictor, cortical thickness as an outcome, and age, sex, education years, intracranial volume and white matter hyperintensity (WMH) as confounders. RESULTS: Poor performances in each neuropsychological test were associated with cortical atrophy in certain brain regions regardless of WMH. Especially, not the medial temporal but the frontal and posterior cingulate regions with cortical atrophy were mainly associated with memory impairment. Poor performance in animal fluency was more likely to be associated with cortical atrophy in the left hemisphere, while poor performance in the visuospatial memory test was more likely to be associated with cortical atrophy in the right hemisphere. CONCLUSIONS: Our findings suggested that cortical atrophy was an important factor of cognitive impairment in Aß (-) SVCI regardless of WMH. Furthermore, our findings might give clinicians a better understanding of specific neural substrates of neuropsychological deficits in patients with SVCI.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Encéfalo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Humanos , Imageamento por Ressonância Magnética , Testes Neuropsicológicos
15.
J Alzheimers Dis ; 82(4): 1591-1599, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34180413

RESUMO

BACKGROUND: An association between Helicobacter pylori (H. pylori) infection and dementia was reported in previous studies; however, the evidence is inconsistent. OBJECTIVE: In the present study, the association between H. pylori infection and brain cortical thickness as a biomarker of neurodegeneration was investigated. METHODS: A cross-sectional study of 822 men who underwent a medical health check-up, including an esophagogastroduodenoscopy and 3.0 T magnetic resonance imaging, was performed. H. pylori infection status was assessed based on histology. Multiple linear regression analyses were conducted to evaluate the relationship between H. pylori infection and brain cortical thickness. RESULTS: Men with H. pylori infection exhibited overall brain cortical thinning (p = 0.022), especially in the parietal (p = 0.008) and occipital lobes (p = 0.050) compared with non-infected men after adjusting for age, educational level, alcohol intake, smoking status, and intracranial volume. 3-dimentional topographical analysis showed that H. pylori infected men had cortical thinning in the bilateral lateral temporal, lateral frontal, and right occipital areas compared with non-infected men with the same adjustments (false discovery rate corrected, Q < 0.050). The association remained significant after further adjusting for inflammatory marker (C-reactive protein) and metabolic factors (obesity, dyslipidemia, fasting glucose, and blood pressure). CONCLUSION: Our results indicate H. pylori infection is associated with neurodegenerative changes in cognitive normal men. H. pylori infection may play a pathophysiologic role in the neurodegeneration and further studies are needed to validate this association.


Assuntos
Espessura Cortical do Cérebro , Encéfalo/patologia , Demência/fisiopatologia , Infecções por Helicobacter/complicações , Estudos Transversais , Demência/etiologia , Endoscopia do Sistema Digestório , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Occipital/patologia , Lobo Parietal/patologia , República da Coreia
16.
Alzheimers Res Ther ; 13(1): 117, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34154648

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified a number of genetic variants for Alzheimer's disease (AD). However, most GWAS were conducted in individuals of European ancestry, and non-European populations are still underrepresented in genetic discovery efforts. Here, we performed GWAS to identify single nucleotide polymorphisms (SNPs) associated with amyloid ß (Aß) positivity using a large sample of Korean population. METHODS: One thousand four hundred seventy-four participants of Korean ancestry were recruited from multicenters in South Korea. Discovery dataset consisted of 1190 participants (383 with cognitively unimpaired [CU], 330 with amnestic mild cognitive impairment [aMCI], and 477 with AD dementia [ADD]) and replication dataset consisted of 284 participants (46 with CU, 167 with aMCI, and 71 with ADD). GWAS was conducted to identify SNPs associated with Aß positivity (measured by amyloid positron emission tomography). Aß prediction models were developed using the identified SNPs. Furthermore, bioinformatics analysis was conducted for the identified SNPs. RESULTS: In addition to APOE, we identified nine SNPs on chromosome 7, which were associated with a decreased risk of Aß positivity at a genome-wide suggestive level. Of these nine SNPs, four novel SNPs (rs73375428, rs2903923, rs3828947, and rs11983537) were associated with a decreased risk of Aß positivity (p < 0.05) in the replication dataset. In a meta-analysis, two SNPs (rs7337542 and rs2903923) reached a genome-wide significant level (p < 5.0 × 10-8). Prediction performance for Aß positivity increased when rs73375428 were incorporated (area under curve = 0.75; 95% CI = 0.74-0.76) in addition to clinical factors and APOE genotype. Cis-eQTL analysis demonstrated that the rs73375428 was associated with decreased expression levels of FGL2 in the brain. CONCLUSION: The novel genetic variants associated with FGL2 decreased risk of Aß positivity in the Korean population. This finding may provide a candidate therapeutic target for AD, highlighting the importance of genetic studies in diverse populations.


Assuntos
Doença de Alzheimer , Estudo de Associação Genômica Ampla , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Fibrinogênio , Humanos , Tomografia por Emissão de Pósitrons , República da Coreia
17.
Alzheimers Res Ther ; 13(1): 113, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127075

RESUMO

BACKGROUND: Although few studies have shown that risk factors for Alzheimer's disease (AD) are associated with cognitive decline in AD, not much is known whether the impact of risk factors differs between early-onset AD (EOAD, symptom onset < 65 years of age) versus late-onset AD (LOAD). Therefore, we evaluated whether the impact of Alzheimer's disease (AD) risk factors on cognitive trajectories differ in EOAD and LOAD. METHODS: We followed-up 193 EOAD and 476 LOAD patients without known autosomal dominant AD mutation for 32.3 ± 23.2 months. Mixed-effects model analyses were performed to evaluate the effects of APOE ε4, low education, hypertension, diabetes, dyslipidemia, and obesity on cognitive trajectories. RESULTS: APOE ε4 carriers showed slower cognitive decline in general cognitive function, language, and memory domains than APOE ε4 carriers in EOAD but not in LOAD. Although patients with low education showed slower cognitive decline than patients with high education in both EOAD and LOAD, the effect was stronger in EOAD, specifically in frontal-executive function. Patients with hypertension showed faster cognitive decline than did patients without hypertension in frontal-executive and general cognitive function in LOAD but not in EOAD. Patients with obesity showed slower decline in general cognitive function than non-obese patients in EOAD but not in LOAD. CONCLUSIONS: Known risk factors for AD were associated with slower cognitive decline in EOAD but rapid cognitive decline in LOAD.


Assuntos
Doença de Alzheimer , Idade de Início , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Cognição , Humanos , Memória , Fatores de Risco
18.
Neurology ; 96(17): e2201-e2211, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33722997

RESUMO

OBJECTIVE: We investigated the frequency of ß-amyloid (Aß) positivity in 9 groups classified according to a combination of 3 different cognition states and 3 distinct levels of white matter hyperintensities (WMH) (minimal, moderate, and severe) and aimed to determine which factors were associated with Aß after controlling for WMH and vice versa. METHODS: A total of 1,047 individuals with subjective cognitive decline (SCD, n = 294), mild cognitive impairment (MCI, n = 237), or dementia (n = 516) who underwent Aß PET scans were recruited from the memory clinic at Samsung Medical Center in Seoul, Korea. We investigated the following: (1) Aß positivity in the 9 groups, (2) the relationship between Aß positivity and WMH severity, and (3) clinical and genetic factors independently associated with Aß or WMH. RESULTS: Aß positivity increased as the severity of cognitive impairment increased (SCD [15.7%], MCI [43.5%], and dementia [76.2%]), whereas it decreased as the severity of WMH increased (minimal [54.5%], moderate [53.9%], and severe [41.0%]) or the number of lacunes (0 [59.0%], 1-3 [42.0%], and >3 [23.4%]) increased. Aß positivity was associated with higher education, absence of diabetes, and presence of APOE ε4 after controlling for cognitive and WMH status. CONCLUSION: Our analysis of Aß positivity involving a large sample classified according to the stratified cognitive states and WMH severity indicates that Alzheimer and cerebral small vessel diseases lie on a continuum. Our results offer clinicians insightful information about the association among Aß, WMH, and cognition.


Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doenças de Pequenos Vasos Cerebrais/metabolismo , Cognição/fisiologia , Disfunção Cognitiva/genética , Demência Vascular/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino
20.
Sci Rep ; 11(1): 6954, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772041

RESUMO

Predicting amyloid positivity in patients with mild cognitive impairment (MCI) is crucial. In the present study, we predicted amyloid positivity with structural MRI using a radiomics approach. From MR images (including T1, T2 FLAIR, and DTI sequences) of 440 MCI patients, we extracted radiomics features composed of histogram and texture features. These features were used alone or in combination with baseline non-imaging predictors such as age, sex, and ApoE genotype to predict amyloid positivity. We used a regularized regression method for feature selection and prediction. The performance of the baseline non-imaging model was at a fair level (AUC = 0.71). Among single MR-sequence models, T1 and T2 FLAIR radiomics models also showed fair performances (AUC for test = 0.71-0.74, AUC for validation = 0.68-0.70) in predicting amyloid positivity. When T1 and T2 FLAIR radiomics features were combined, the AUC for test was 0.75 and AUC for validation was 0.72 (p vs. baseline model < 0.001). The model performed best when baseline features were combined with a T1 and T2 FLAIR radiomics model (AUC for test = 0.79, AUC for validation = 0.76), which was significantly better than those of the baseline model (p < 0.001) and the T1 + T2 FLAIR radiomics model (p < 0.001). In conclusion, radiomics features showed predictive value for amyloid positivity. It can be used in combination with other predictive features and possibly improve the prediction performance.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/análise , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Imageamento por Ressonância Magnética/métodos , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Apolipoproteínas E/metabolismo , Biomarcadores/análise , Disfunção Cognitiva/diagnóstico , Biologia Computacional , Diagnóstico Precoce , Feminino , Humanos , Masculino
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