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1.
Alzheimers Res Ther ; 13(1): 138, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389066

RESUMO

BACKGROUND: Changes in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer's disease (AD) and have been associated with amyloid-ß (Aß) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau-related connectivity changes across different stages of AD might be expected. We aimed to assess the relationship between tau aggregation and grey matter network alterations across the AD continuum. METHODS: We included 533 individuals (178 Aß-negative cognitively unimpaired (CU) subjects, 105 Aß-positive CU subjects, 122 Aß-positive patients with mild cognitive impairment, and 128 patients with AD dementia) from the BioFINDER-2 study. Single-subject grey matter networks were extracted from T1-weighted images and graph theory properties including degree, clustering coefficient, path length, and small world topology were calculated. Associations between tau positron emission tomography (PET) values and global and regional network measures were examined using linear regression models adjusted for age, sex, and total intracranial volume. Finally, we tested whether the association of tau pathology with cognitive performance was mediated by grey matter network disruptions. RESULTS: Across the whole sample, we found that higher tau load in the temporal meta-ROI was associated with significant changes in degree, clustering, path length, and small world values (all p < 0.001), indicative of a less optimal network organisation. Already in CU Aß-positive individuals associations between tau burden and lower clustering and path length were observed, whereas in advanced disease stages elevated tau pathology was progressively associated with more brain network abnormalities. Moreover, the association between higher tau load and lower cognitive performance was only partly mediated (9.3 to 9.5%) through small world topology. CONCLUSIONS: Our data suggest a close relationship between grey matter network disruptions and tau pathology in individuals with abnormal amyloid. This might reflect a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions with tau pathology, indicative of a more random network topology across different AD stages.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo
2.
Ann Clin Transl Neurol ; 8(2): 348-358, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33421355

RESUMO

OBJECTIVE: To investigate the relationship between amyloid-ß (Aß) deposition and markers of brain structure on cognitive decline in oldest-old individuals with initial normal cognition. METHODS: We studied cognitive functioning in four domains at baseline and change over time in fifty-seven cognitively intact individuals from the EMIF-AD 90+ study. Predictors were Aß status determined by [18 F]-flutemetamol PET (normal = Aß - vs. abnormal = Aß+), cortical thickness in 34 regions and hippocampal volume. Mediation analyses were performed to test whether effects of Aß on cognitive decline were mediated by atrophy of specific anatomical brain areas. RESULTS: Subjects had a mean age of 92.7 ± 2.9 years, of whom 19 (33%) were Aß+. Compared to Aß-, Aß+ individuals showed steeper decline on memory (ß ± SE = -0.26 ± 0.09), and processing speed (ß ± SE = -0.18 ± 0.08) performance over 1.5 years (P < 0.05). Furthermore, medial and lateral temporal lobe atrophy was associated with steeper decline in memory and language across individuals. Mediation analyses revealed that part of the memory decline observed in Aß+ individuals was mediated through parahippocampal atrophy. INTERPRETATION: These results show that Aß abnormality even in the oldest old with initially normal cognition is not part of normal aging, but is associated with a decline in cognitive functioning. Other pathologies may also contribute to decline in the oldest old as cortical thickness predicted cognitive decline similarly in individuals with and without Aß pathology.

3.
Disabil Rehabil Assist Technol ; : 1-13, 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33245000

RESUMO

PURPOSE: FindMyApps is a web-based selection-tool and errorless learning training program to help people with mild dementia/Mild Cognitive Impairment (MCI) and caregivers find user-friendly apps. In preparation of a definitive trial, the impact and feasibility of the FindMyApps intervention on self-management and engagement in meaningful activities, including social participation, was explored. MATERIALS AND METHODS: An exploratory pilot randomised controlled trial (trial registration approval number: NL7210) with pre/post measurements was conducted with community-dwelling people with mild dementia/MCI and their caregivers (n = 59) in the Netherlands. Dyads in the experimental group (n = 28) received training to use the tablet and FindMyApps, and the errorless learning method was taught to their caregivers. Control group dyads (n = 31) received a tablet (without FindMyApps), instructions on tablet-use and links to dementia-friendly apps. Validated instruments were used to assess person with dementia's self-management, meaningful activities and social participation, caregiver's sense of competence and both their quality of life. RESULTS AND CONCLUSIONS: No statistical significant group differences on the outcomes were found. Small to moderate effect-sizes in favour of the FindMyApps group were found for self-management and social participation. Caregivers tended to have more positive care experiences. Subgroup analyses showed that people older than 70 benefitted more from FindMyApps regarding self-management and higher educated people benefitted more regarding social participation. FindMyApps is feasible for the target group and may have potential to improve self-management and social participation. For a future definitive effectiveness trial a larger sample size is recommended, as well as taking into account the possible impact of education and age.IMPLICATIONS FOR REHABILITATIONThe FindMyApps program is feasible for people with dementia/MCI and may have potential to improve their self-management and social participation.Informal caregivers may develop a more positive care experience when utilizing FindMyApps to find suitable apps for self-management and social participation for the person with dementia/MCI.

4.
Neurology ; 93(17): e1635-e1646, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31597710

RESUMO

OBJECTIVE: To apply the ATN scheme to memory clinic patients, to assess whether it discriminates patient populations with specific features. METHODS: We included 305 memory clinic patients (33% subjective cognitive decline [SCD]: 60 ± 9 years, 61% M; 19% mild cognitive impairment [MCI]: 68 ± 9 years, 68% M; 48% dementia: 66 ± 10 years, 58% M) classified for positivity (±) of amyloid (A) ([18F]Florbetaben PET), tau (T) (CSF p-tau), and neurodegeneration (N) (medial temporal lobe atrophy). We assessed ATN profiles' demographic, clinical, and cognitive features at baseline, and cognitive decline over time. RESULTS: The proportion of A+T+N+ patients increased with syndrome severity (from 1% in SCD to 14% in MCI and 35% in dementia), while the opposite was true for A-T-N- (from 48% to 19% and 6%). Compared to A-T-N-, patients with the Alzheimer disease profiles (A+T+N- and A+T+N+) were older (both p < 0.05) and had a higher prevalence of APOE ε4 (both p < 0.05) and lower Mini-Mental State Examination (MMSE) (both p < 0.05), memory (both p < 0.05), and visuospatial abilities (both p < 0.05) at baseline. Non-Alzheimer profiles A-T-N+ and A-T+N+ showed more severe white matter hyperintensities (both p < 0.05) and worse language performance (both p < 0.05) than A-T-N-. A linear mixed model showed faster decline on MMSE over time in A+T+N- and A+T+N+ (p = 0.059 and p < 0.001 vs A-T-N-), attributable mainly to patients without dementia. CONCLUSIONS: The ATN scheme identified different biomarker profiles with overlapping baseline features and patterns of cognitive decline. The large number of profiles, which may have different implications in patients with vs without dementia, poses a challenge to the application of the ATN scheme.


Assuntos
Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Demência/diagnóstico por imagem , Idoso , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Demência/genética , Demência/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico por imagem , Degeneração Neural/metabolismo , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Proteínas tau/metabolismo
5.
Alzheimers Dement ; 15(11): 1458-1467, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31594684

RESUMO

INTRODUCTION: The objective of this study was to assess the usefulness of the appropriate use criteria (AUC) for amyloid imaging in an unselected cohort. METHODS: We calculated sensitivity and specificity of appropriate use (increased confidence and management change), as defined by Amyloid Imaging Taskforce in the AUC, and other clinical utility outcomes. Furthermore, we compared differences in post-positron emission tomography diagnosis and management change between "AUC-consistent" and "AUC-inconsistent" patients. RESULTS: Almost half (250/507) of patients were AUC-consistent. In both AUC-consistent and AUC-inconsistent patients, post-positron emission tomography diagnosis (28%-21%) and management (32%-17%) change was substantial. The Amyloid Imaging Taskforce's definition of appropriate use occurred in 55/507 (13%) patients, detected by the AUC with a sensitivity of 93%, and a specificity of 56%. Diagnostic changes occurred independently of AUC status (sensitivity: 57%, specificity: 53%). DISCUSSION: The current AUC are not sufficiently able to discriminate between patients who will benefit from amyloid positron emission tomography and those who will not.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Amiloide/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Idoso , Encéfalo/metabolismo , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
6.
JMIR Form Res ; 3(3): e13417, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31287061

RESUMO

BACKGROUND: As a result of advances in diagnostic testing in the field of Alzheimer disease (AD), patients are diagnosed in earlier stages of the disease, for example, in the stage of mild cognitive impairment (MCI). This poses novel challenges for a clinician during the diagnostic workup with regard to diagnostic testing itself, namely, which tests are to be performed, but also on how to engage patients in this decision and how to communicate test results. As a result, tools to support decision making and improve risk communication could be valuable for clinicians and patients. OBJECTIVE: The aim of this study was to present the design, development, and testing of a Web-based tool for clinicians in a memory clinic setting and to ascertain whether this tool can (1) facilitate the interpretation of biomarker results in individual patients with MCI regarding their risk of progression to dementia, (2) support clinicians in communicating biomarker test results and risks to MCI patients and their caregivers, and (3) support clinicians in a process of shared decision making regarding the diagnostic workup of AD. METHODS: A multiphase mixed-methods approach was used. Phase 1 consisted of a qualitative needs assessment among professionals, patients, and caregivers; phase 2, consisted of an iterative process of development and the design of the tool (ADappt); and phase 3 consisted of a quantitative and qualitative assessment of usability and acceptability of ADappt. Across these phases, co-creation was realized via a user-centered qualitative approach with clinicians, patients, and caregivers. RESULTS: In phase 1, clinicians indicated the need for risk calculation tools and visual aids to communicate test results to patients. Patients and caregivers expressed their needs for more specific information on their risk for developing AD and related consequences. In phase 2, we developed the content and graphical design of ADappt encompassing 3 modules: a risk calculation tool, a risk communication tool including a summary sheet for patients and caregivers, and a conversation starter to support shared decision making regarding the diagnostic workup. In phase 3, ADappt was considered to be clear and user-friendly. CONCLUSIONS: Clinicians in a memory clinic setting can use ADappt, a Web-based tool, developed using multiphase design and co-creation, for support that includes an individually tailored interpretation of biomarker test results, communication of test results and risks to patients and their caregivers, and shared decision making on diagnostic testing.

7.
Hum Brain Mapp ; 40(13): 3900-3909, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31157938

RESUMO

Myelin determines the conduction of neuronal signals along axonal connections in networks of the brain. Loss of myelin integrity in neuronal circuits might result in cognitive decline in Alzheimer's disease (AD). Recently, the ratio of T1-weighted by T2-weighted MRI has been used as a proxy for myelin content in gray matter of the cortex. With this approach, we investigated whether AD dementia patients show lower cortical myelin content (i.e., a lower T1-w/T2-w ratio value). We selected structural T1-w and T2-w MR images of 293 AD patients and 172 participants with normal cognition (NC). T1-w/T2-w ratios were computed for the whole brain and within 90 automated anatomical labeling atlas regions using SPM12, compared between groups and correlated with the neuronal injury marker tau in cerebrospinal fluid (CSF) and Mini Mental State Examination (MMSE). In contrast to our hypothesis, AD patients showed higher whole brain T1-w/T2-w ratios than NC, and regionally in 31 anatomical areas (p < .0005; d = 0.21 to 0.48), predominantly in the inferior parietal lobule, angular gyrus, anterior cingulate, and precuneus. Regional higher T1-w/T2-w values were associated with higher CSF tau concentrations (p < .0005; r = .16 to .22) and worse MMSE scores (p < .0005; r = -.16 to -.21). These higher T1-w/T2-w values in AD seem to contradict previous pathological findings of demyelination and disconnectivity in AD. Future research should further investigate the biological processes reflected by increases in T1-w/T2-w values.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Imageamento por Ressonância Magnética , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
JAMA Neurol ; 75(9): 1062-1070, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29889941

RESUMO

Importance: Previous studies have evaluated the diagnostic effect of amyloid positron emission tomography (PET) in selected research cohorts. However, these research populations do not reflect daily practice, thus hampering clinical implementation of amyloid imaging. Objective: To evaluate the association of amyloid PET with changes in diagnosis, diagnostic confidence, treatment, and patients' experiences in an unselected memory clinic cohort. Design, Setting, and Participants: Amyloid PET using fluoride-18 florbetaben was offered to 866 patients who visited the tertiary memory clinic at the VU University Medical Center between January 2015 and December 2016 as part of their routine diagnostic dementia workup. Of these patients, 476 (55%) were included, 32 (4%) were excluded, and 358 (41%) did not participate. To enrich this sample, 31 patients with mild cognitive impairment from the University Medical Center Utrecht memory clinic were included. For each patient, neurologists determined a preamyloid and postamyloid PET diagnosis that existed of both a clinical syndrome (dementia, mild cognitive impairment, or subjective cognitive decline) and a suspected etiology (Alzheimer disease [AD] or non-AD), with a confidence level ranging from 0% to 100%. In addition, the neurologist determined patient treatment in terms of ancillary investigations, medication, and care. Each patient received a clinical follow-up 1 year after being scanned. Main Outcomes and Measures: Primary outcome measures were post-PET changes in diagnosis, diagnostic confidence, and patient treatment. Results: Of the 507 patients (mean [SD] age, 65 (8) years; 201 women [39%]; mean [SD] Mini-Mental State Examination score, 25 [4]), 164 (32%) had AD dementia, 70 (14%) non-AD dementia, 114 (23%) mild cognitive impairment, and 159 (31%) subjective cognitive decline. Amyloid PET results were positive for 242 patients (48%). The suspected etiology changed for 125 patients (25%) after undergoing amyloid PET, more often due to a negative (82 of 265 [31%]) than a positive (43 of 242 [18%]) PET result (P < .01). Post-PET changes in suspected etiology occurred more frequently in patients older (>65 years) than younger (<65 years) than the typical age at onset of 65 years (74 of 257 [29%] vs 51 of 250 [20%]; P < .05). Mean diagnostic confidence (SD) increased from 80 (13) to 89 (13%) (P < .001). In 123 patients (24%), there was a change in patient treatment post-PET, mostly related to additional investigations and therapy. Conclusions and Relevance: This prospective diagnostic study provides a bridge between validating amyloid PET in a research setting and implementing this diagnostic tool in daily clinical practice. Both amyloid-positive and amyloid-negative results had substantial associations with changes in diagnosis and treatment, both in patients with and without dementia.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Tomada de Decisão Clínica , Demência/diagnóstico por imagem , Demência/terapia , Tomografia por Emissão de Pósitrons/métodos , Idoso , Compostos de Anilina , Encéfalo/metabolismo , Estudos de Coortes , Demência/etiologia , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Estudos Prospectivos , Estilbenos
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