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1.
Alzheimers Dement ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31409541

RESUMO

INTRODUCTION: The purpose of this study was to determine the cost-effectiveness of collaborative dementia care management (DCM). METHODS: The cost-effectiveness analysis was based on the data of 444 patients of a cluster-randomized, controlled trial, conceptualized to evaluate a collaborative DCM that aimed to optimize treatment and care in dementia. Health-care resource use, costs, quality-adjusted life years (QALYs), and incremental cost per QALY gained were measured over a 24-month time horizon. RESULTS: DCM increased QALYs (+0.05) and decreased costs (-569€) due to a lower hospitalization and a delayed institutionalization (7 months) compared with usual care. The probability of DCM being cost-effective was 88% at willingness-to-pay thresholds of 40,000€ per QALY gained and higher in patients living alone compared to those not living alone (96% vs. 26%). DISCUSSION: DCM is likely to be a cost-effective strategy in treating dementia and thus beneficial for public health-care payers and patients, especially for those living alone.

2.
Alzheimers Res Ther ; 11(1): 66, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366409

RESUMO

BACKGROUND: Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer's disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers. METHODS: We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers. RESULTS: Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181. CONCLUSIONS: Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.

3.
Gerontology ; : 1-10, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362286

RESUMO

BACKGROUND: Detecting manifestations of spatial disorientation in real time is a key requirement for adaptive assistive navigation systems for people with dementia. OBJECTIVE: To identify predictive patterns of spatial disorientation in cognitively impaired people during unconstrained locomotion behavior in an urban environment. METHODS: Accelerometric data and GPS records were gathered during a wayfinding task along a route of about 1 km in 15 people with amnestic mild cognitive impairment or clinically probable Alzheimer's disease dementia (13 completers). We calculated a set of 48 statistical features for each 10-s segment of the acceleration sensor signal to characterize the physical motion. We used different classifiers with the wrapper method and leave-one-out cross-validation for feature selection and for determining accuracy of disorientation detection. RESULTS: Linear discriminant analysis using three features showed the best classification results, with a cross-validated ROC AUC of 0.75, detecting 65% of all scenes of spatial disorientation in real time. Consideration of an additional feature that informed about a person's distance to the next traffic junction did not provide an additional information gain. CONCLUSIONS: Accelerometric data are able to capture the uniformity and activity of a person's walking, which are identified as the most informative locomotion features of spatially disoriented behavior. This serves as an important basis for real-time navigation assistance. To improve the required accuracy of real-time disorientation prediction, as a next step we will analyze whether location-based behavior is able to inform about person-centered habitual factors of orientation.

4.
J Neurol ; 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227891

RESUMO

INTRODUCTION: Subjective cognitive decline (SCD) can represent a preclinical stage of Alzheimer's disease. Diffusion tensor imaging (DTI) could aid an early diagnosis, yet only few monocentric DTI studies in SCD have been conducted, reporting heterogeneous results. We investigated microstructural changes in SCD in a larger, multicentric cohort. METHODS: 271 participants with SCD, mild cognitive impairment (MCI) or Alzheimer's dementia (AD) and healthy controls (CON) were included, recruited prospectively at nine centers of the observational DELCODE study. DTI was acquired using identical protocols. Using voxel-based analyses, we investigated fractional anisotropy (FA), mean diffusivity (MD) and mode (MO) in the white matter (WM). Discrimination accuracy was determined by cross-validated elastic-net penalized regression. Center effects were explored using variance analyses. RESULTS: MO and FA were lower in SCD compared to CON in several anterior and posterior WM regions, including the anterior corona radiata, superior and inferior longitudinal fasciculus, cingulum and splenium of the corpus callosum (p < 0.01, uncorrected). MD was higher in the superior and inferior longitudinal fasciculus, cingulum and superior corona radiata (p < 0.01, uncorrected). The cross-validated accuracy for discriminating SCD from CON was 67% (p < 0.01). As expected, the AD and MCI groups had higher MD and lower FA and MO in extensive regions, including the corpus callosum and temporal brain regions. Within these regions, center accounted for 3-15% of the variance. CONCLUSIONS: DTI revealed subtle WM alterations in SCD that were intermediate between those in MCI and CON and may be useful to detect individuals with an increased risk for AD in clinical studies.

5.
Alzheimers Dement ; 15(5): 605-614, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30894299

RESUMO

INTRODUCTION: Evidence for the efficacy of cognitive training in patients with subcortical vascular cognitive impairment no dementia is still lacking. METHODS: A randomized, active controlled design using multidomain, adaptive, computerized cognitive training for 30 minutes, 5 days/week for 7 weeks. Assessments included global cognitive function and executive function (primary outcomes) and brain functional connectivity and structural changes (secondary outcomes). RESULTS: Sixty patients were randomized across three medical centers in Beijing. At the end of the intervention, the cognitive training group showed significant improvement in Montreal Cognitive Assessment relative to the active control group (P = .013) and significantly increased functional connectivity between the left dorsolateral prefrontal cortex and medial prefrontal cortex, which was significantly correlated with Montreal Cognitive Assessment change (P = .017). DISCUSSION: Computerized cognitive training significantly improved global cognitive function, which was supported by the improved brain plasticity. Incorporation of biomarkers should be implemented in cognitive training trials.

6.
Mol Psychiatry ; 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30899092

RESUMO

In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aß) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aß, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aß-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.

7.
Alzheimers Res Ther ; 11(1): 15, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704537

RESUMO

BACKGROUND: Current methods of amyloid PET interpretation based on the binary classification of global amyloid signal fail to identify early phases of amyloid deposition. A recent analysis of 18F-florbetapir PET data from the Alzheimer's disease Neuroimaging Initiative cohort suggested a hierarchical four-stage model of regional amyloid deposition that resembles neuropathologic estimates and can be used to stage an individual's amyloid burden in vivo. Here, we evaluated the validity of this in vivo amyloid staging model in an independent cohort of older people with subjective memory complaints (SMC). We further examined its potential association with subtle cognitive impairments in this population at elevated risk for Alzheimer's disease (AD). METHODS: The monocentric INSIGHT-preAD cohort includes 318 cognitively intact older individuals with SMC. All individuals underwent 18F-florbetapir PET scanning and extensive neuropsychological testing. We projected the regional amyloid uptake signal into the previously proposed hierarchical staging model of in vivo amyloid progression. We determined the adherence to this model across all cases and tested the association between increasing in vivo amyloid stage and cognitive performance using ANCOVA models. RESULTS: In total, 156 participants (49%) showed evidence of regional amyloid deposition, and all but 2 of these (99%) adhered to the hierarchical regional pattern implied by the in vivo amyloid progression model. According to a conventional binary classification based on global signal (SUVRCereb = 1.10), individuals in stages III and IV were classified as amyloid-positive (except one in stage III), but 99% of individuals in stage I and even 28% of individuals in stage II were classified as amyloid-negative. Neither in vivo amyloid stage nor conventional binary amyloid status was significantly associated with cognitive performance in this preclinical cohort. CONCLUSIONS: The proposed hierarchical staging scheme of PET-evidenced amyloid deposition generalizes well to data from an independent cohort of older people at elevated risk for AD. Future studies will determine the prognostic value of the staging approach for predicting longitudinal cognitive decline in older individuals at increased risk for AD.

8.
Alzheimers Res Ther ; 11(1): 8, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30654834

RESUMO

INTRODUCTION: Subjective cognitive decline (SCD) in cognitively unimpaired older individuals has been recognized as an early clinical at-risk state for Alzheimer's disease (AD) dementia and as a target population for future dementia prevention trials. Currently, however, SCD is heterogeneously defined across studies, potentially leading to variations in the prevalence of AD pathology. Here, we compared the prevalence and identified common determinants of abnormal AD biomarkers in SCD across three European memory clinics participating in the European initiative on harmonization of SCD in preclinical AD (Euro-SCD). METHODS: We included three memory clinic SCD samples with available cerebrospinal fluid (CSF) biomaterial (IDIBAPS, Barcelona, Spain, n = 44; Amsterdam Dementia Cohort (ADC), The Netherlands, n = 50; DELCODE multicenter study, Germany, n = 42). CSF biomarkers (amyloid beta (Aß)42, tau, and phosphorylated tau (ptau181)) were centrally analyzed in Amsterdam using prespecified cutoffs to define prevalence of pathological biomarker concentrations. We used logistic regression analysis in the combined sample across the three centers to investigate center effects with regard to likelihood of biomarker abnormality while taking potential common predictors (e.g., age, sex, apolipoprotein E (APOE) status, subtle cognitive deficits, depressive symptoms) into account. RESULTS: The prevalence of abnormal Aß42, but not tau or ptau181, levels was different across centers (64% DELCODE, 57% IDIBAPS, 22% ADC; p < 0.001). Logistic regression analysis revealed that the likelihood of abnormal Aß42 (and also abnormal tau or ptau181) levels was predicted by age and APOE status. For Aß42 abnormality, we additionally observed a center effect, indicating between-center heterogeneity not explained by age, APOE, or the other included covariates. CONCLUSIONS: While heterogeneous frequency of abnormal Aß42 was partly explained by between-sample differences in age range and APOE status, the additional observation of center effects indicates between-center heterogeneity that may be attributed to different recruitment procedures. These findings highlight the need for the development of harmonized recruitment protocols for SCD case definition in multinational studies to achieve similar enrichment rates of preclinical AD.

9.
Z Gerontol Geriatr ; 2019 Jan 14.
Artigo em Alemão | MEDLINE | ID: mdl-30643963

RESUMO

INTRODUCTION: Family caregivers of people with dementia (PwD) have a high burden and therefore are themselves at a high risk for psychiatric and somatic morbidities. Although individual psychotherapy has been shown to be a potentially effective treatment, it is rarely used by family caregivers. Possible reasons are poor accessibility and time restrictions on the side of the caregiver. AIM: To test the efficacy of a short-term and low threshold psychotherapeutic group intervention for family caregivers of PwD with respect to mental stability of the caregivers. MATERIAL AND METHODS: Data from a 12-week psychotherapeutic group intervention (10 participants each in the intervention and control groups) were analyzed. Main topics of the intervention were: personal limits, dysfunctional thoughts, emotions and resource activation. Primary endpoints were an increase of perceived self-efficacy and reduction of depressive symptoms using SWE and ADS questionnaires before, directly and 3 months after the end of the intervention. RESULTS: A gain in perceived self-efficacy did not reach statistical significance, whereas depressive symptoms showed a statistically significant increase in the intervention group over time compared to the control group. DISCUSSION: The intervention did not reach its primary endpoints. Possible reasons are the fact that the group was highly heterogeneous with respect to dementia etiology and the low number of participants. The short duration of the intervention may have reduced the potential of the program to address all urgent needs of the participants.

10.
Neuroimage Clin ; 21: 101612, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30555006

RESUMO

Subjective cognitive decline (SCD) patients are considered as a risk population for preclinical Alzheimer's Disease (AD). Supporting this idea, previous studies in SCD populations report subtle alterations in various cognitive and neuroimaging biomarkers that are typically affected during AD progression. To extend these observations, the present study examined whether SCD patients show atrophy of cholinergic basal forebrain nuclei (chBFN), analogous with recent findings in prodromal and clinical AD patients. We assessed volume reductions of the chBFN in 24 SCD subjects compared to 49 matched controls on 3D-T1-weighted MR images based on a postmortem derived atlas. Furthermore, we assessed whether chBFN atrophy was linked with cognitive, structural and metabolic biomarker alterations we previously reported in this SCD cohort: Using correlation analyses we tested for associations between the volumes of the chBFN with the hippocampal gray matter volume, and posterior medial glucose consumption, and the trajectory of verbal memory performance. The SCD cases showed a significant total volume reduction of the chBFN, with largest effect sizes in the Ch1/2 and Ch4p subdivisions of the chBFN. The latter was associated with a reduced glucose metabolism in the precuneus for the SCD group only. These data show an early involvement of the cholinergic basal forebrain nuclei in SCD predominantly in Ch1/2 and Ch4p which supports the conceptual link between SCD and preclinical AD.

11.
J Alzheimers Dis ; 67(2): 527-539, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30584136

RESUMO

BACKGROUND: Caregivers providing informal care for people with dementia (PwD) often report unmet needs, burden, and health impairments. Optimal support for family dementia caregivers will likely benefit from better understanding and assessment of the prevalence and types of caregivers' unmet needs and associated socio-demographic and clinical characteristics. OBJECTIVE: The present study investigates 1) the number and types of caregivers' unmet needs, 2) socio-demographic and clinical characteristics of both PwD and caregivers, and 3) caregivers' burden and health-related outcomes that are related to caregivers' unmet needs. METHODS: The present analyses are based on cross-sectional data of n = 226 dyads of caregivers and their community-dwelling PwD participating in a comprehensive standardized, computer-based caregivers' needs assessment within a general practitioner (GP)-based, cluster-randomized intervention trial. RESULTS: A total of n = 505 unmet needs were identified for n = 171 caregivers from the intervention group at baseline. Only 24.3% caregivers reported no unmet need (n = 55), whereas 75.7% caregivers had at least one unmet need (n = 171). Caregivers had on average 2.19 unmet needs (mean = 2.19, SD = 2.15). Specifically, 53.1% of caregivers had one up to three unmet needs (n = 120), 18.6% (n = 42) had three up to six unmet needs, and 4.0% (n = 9) had more than six unmet needs. DISCUSSION: Our results underline the importance of a comprehensive needs assessment for family dementia caregivers to develop and implement concepts that can provide family dementia caregivers with optimal support.

12.
Radiology ; : 180268, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30351255

RESUMO

Purpose To evaluate the association between the global fibrillary amyloid-ß pathology and the basal forebrain connectivity at rest in cognitively intact older adults at risk for Alzheimer disease. Materials and Methods This retrospective study was approved by the local ethics committee and written informed consent was obtained from all participants. Resting-state functional connectivity (RSFC) of anterior and posterior basal forebrain seeds was investigated, as well as PET-measured global amyloid-ß load by using standardized uptake value ratio (SUVR) in 267 older cognitively intact individuals with subjective memory complaints (age range, 70-85 years; overall mean age, 75.8 years; 167 women [mean age, 75.9 years] and 100 men [mean age, 75.8 years]). The participants were from the Investigation of Alzheimer's Predictors in Subjective Memory Complainers (INSIGHT-preAD) cohort (date range, 2013-present). The relationship between SUVR and the basal forebrain RSFC was assessed, followed by the effects of apolipoprotein E (APOE) genotype and sex on the basal forebrain RSFC. Results Higher SUVR values correlated with lower posterior basal forebrain RSFC in the hippocampus and the thalamus (Pearson r =-0.23; P <.001 corrected for familywise error [FWE]). Both sex and APOE genotype impacted the associations between basal forebrain RSFC and the global amyloid deposition (t values >3.59; P <.05 corrected for FWE). Conclusion Data indicate a distinct in vivo association between posterior basal forebrain dynamics and global fibrillary amyloid-ß pathology in cognitively intact older adults with subjective memory complaints; both apolipoprotein E and sex moderate such association. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Caspers in this issue.

13.
Hum Brain Mapp ; 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311315

RESUMO

The cholinergic basal forebrain (CBF), comprising different groups of cortically projecting cholinergic neurons, plays a crucial role in higher cognitive processes and has been implicated in diverse neuropsychiatric disorders. A distinct corticotopic organization of CBF projections has been revealed in animal studies, but little is known about their organization in the human brain. We explored regional differences in functional connectivity (FC) profiles within the human CBF by applying a clustering approach to resting-state functional magnetic resonance imaging (rs-fMRI) data of healthy adult individuals (N = 85; 19-85 years). We further examined effects of age on FC of the identified CBF clusters and assessed the reproducibility of cluster-specific FC profiles in independent data from healthy older individuals (N = 25; 65-89 years). Results showed that the human CBF is functionally organized into distinct anterior-medial and posterior-lateral subdivisions that largely follow anatomically defined boundaries of the medial septum/diagonal band and nucleus basalis Meynert. The anterior-medial CBF subdivision was characterized by connectivity with the hippocampus and interconnected nodes of an extended medial cortical memory network, whereas the posterior-lateral subdivision was specifically connected to anterior insula and dorsal anterior cingulate components of a salience/attention network. FC of both CBF subdivisions declined with increasing age, but the overall topography of subregion-specific FC profiles was reproduced in independent rs-fMRI data of healthy older individuals acquired in a typical clinical setting. Rs-fMRI-based assessments of subregion-specific CBF function may complement established volumetric approaches for the in vivo study of CBF involvement in neuropsychiatric disorders.

14.
Alzheimers Dement ; 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30321506

RESUMO

INTRODUCTION: Previous studies showed associations of brain volume differences and biomarker evidence for Alzheimer's disease (AD) in subjective cognitive decline (SCD). The consistency of this finding across SCD studies has not been investigated. METHODS: We studied gray matter volume differences between SCD subjects with and without cerebrospinal fluid biomarker evidence for AD across three European memory clinic samples (German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia study, Amsterdam, Barcelona). Analysis of covariance models with samples and cerebrospinal fluid biomarkers as between-subject factors were calculated. RESULTS: A significant main effect for AD biomarker (Aß42- > Aß42+) in the left medial temporal lobe (MTL) was found, with the absence of main effects for sample or interaction effects between AD biomarker and sample. This indicates consistent lower left MTL volume across three samples in SCD subjects with abnormal Aß42 levels. DISCUSSION: Our results support the model that in the presence of AD pathology, SCD corresponds to the late preclinical stage (stage 2 of AD) with smaller MTL volumes.

15.
Alzheimers Dement ; 14(9): 1204-1215, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30201102

RESUMO

INTRODUCTION: Observational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers. METHODS: Positron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose-positron emission tomography metabolism), and brain resting-state functional connectivity were analyzed in 318 cognitively intact older adults from the INSIGHT-preAD cohort (female n = 201, male n = 117). A linear mixed-effects model was performed to investigate sex effects and sex∗apolipoprotein E genotype interaction on each marker as well as sex∗amyloid group interaction for non-amyloid markers. RESULTS: Men compared with women showed higher anterior cingulate cortex amyloid load (P = .009), glucose hypometabolism in the precuneus (P = .027), posterior cingulate (P < .001) and inferior parietal (P = .043) cortices, and lower resting-state functional connectivity in the default mode network (P = .024). No brain volumetric markers showed differences between men and women. Sex∗apolipoprotein E genotype and sex∗amyloid status interactions were not significant. DISCUSSION: Our findings suggest that cognitively intact older men compared with women have higher resilience to pathophysiological processes of Alzheimer's disease.

16.
Front Neurol ; 9: 642, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30158893

RESUMO

Background: Predicting the progression of cognitive decline in Alzheimer's disease (AD) is important for treatment selection and patient counseling. Structural MRI markers such as hippocampus or basal forebrain volumes might represent useful instruments for the prediction of cognitive decline. The primary objective was to determine the predictive value of hippocampus and basal forebrain volumes for global and domain specific cognitive decline in AD dementia during cholinergic treatment. Methods: We used MRI and cognitive data from 124 patients with the clinical diagnosis of AD dementia, derived from the ADNI-1 cohort, who were on standard of care cholinesterase inhibitor treatment during a follow-up period between 0.4 and 3.1 years. We used linear mixed effects models with cognitive function as outcome to assess the main effects as well as two-way interactions between baseline volumes and time controlling for age, sex, and total intracranial volume. This model accounts for individual variation in follow-up times. Results: Basal forebrain volume, but not hippocampus volume, was a significant predictor of rates of global cognitive decline. Larger volumes were associated with smaller rates of cognitive decline. Left hippocampus volume had a modest association with rates of episodic memory decline. Baseline performance in global cognition and memory was significantly associated with hippocampus and basal forebrain volumes; in addition, basal forebrain volume was associated with baseline performance in executive function. Conclusions: Our findings indicate that in AD dementia patients, basal forebrain volume may be a useful marker to predict subsequent cognitive decline during cholinergic treatment.

17.
J Alzheimers Dis ; 64(4): 1091-1097, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30010118

RESUMO

BACKGROUND: There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation. OBJECTIVE: 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α1-adrenergic receptors (α1-AR-agAAB) and agABB directed against ß2-adrenergic receptors (ß2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care. METHODS: Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked. RESULTS: In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α1-AR-agAAB and n = 21 (22%) ß2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment. DISCUSSION: For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB.

18.
Brain ; 141(9): 2755-2771, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30016411

RESUMO

Amyloid deposition and neurofibrillary degeneration in Alzheimer's disease specifically affect discrete neuronal systems, but the underlying mechanisms that render some brain regions more vulnerable to Alzheimer's disease pathology than others remain largely unknown. Here we studied molecular properties underlying these distinct regional vulnerabilities by analysing Alzheimer's disease-typical neuroimaging patterns of amyloid deposition and neurodegeneration in relation to regional gene expression profiles of the human brain. Graded patterns of brain-wide vulnerability to amyloid deposition and neurodegeneration in Alzheimer's disease were estimated by contrasting multimodal amyloid-sensitive PET and structural MRI data between patients with Alzheimer's disease dementia (n = 76) and healthy controls (n = 126) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen brain atlas of the adult human brain transcriptome. In a hypothesis-driven analysis focusing on the genes coding for the amyloid precursor (APP) and tau proteins (MAPT), regional expression levels of APP were positively correlated with the severity of regional amyloid deposition (r = 0.44, P = 0.009), but not neurodegeneration (r = 0.01, P = 0.96), whereas the opposite pattern was observed for MAPT (neurodegeneration: r = 0.46, P = 0.006; amyloid: r = 0.08, P = 0.65). Using explorative gene set enrichment analysis, amyloid-vulnerable regions were found to be characterized by relatively low expression levels of gene sets implicated in protein synthesis and mitochondrial respiration. By contrast, neurodegeneration-vulnerable regions were characterized by relatively high expression levels of gene sets broadly implicated in neural plasticity, with biological functions ranging from neurite outgrowth and synaptic contact over intracellular signalling cascades to proteoglycan metabolism. At the individual gene level this data-driven analysis further corroborated the association between neurodegeneration and MAPT expression, and additionally identified associations with known tau kinases (CDK5, MAPK1/ERK2) alongside components of their intracellular (Ras-ERK) activation pathways. Sensitivity analyses showed that these pathology-specific imaging-genetic associations were largely robust against changes in some of the methodological parameters, including variation in the brain donor sample used for estimating regional gene expression profiles, and local variations in the Alzheimer's disease-typical imaging patterns when these were derived from an independent patient cohort (BioFINDER study). These findings highlight that the regionally selective vulnerability to Alzheimer's disease pathology relates to specific molecular-functional properties of the affected neural systems, and that the implicated biochemical pathways largely differ for amyloid accumulation versus neurodegeneration. The data provide novel insights into the complex pathophysiological mechanisms of Alzheimer's disease and point to pathology-specific treatment targets that warrant further exploration in independent studies.

19.
J Alzheimers Dis ; 64(3): 925-932, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29889067

RESUMO

BACKGROUND: The current guidelines imply that basic medical diagnostics for dementia should be provided by general practitioners in cooperation with other specialists such as neurologists and psychiatrists. OBJECTIVES: The aims of this paper were to 1) compare the dementia patients of general practice residents whose care is co-managed by neurology/psychiatry residents with those whose care is not; 2) identify the patient variables associated with the utilization of neurological and psychiatric specialists; and 3) describe the frequency of imaging used for dementia patients in primary care. METHODS: The analyses utilized data from 485 individuals who screened positive for dementia in primary care (PWD). Clinical variables and the utilization of specialists were assessed via medical records and face-to-face interviews. The factors associated with the utilization of specialists were assessed using multivariate linear regression and included age, sex, relationship status, cognitive impairment, depression, activities of daily living, and formal diagnosis of dementia. RESULTS: Our results show that 89 out of 485 study participants (18.4%) were referred to specialists 12 months prior to assessment. Of these 89 individuals, 14.6% (n = 13) did not receive imaging diagnostics, while 39.3% (n = 35) received brain imaging by CT scan and 46.1% (n = 41) by MRI. PWD referred to specialists differed from those not referred, in age, relationship status, and the presence of a formal diagnosis. Our multivariate analysis revealed that younger age (OR = 0.95; 95% -confidence interval 0.90-0.99; p = 0.04) and higher functional impairment (OR = 1.15; 95% -confidence interval 1.02-1.30; p = 0.02) were associated with a visit to a specialist. DISCUSSION: Only 1 out of every 4 to 5 individuals who have screened positive for dementia have visited a specialist in psychiatry or neurology. While in general, women utilized specialists less often than men, younger and more functionally impaired patients were more likely to be sent to a specialist by their treating general practitioner. Almost 90% of the patients sent to a specialist received cranial neuroimaging, suggesting high adherence to diagnostic guidelines in specialized care.

20.
Alzheimers Dement ; 14(9): 1216-1231, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29936147

RESUMO

Cognitive function is an important end point of treatments in dementia clinical trials. Measuring cognitive function by standardized tests, however, is biased toward highly constrained environments (such as hospitals) in selected samples. Patient-powered real-world evidence using information and communication technology devices, including environmental and wearable sensors, may help to overcome these limitations. This position paper describes current and novel information and communication technology devices and algorithms to monitor behavior and function in people with prodromal and manifest stages of dementia continuously, and discusses clinical, technological, ethical, regulatory, and user-centered requirements for collecting real-world evidence in future randomized controlled trials. Challenges of data safety, quality, and privacy and regulatory requirements need to be addressed by future smart sensor technologies. When these requirements are satisfied, these technologies will provide access to truly user relevant outcomes and broader cohorts of participants than currently sampled in clinical trials.

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