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1.
Sci Transl Med ; 11(505)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413141

RESUMO

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 × 10-15); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.

2.
Sci Transl Med ; 11(507)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462511

RESUMO

Loss of function of TREM2, a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). We therefore examined whether soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) were associated with reduced rates of cognitive decline and clinical progression in subjects with AD or mild cognitive impairment (MCI). We measured sTREM2 in CSF samples from 385 elderly subjects, including cognitively normal controls, individuals with MCI, and subjects with AD dementia (follow-up period: mean, 4 years; range 1.5 to 11.5 years). In subjects with AD defined by evidence of CSF Aß1-42 (amyloid ß-peptide 1 to 42; A+) and CSF p-tau181 (tau phosphorylated on amino acid residue 181; T+), higher sTREM2 concentrations in CSF at baseline were associated with attenuated decline in memory and cognition. When analyzed in clinical subgroups, an association between higher CSF sTREM2 concentrations and subsequent reduced memory decline was consistently observed in individuals with MCI or AD dementia, who were positive for CSF Aß1-42 and CSF p-tau181 (A+T+). Regarding clinical progression, a higher ratio of CSF sTREM2 to CSF p-tau181 concentrations predicted slower conversion from cognitively normal to symptomatic stages or from MCI to AD dementia in the subjects who were positive for CSF Aß1-42 and CSF p-tau181. These results suggest that sTREM2 is associated with attenuated cognitive and clinical decline, a finding with important implications for future clinical trials targeting the innate immune response in AD.

3.
Neuroimage Clin ; 24: 101949, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31398553

RESUMO

OBJECTIVES: Many predictive or influencing factors have emerged in investigations of the cognitive reserve model of patients with Alzheimer's disease (AD). For example, neuronal injury, which correlates with cognitive decline in AD, can be assessed by [18F]-fluorodeoxyglucose positron-emission-tomography (FDG-PET), structural magnetic resonance imaging (MRI) and total tau in cerebrospinal fluid (CSFt-tau), all according to the A/T/N-classification. The aim of this study was to calculate residual cognitive performance based on neuronal injury biomarkers as a surrogate of cognitive reserve, and to test the predictive value of this index for the individual clinical course. METHODS: 110 initially mild cognitive impaired and demented subjects (age 71 ±â€¯8 years) with a final diagnosis of AD dementia were assessed at baseline by clinical mini-mental-state-examination (MMSE), FDG-PET, MRI and CSFt-tau. All neuronal injury markers were tested for an association with clinical MMSE and the resulting residuals were correlated with years of education. We used multiple regression analysis to calculate the expected MMSE score based on neuronal injury biomarkers and covariates. The residuals of the partial correlation for each biomarker and the predicted residualized memory function were correlated with individual cognitive changes measured during clinical follow-up (27 ±â€¯13 months). RESULTS: FDG-PET correlated highly with clinical MMSE (R = -0.49, p < .01), whereas hippocampal atrophy to MRI (R = -0.15, p = .14) and CSFt-tau (R = -0.12, p = .22) showed only weak correlations. Residuals of all neuronal injury biomarker regressions correlated significantly with education level, indicating them to be surrogates of cognitive reserve. A positive residual was associated with faster cognitive deterioration at follow-up for the residuals of stand-alone FDG-PET (R = -0.36, p = .01) and the combined residualized memory function model (R = -0.35, p = .02). CONCLUSIONS: These findings suggest that subjects with higher cognitive reserve had accumulated more pathology, which subsequently caused a faster cognitive decline over time. Together with previous findings suggesting that higher reserve is associated with slower cognitive decline, we propose a biphasic reserve effect, with an initially protective phase followed by more rapid decompensation once the protection is overwhelmed.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31292699

RESUMO

Our understanding on human neurodegenerative disease was previously limited to clinical data and inferences about the underlying pathology based on histopathological examination. Animal models and in vitro experiments have provided evidence for a cell-autonomous and a non-cell-autonomous mechanism for the accumulation of neuropathology. Combining modern neuroimaging tools to identify distinct neural networks (connectomics) with target-specific positron emission tomography (PET) tracers is an emerging and vibrant field of research with the potential to examine the contributions of cell-autonomous and non-cell-autonomous mechanisms to the spread of pathology. The evidence provided here suggests that both cell-autonomous and non-cell-autonomous processes relate to the observed in vivo characteristics of protein pathology and neurodegeneration across the disease spectrum. We propose a synergistic model of cell-autonomous and non-cell-autonomous accounts that integrates the most critical factors (i.e., protein strain, susceptible cell feature and connectome) contributing to the development of neuronal dysfunction and in turn produces the observed clinical phenotypes. We believe that a timely and longitudinal pursuit of such research programs will greatly advance our understanding of the complex mechanisms driving human neurodegenerative diseases.

5.
J Cereb Blood Flow Metab ; : 271678X19865916, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31342832

RESUMO

The fate of subcortical diffusion-weighted imaging (DWI) lesions in stroke patients is highly variable, ranging from complete tissue loss to no visible lesion on follow-up. Little is known about within-lesion heterogeneity and its relevance for stroke outcome. Patients with subcortical stroke and recruited through the prospective DEDEMAS study (NCT01334749) were examined at baseline (n = 45), six months (n = 45), and three years (n = 28) post-stroke. We performed high-resolution structural MRI including DWI. Tissue fate was determined voxel-wise using fully automated tissue segmentation. Within-lesion heterogeneity at baseline was assessed by free water diffusion imaging measures. The majority of DWI lesions (66%) showed cavitation on six months follow-up but the proportion of tissue turning into a cavity was small (9 ± 13.5% of the DWI lesion). On average, 69 ± 25% of the initial lesion resolved without any visually apparent signal abnormality. The extent of cavitation at six months post-stroke was independently associated with clinical outcome, i.e. modified Rankin scale score at six months (OR = 4.71, p = 0.005). DWI lesion size and the free water-corrected tissue mean diffusivity at baseline independently predicted cavitation. In conclusion, the proportion of cavitating tissue is typically small, but relevant for clinical outcome. Within-lesion heterogeneity at baseline on advanced diffusion imaging is predictive of tissue fate.

6.
Alzheimers Res Ther ; 11(1): 50, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159873

RESUMO

BACKGROUND: Subjective cognitive decline (SCD) is characterized by self-reported cognitive deficits without measurable cognitive impairment. It has been suggested that individuals with SCD exhibited brain structural alterations in widespread cortical thinning or gray matter loss in the medial temporal and frontotemporal regions. Apolipoprotein E (APOE) ε4 allele is thought to be a genetic marker associated with risk of SCD. Neuropsychiatric symptoms may provide insight in detecting higher-risk elders for early Alzheimer's disease as well. Therefore, we aim to explore the characteristics of brain morphology in SCD and to determine whether it is influenced by APOE ε4 as well as neuropsychiatric symptoms in SCD. METHODS: A total of 138 cognitively normal older individuals from the SILCODE cohort underwent a clinical interview, neuropsychological assessments, a blood test, and MRI. A two-sample t-test was used to examine the cortex volume and bilateral cortical surface area alterations between SCD (n = 65) and controls (n = 73). A general linear model analysis was used to test for both main and interaction effects of clinical phenotype (SCD vs. controls) and APOE on global and regional cortex volume and bilateral cortical surface area and thickness. A multiple linear regression analysis was conducted to determine the effects of the APOE genotype on the relationships between morphometric features and neuropsychiatric symptoms in SCD. RESULTS: Compared with controls, individuals with SCD showed decreased total cortical volumes and cortical surface area. SCD APOE ε4 carriers showed additive reduction in the right cortical surface area. The evaluation scores of anxiety symptoms were negatively associated with the right cortical surface area in SCD APOE 4 non-carriers. CONCLUSIONS: Individuals with SCD had an altered cortical surface area, and APOE genotype and anxiety symptoms are modified factors on the cortical surface area decrease in SCD. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT03370744 ). Registered 15 March 2017.

7.
Neurology ; 93(4): e347-e357, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31235661

RESUMO

OBJECTIVE: To investigate whether higher global left frontal cortex (gLFC) connectivity, a putative neural substrate of cognitive reserve, attenuates the effect of entorhinal tau PET levels on episodic memory in older adults. METHODS: Cross-sectional 18F-AV-1451 PET (to assess tau pathology), 18F-AV-45 or 18F-BAY94-9172 PET (to assess ß-amyloid [Aß]), and resting-state fMRI were obtained in 125 elderly participants from the Alzheimer's Neuroimaging Initiative, including 82 cognitively normal participants (amyloid PET-positive [Aß+], n = 27) and 43 patients with amnestic mild cognitive impairment (Aß+ = 15). Resting-state fMRI gLFC connectivity was computed for each participant as the average functional connectivity between the left frontal cortex (LFC) (seed) and each remaining voxel in the gray matter. As a measure of tau pathology, we assessed the mean tau PET uptake in the entorhinal cortex. In linear mixed-effects regression analysis, we tested the interaction term gLFC connectivity × entorhinal tau PET on delayed free recall performance. In addition, we assessed whether higher connectivity of the whole frontoparietal control network (FPCN), of which the LFC is a major hub, is associated with reserve. RESULTS: Higher entorhinal tau PET was strongly associated with poorer delayed free recall performance (ß/SE = -0.49/0.07, p < 0.001). A significant gLFC connectivity × entorhinal tau PET interaction was found (ß/SE = 0.19/0.06, p = 0.003), such that at higher levels of gLFC connectivity, the decrease in memory score per unit of entorhinal tau PET was attenuated. The FPCN connectivity × tau interaction was also significant (ß/SE = 0.10/0.04, p = 0.012). CONCLUSION: Both gLFC and FPCN connectivity are associated with higher resilience against the adverse effect of early-stage entorhinal tau pathology on memory performance.

8.
Z Evid Fortbild Qual Gesundhwes ; 141-142: 24-32, 2019 May.
Artigo em Alemão | MEDLINE | ID: mdl-31056350

RESUMO

INTRODUCTION AND OBJECTIVES: In selected healthcare sectors and settings, patients and their relatives are now regarded as co-producers of the healthcare system. This is associated with modified patient roles and new relationship models. Physiotherapists also have to face them by including educational interventions into their traditional scope of practice. However, corresponding intervention concepts for physiotherapy do not yet exist. Therefore, the aim of this contribution is to initiate an empirically supported concept development. METHODS: As part of a qualitative empirical study, interviews were conducted with 15 parents of children with life-limiting diseases in four federal states of Germany and then evaluated using the reconstruction method of the documentary method according to Bohnsack. The parents' experiences with the assumption of physiotherapeutic care were used as input for first reflections on an instructive intervention concept with reference to relevant learning theory approaches. RESULTS: In the course of the data evaluation, three divergent orientations (parent types) were identified. Parent type A (autonomy) acts largely autonomously and requires only occasional support. Parent type B (understanding) and C (relief) need more intensive support. While parent type B requires education in order to satisfy their pronounced need for knowledge, parent type C generally questions why they should have to carry out physiotherapeutic task and delegates responsibility back to the professional help system. DISCUSSION: Physiotherapeutic instruction should take into account the different types of parents with regard to the provision of care. Parents who are motivated to engage in learning processes would like to a) focus on central physiotherapeutic measures, b) be instructed face-to-face and c) be recognized as experts for their child and their situation. CONCLUSION: Supplemented by the perspective of professionals, insights into the parents' perspective can serve as the basis for empirical impact analysis. The empirically validated intervention concepts for instructive action must be integrated into existing educational, training and further education courses in order to ensure systematic dissemination of knowledge into physiotherapy. In addition, a debate on professional policy must be launched in order to secure instructive action more strongly in the physiotherapeutic repertoire.


Assuntos
Estado Terminal/psicologia , Assistência à Saúde , Pais , Modalidades de Fisioterapia , Adulto , Criança , Alemanha , Humanos , Aprendizagem , Cuidados Paliativos/psicologia , Pais/psicologia , Relações Profissional-Família , Pesquisa Qualitativa
9.
Nat Commun ; 10(1): 1766, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992433

RESUMO

The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer's disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II-VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Memória , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras de Tumor/genética , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagem , Cognição , Citoesqueleto/metabolismo , Endocitose , Feminino , Variação Genética , Humanos , Imagem por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Fatores de Risco
10.
Brain ; 142(4): 1093-1107, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30770704

RESUMO

In Alzheimer's disease, tau pathology spreads hierarchically from the inferior temporal lobe throughout the cortex, ensuing cognitive decline and dementia. Similarly, circumscribed patterns of pathological tau have been observed in normal ageing and small vessel disease, suggesting a spatially ordered distribution of tau pathology across normal ageing and different diseases. In vitro findings suggest that pathological tau may spread 'prion-like' across neuronal connections in an activity-dependent manner. Supporting this notion, functional brain networks show a spatial correspondence to tau deposition patterns. However, it remains unclear whether higher network-connectivity facilitates tau propagation. To address this, we included 55 normal aged elderly (i.e. cognitively normal, amyloid-negative), 50 Alzheimer's disease patients (i.e. amyloid-positive) covering the preclinical to dementia spectrum, as well as 36 patients with pure (i.e. amyloid-negative) vascular cognitive impairment due to small vessel disease. All subjects were assessed with AV1451 tau-PET and resting-state functional MRI. Within each group, we computed atlas-based resting-state functional MRI functional connectivity across 400 regions of interest covering the entire neocortex. Using the same atlas, we also assessed within each group the covariance of tau-PET levels among the 400 regions of interest. We found that higher resting-state functional MRI assessed functional connectivity between any given region of interest pair was associated with higher covariance in tau-PET binding in corresponding regions of interest. This result was consistently found in normal ageing, Alzheimer's disease and vascular cognitive impairment. In particular, inferior temporal tau-hotspots, as defined by highest tau-PET uptake, showed high predictive value of tau-PET levels in functionally closely connected regions of interest. These associations between functional connectivity and tau-PET uptake were detected regardless of presence of dementia symptoms (mild cognitive impairment or dementia), amyloid deposition (as assessed by amyloid-PET) or small vessel disease. Our findings suggest that higher functional connectivity between brain regions is associated with shared tau-levels, supporting the view of prion-like tau spreading facilitated by neural activity.

11.
BMC Med ; 17(1): 47, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30808345

RESUMO

BACKGROUND: The concept of reserve was established to account for the observation that a given degree of neurodegenerative pathology may result in varying degrees of symptoms in different individuals. There is a large amount of evidence on epidemiological risk and protective factors for neurodegenerative diseases and dementia, yet the biological mechanisms that underpin the protective effects of certain lifestyle and physiological variables remain poorly understood, limiting the development of more effective preventive and treatment strategies. Additionally, different definitions and concepts of reserve exist, which hampers the coordination of research and comparison of results across studies. DISCUSSION: This paper represents the consensus of a multidisciplinary group of experts from different areas of research related to reserve, including clinical, epidemiological and basic sciences. The consensus was developed during meetings of the working groups of the first International Conference on Cognitive Reserve in the Dementias (24-25 November 2017, Munich, Germany) and the Alzheimer's Association Reserve and Resilience Professional Interest Area (25 July 2018, Chicago, USA). The main objective of the present paper is to develop a translational perspective on putative mechanisms underlying reserve against neurodegenerative disease, combining evidence from epidemiological and clinical studies with knowledge from animal and basic research. The potential brain functional and structural basis of reserve in Alzheimer's disease and other brain disorders are discussed, as well as relevant lifestyle and genetic factors assessed in both humans and animal models. CONCLUSION: There is an urgent need to advance our concept of reserve from a hypothetical model to a more concrete approach that can be used to improve the development of effective interventions aimed at preventing dementia. Our group recommends agreement on a common dictionary of terms referring to different aspects of reserve, the improvement of opportunities for data sharing across individual cohorts, harmonising research approaches across laboratories and groups to reduce heterogeneity associated with human data, global coordination of clinical trials to more effectively explore whether reducing epidemiological risk factors leads to a reduced burden of neurodegenerative diseases in the population, and an increase in our understanding of the appropriateness of animal models for reserve research.

12.
Mol Neurodegener ; 14(1): 1, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630532

RESUMO

BACKGROUND: TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid ß-peptide (Aß) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD. METHODS: A cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of Aß1-42 (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score. RESULTS: CSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal Aß pathology (A+) but no tau pathology or neurodegeneration (TN-), is present. CONCLUSIONS: Aß pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, Aß pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Glicoproteínas de Membrana/líquido cefalorraquidiano , Degeneração Neural/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Receptores Imunológicos/genética , Proteínas tau/líquido cefalorraquidiano
13.
Alzheimers Dement ; 15(2): 292-312, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30555031

RESUMO

Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

14.
Alzheimers Res Ther ; 10(1): 112, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30376881

RESUMO

BACKGROUND: In Alzheimer's disease (AD), pathological changes may arise up to 20 years before the onset of dementia. This pre-dementia window provides a unique opportunity for secondary prevention. However, exposing non-demented subjects to putative therapies requires reliable biomarkers for subject selection, stratification, and monitoring of treatment. Neuroimaging allows the detection of early pathological changes, and longitudinal imaging can assess the effect of interventions on markers of molecular pathology and rates of neurodegeneration. This is of particular importance in pre-dementia AD trials, where clinical outcomes have a limited ability to detect treatment effects within the typical time frame of a clinical trial. We review available evidence for the use of neuroimaging in clinical trials in pre-dementia AD. We appraise currently available imaging markers for subject selection, stratification, outcome measures, and safety in the context of such populations. MAIN BODY: Amyloid positron emission tomography (PET) is a validated in-vivo marker of fibrillar amyloid plaques. It is appropriate for inclusion in trials targeting the amyloid pathway, as well as to monitor treatment target engagement. Amyloid PET, however, has limited ability to stage the disease and does not perform well as a prognostic marker within the time frame of a pre-dementia AD trial. Structural magnetic resonance imaging (MRI), providing markers of neurodegeneration, can improve the identification of subjects at risk of imminent decline and hence play a role in subject inclusion. Atrophy rates (either hippocampal or whole brain), which can be reliably derived from structural MRI, are useful in tracking disease progression and have the potential to serve as outcome measures. MRI can also be used to assess comorbid vascular pathology and define homogeneous groups for inclusion or for subject stratification. Finally, MRI also plays an important role in trial safety monitoring, particularly the identification of amyloid-related imaging abnormalities (ARIA). Tau PET to measure neurofibrillary tangle burden is currently under development. Evidence to support the use of advanced MRI markers such as resting-state functional MRI, arterial spin labelling, and diffusion tensor imaging in pre-dementia AD is preliminary and requires further validation. CONCLUSION: We propose a strategy for longitudinal imaging to track early signs of AD including quantitative amyloid PET and yearly multiparametric MRI.

15.
EMBO Mol Med ; 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30482868

RESUMO

Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity-specific manner in AD We measured PGRN in cerebrospinal fluid (CSF) in two of the best-characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross-sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non-carriers 10 years before the expected symptom onset. In late-onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.

16.
Front Aging Neurosci ; 10: 362, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30467476

RESUMO

Resting-state fMRI studies demonstrated temporally synchronous fluctuations in brain activity among ensembles of brain regions, suggesting the existence of intrinsic functional networks. A spatial match between some of the resting-state networks and regional brain activation during cognitive tasks has been noted, suggesting that resting-state networks support particular cognitive abilities. However, the spatial match and predictive value of any resting-state network and regional brain activation during episodic memory is only poorly understood. In order to address this research gap, we obtained fMRI acquired both during rest and a face-name association task in 38 healthy elderly subjects. In separate independent component analyses, networks of correlated brain activity during rest or the episodic memory task were identified. For the independent components identified for task-based fMRI, the design matrix of successful encoding or retrieval trials was regressed against the time course of each of the component to identify significantly activated networks. Spatial regression was used to assess the match of resting-state networks against those related to successful memory encoding or retrieval. We found that resting-state networks covering the medial temporal, middle temporal, and frontal areas showed increased activity during successful encoding. Resting-state networks located within posterior brain regions showed increased activity during successful recognition. However, the level of resting-state network connectivity was not predictive of the task-related activity in these networks. These results suggest that a circumscribed number of functional networks detectable during rest become engaged during successful episodic memory. However, higher intrinsic connectivity at rest may not translate into higher network expression during episodic memory.

17.
Gesundheitswesen ; 2018 Oct 15.
Artigo em Alemão | MEDLINE | ID: mdl-30321878

RESUMO

INTRODUCTION: There is an increasing number of ventilated and other technology-dependent patients, cared for in their own homes or in shared apartments in Germany. Issues of patient safety have hardly been examined in this context. In this follow-up of a survey of patients and their relatives, the perspective of professional players on the subject of safety in intensive home care is explored. METHODS: Professional players in 6 heterogeneous, non-natural focus groups were faced with experiences and perspectives of ventilated patients and their relatives in a qualitative health care services research. These players were asked for their perspectives on the issue of patient safety in intensive home care. The collected data were analyzed in terms of discourse as well as content. RESULTS: The subjective safety dimensions addressed by the ventilated patients and their relatives was considered as important by the professional players in many respects. However, demands from relatives for more participation were considered with skepticism. Safety in intensive home care was perceived as under threat by a lack of cooperation and coordination, skills shortage and skills gaps. In particular, caregivers with key tasks of care provision and thus with special responsibility for patient safety see these corresponding challenges. CONCLUSION: The results provide a basis for safety work in intensive home care. Among other things they point out the need to develop user-centered safety concepts, a safety culture at the organizational level as well as accompanying legal regulation.

18.
Alzheimers Res Ther ; 10(1): 103, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30261914

RESUMO

BACKGROUND: The protective effect of education has been well established in Alzheimer's disease, whereas its role in patients with isolated cerebrovascular diseases remains unclear. We examined the correlation of education with cortical thickness and cerebral small vessel disease markers in patients with pure subcortical vascular mild cognitive impairment (svMCI) and patients with pure subcortical vascular dementia (SVaD). METHODS: We analyzed 45 patients with svMCI and 47 patients with SVaD with negative results on Pittsburgh compound B positron emission tomographic imaging who underwent structural brain magnetic resonance imaging. The main outcome was cortical thickness measured using surface-based morphometric analysis. We also assessed the volumes of white matter hyperintensities (WMH) and numbers of lacunes as other outcomes. To investigate the correlation of education with cortical thickness, WMH volume, and number of lacunes, multiple linear regression analyses were performed after controlling for covariates, including Mini Mental State Examination, in the svMCI and SVaD groups. RESULTS: In the SVaD group, higher education was correlated with more severe cortical thinning in the bilateral dorsolateral frontal, left medial frontal, and parahippocampal areas, whereas there was no correlation of education with cortical thickness in the svMCI group. There was no correlation between education and cerebral small vessel disease, including WMH and lacunes, in both patients with svMCI and patients with SVaD. CONCLUSIONS: Our findings suggest that the compensatory effects of education on cortical thinning apply to patients with SVaD, which might be explained by the cognitive reserve hypothesis.

19.
Alzheimers Dement ; 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30222945

RESUMO

Several concepts, which in the aggregate get might be used to account for "resilience" against age- and disease-related changes, have been the subject of much research. These include brain reserve, cognitive reserve, and brain maintenance. However, different investigators have use these terms in different ways, and there has never been an attempt to arrive at consensus on the definition of these concepts. Furthermore, there has been confusion regarding the measurement of these constructs and the appropriate ways to apply them to research. Therefore the reserve, resilience, and protective factors professional interest area, established under the auspices of the Alzheimer's Association, established a whitepaper workgroup to develop consensus definitions for cognitive reserve, brain reserve, and brain maintenance. The workgroup also evaluated measures that have been used to implement these concepts in research settings and developed guidelines for research that explores or utilizes these concepts. The workgroup hopes that this whitepaper will form a reference point for researchers in this area and facilitate research by supplying a common language.

20.
Brain ; 141(10): 3065-3080, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30239611

RESUMO

White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-ß1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.

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