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Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aß42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aß when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Encéfalo , Cognição , Disfunção Cognitiva , Inflamação , Imageamento por Ressonância Magnética , Substância Branca , Proteínas tau , Humanos , Masculino , Feminino , Biomarcadores/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Pessoa de Meia-Idade , Encéfalo/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Cognição/fisiologia , Inflamação/líquido cefalorraquidiano , Imageamento por Ressonância Magnética/métodos , Disfunção Cognitiva/líquido cefalorraquidiano , Substância Branca/patologia , Proteínas tau/líquido cefalorraquidiano , Estudos Longitudinais , Substância Cinzenta/patologia , Estudos de CoortesRESUMO
Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants' whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aß-positive and Aß-negative individuals in SCD and AD-rel, and between ApoE ε4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.
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Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer's disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer's disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer's disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer's disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer's disease.
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Doença de Alzheimer , Atrofia , Disfunção Cognitiva , Progressão da Doença , Imageamento por Ressonância Magnética , Humanos , Feminino , Masculino , Atrofia/patologia , Idoso , Disfunção Cognitiva/patologia , Imageamento por Ressonância Magnética/métodos , Doença de Alzheimer/patologia , Pessoa de Meia-Idade , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Testes Neuropsicológicos , Estudos de Coortes , Idoso de 80 Anos ou mais , Memória Episódica , Transtornos da Memória/patologiaRESUMO
BACKGROUND: The Target Product Profile (TPP) is a tool used in industry to guide development strategies by addressing user needs and fostering effective communication among stakeholders. However, they are not frequently used in academic research, where they may be equally useful. This systematic review aims to extract the features of accessible TPPs, to identify commonalities and facilitate their integration in academic research methodology. METHODS: We searched peer-reviewed papers published in English developing TPPs for different products and health conditions in four biomedical databases. Interrater agreement, computed on random abstract and paper sets (Cohen's Kappa; percentage agreement with zero tolerance) was > 0.91. We interviewed experts from industry contexts to gain insight on the process of TPP development, and extracted general and specific features on TPP use and structure. RESULTS: 138 papers were eligible for data extraction. Of them, 92% (n = 128) developed a new TPP, with 41.3% (n = 57) focusing on therapeutics. The addressed disease categories were diverse; the largest (47.1%, n = 65) was infectious diseases. Only one TPP was identified for several fields, including global priorities like dementia. Our analyses found that 56.5% of papers (n = 78) was authored by academics, and 57.8% of TPPs (n = 80) featured one threshold level of product performance. The number of TPP features varied widely across and within product types (n = 3-44). Common features included purpose/context of use, shelf life for drug stability and validation aspects. Most papers did not describe the methods used to develop the TPP. We identified aspects to be taken into account to build and report TPPs, as a starting point for more focused initiatives guiding use by academics. DISCUSSION: TPPs are used in academic research mostly for infectious diseases and have heterogeneous features. Our extraction of key features and common structures helps to understand the tool and widen its use in academia. This is of particular relevance for areas of notable unmet needs, like dementia. Collaboration between stakeholders is key for innovation. Tools to streamline communication such as TPPs would support the development of products and services in academia as well as industry.
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Pesquisa Biomédica , HumanosRESUMO
Cognitive decline in Parkinson's disease is related to cholinergic system degeneration, which can be assessed in vivo using structural MRI markers of basal forebrain volume and PET measures of cortical cholinergic activity. In the present study we aimed to examine the interrelation between basal forebrain degeneration and PET-measured depletion of cortical acetylcholinesterase activity as well as their relative contribution to cognitive impairment in Parkinson's disease. This cross-sectional study included 143 Parkinson's disease participants without dementia and 52 healthy control participants who underwent structural MRI, PET scanning with 11C-methyl-4-piperidinyl propionate (PMP) as a measure of cortical acetylcholinesterase activity, and a detailed cognitive assessment. Based on the fifth percentile of the overall cortical PMP PET signal from the control group, people with Parkinson's disease were subdivided into a normo-cholinergic (n = 94) and a hypo-cholinergic group (n = 49). Volumes of functionally defined posterior and anterior basal forebrain subregions were extracted using an established automated MRI volumetry approach based on a stereotactic atlas of cholinergic basal forebrain nuclei. We used Bayesian t-tests to compare basal forebrain volumes between controls, and normo- and hypo-cholinergic Parkinson's participants after covarying out age, sex and years of education. Associations between the two cholinergic imaging measures were assessed across all people with Parkinson's disease using Bayesian correlations and their respective relations with performance in different cognitive domains were assessed with Bayesian ANCOVAs. As a specificity analysis, hippocampal volume was added to the analysis. We found evidence for a reduction of posterior basal forebrain volume in the hypo-cholinergic compared to both normo-cholinergic Parkinson's disease [Bayes factor against the null model (BF10) = 8.2] and control participants (BF10 = 6.0), while for the anterior basal forebrain the evidence was inconclusive (BF10 < 3). In continuous association analyses, posterior basal forebrain volume was significantly associated with cortical PMP PET signal in a temporo-posterior distribution. The combined models for the prediction of cognitive scores showed that both cholinergic markers (posterior basal forebrain volume and cortical PMP PET signal) were independently related to multi-domain cognitive deficits, and were more important predictors for all cognitive scores, including memory scores, than hippocampal volume. We conclude that degeneration of the posterior basal forebrain in Parkinson's disease is accompanied by functional cortical changes in acetylcholinesterase activity and that both PET and MRI cholinergic imaging markers are independently associated with multi-domain cognitive deficits in Parkinson's disease without dementia. Comparatively, hippocampal atrophy only seems to have minimal involvement in the development of early cognitive impairment in Parkinson's disease.
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Prosencéfalo Basal , Disfunção Cognitiva , Demência , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Acetilcolinesterase/metabolismo , Teorema de Bayes , Estudos Transversais , Tomografia por Emissão de Pósitrons/métodos , Colinérgicos , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/complicações , Imageamento por Ressonância Magnética , Demência/complicações , Prosencéfalo Basal/diagnóstico por imagem , Prosencéfalo Basal/metabolismoRESUMO
Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer's disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the Alzheimer's disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer's disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer's disease continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was used to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the Alzheimer's disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer's disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer's disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer's disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer's disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert.
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Doença de Alzheimer , Disfunção Cognitiva , Substância Branca , Humanos , Doença de Alzheimer/psicologia , Encéfalo , Disfunção Cognitiva/psicologia , ColinérgicosRESUMO
BACKGROUND: The aim of this study was to investigate the role of support from the social environment for the life expectancy in people with dementia beyond well-established individual demographic and clinical predictors over a period of up to 8 years. METHODS: The analyses are based on data from 500 community-dwelling individuals in Germany who tested positive for dementia and were followed up for up to 8 years. Life expectancy was examined in relation to perceived social support as well as well-established socio-demographic (age, sex) and clinical predictors (cognitive status, functional status, comorbidities), using Cox regressions. RESULTS: Greater support from the social environment reduced the risk of mortality (hazard ratio [HR]: 0.78; 95% confidence interval [CI]: 0.63-0.98), with the role of emotional support being particularly important. Furthermore, higher age was associated with an increased mortality risk (HR: 1.08; 95% CI: 1.05-1.11), while female sex (HR: 0.64; 95% CI: 0.48-0.85) and higher cognitive (HR: 0.96; 95% CI: 0.93-0.98) and functional status (HR: 0.91; 95% CI: 0.86-0.97) were associated with higher life expectancy. CONCLUSION: Our study provides novel evidence that less support from the social environment, especially emotional support, is a risk factor for shorter life expectancy in people with dementia-beyond known clinical factors. Not only the clinical and caregiving needs but also their psychosocial needs of individuals with dementia should be emphasised.
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Demência , Humanos , Feminino , Demência/diagnóstico , Fatores de Proteção , Apoio Social , Modelos de Riscos Proporcionais , Expectativa de VidaRESUMO
BACKGROUND: Dementia impairs the ability of people with dementia to be autonomous and independent. They need support from third parties, who should ideally respect their autonomy and independence as much as possible. Supporting people with dementia can be very burdensome for caregivers and numbers of patients increase while numbers of potential caregivers decline. Digital assistive technologies (DATs) that directly support patients or their caregivers may help bridging the increasing gap between need of support and available resources. DATs have the potential to preserve the autonomy and independence of people with dementia and promote their abilities, if they are properly designed in close interaction with future users. In our study, we focused on ethical concerns, technological requirements, and implementation criteria for DAT in general and specifically to support outdoor mobility of people with dementia. METHODS: We applied a qualitative approach and conducted a World Café (2 tables, n = 7) and an online focus group (n = 6) with people with dementia, relatives, healthcare professionals, scientists, ethics experts, and experts for digitally-assisted medical care. We descriptively analyzed the data using a content analysis approach. RESULTS: The participants reported technological (e.g., lack of Wi-Fi), financial (e.g., expensive devices or lack of budget for DATs), political (e.g., legal hurdles such as the European Medical Device Law or data protection regulations) as well as user-related hurdles (e.g., lack of digital competence) for the implementation of DAT in dementia care. Among the issues discussed were the importance of autonomy, independence, safety, privacy, and questions of decision making capacity in DAT's use. Participants identified opportunities and benefits in self-learning, situation-aware DATs and wished for dementia-friendly communities. They emphasized the value of personal interaction that should not be replaced, but rather supported by DAT. CONCLUSION: The results revealed multiple hurdles and ethical concerns for DAT use and provided recommendations for designing and implementing DATs. Further investigations are needed on the impact of DAT on personal interactions in caregiving and the role of DAT in dementia-friendly communities.
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Cuidadores , Demência , Autonomia Pessoal , Pesquisa Qualitativa , Tecnologia Assistiva , Participação dos Interessados , Humanos , Demência/terapia , Tecnologia Assistiva/ética , Feminino , Masculino , Grupos Focais , Tecnologia Digital , Idoso , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Blood-based biomarkers are a cost-effective and minimally invasive method for diagnosing the early and preclinical stages of amyloid positivity (AP). Our study aims to investigate our novel immunoprecipitation-immunoassay (IP-IA) as a test for predicting cognitive decline. METHODS: We measured levels of amyloid beta (Aß)X-40 and AßX-42 in immunoprecipitated eluates from the DELCODE cohort. Receiver-operating characteristic (ROC) curves, regression analyses, and Cox proportional hazard regression models were constructed to predict AP by Aß42/40 classification in cerebrospinal fluid (CSF) and conversion to mild cognitive impairment (MCI) or dementia. RESULTS: We detected a significant correlation between AßX-42/X-40 in plasma and CSF (r = 0.473). Mixed-modeling analysis revealed a substantial prediction of AßX-42/X-40 with an area under the curve (AUC) of 0.81 for AP (sensitivity: 0.79, specificity: 0.74, positive predictive value [PPV]: 0.71, negative predictive value [NPV]: 0.81). In addition, lower AßX-42/X-40 ratios were associated with negative PACC5 slopes, suggesting cognitive decline. DISCUSSION: Our results suggest that assessing the plasma AßX-42/X-40 ratio via our semiautomated IP-IA is a promising biomarker when examining patients with early or preclinical AD. HIGHLIGHTS: New plasma Aß42/Aß40 measurement using immunoprecipitation-immunoassay Plasma Aß42/Aß40 associated with longitudinal cognitive decline Promising biomarker to detect subjective cognitive decline at-risk for brain amyloid positivity.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Biomarcadores , Disfunção Cognitiva , Fragmentos de Peptídeos , Humanos , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Disfunção Cognitiva/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Masculino , Feminino , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Pessoa de Meia-Idade , Curva ROC , Imunoprecipitação , Progressão da DoençaRESUMO
BACKGROUND: It is not clear to which degree limbic TDP-43 pathology associates with a cholinergic deficit in the absence of Alzheimer's disease (AD) pathology. OBJECTIVE: Replicate and extend recent evidence on cholinergic basal forebrain atrophy in limbic TDP-43 and evaluate MRI based patterns of atrophy as a surrogate marker for TDP-43. METHODS: We studied ante-mortem MRI data of 11 autopsy cases with limbic TDP-43 pathology, 47 cases with AD pathology, and 26 mixed AD/TDP-43 cases from the ADNI autopsy sample, and 17 TDP-43, 170 AD, and 58 mixed AD/TDP-43 cases from the NACC autopsy sample. Group differences in basal forebrain and other brain volumes of interest were assessed using Bayesian ANCOVA. We assessed the diagnostic utility of MRI based patterns of brain atrophy using voxel-based receiver operating characteristics and random forest analyses. RESULTS: In the NACC sample, we found moderate evidence for the absence of a difference in basal forebrain volumes between AD, TDP-43, and mixed pathologies (Bayes factor(BF)10 = 0.324), and very strong evidence for lower hippocampus volume in TDP-43 and mixed cases compared with AD cases (BF10 = 156.1). The ratio of temporal to hippocampus volume reached an AUC of 75% for separating pure TDP-43 from pure AD cases. Random-forest analysis between TDP-43, AD, and mixed pathology reached only a multiclass AUC of 0.63 based on hippocampus, middle-inferior temporal gyrus, and amygdala volumes. Findings in the ADNI sample were consistent with these results. CONCLUSION: A comparable degree of basal forebrain atrophy in pure TDP-43 cases compared to AD cases encourages studies on the effect of cholinergic treatment in amnestic dementia due to TDP-43. A distinct pattern of temporo-limbic brain atrophy may serve as a surrogate marker to enrich samples in clinical trials for the presence of TDP-43 pathology.
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Doença de Alzheimer , Prosencéfalo Basal , Humanos , Doença de Alzheimer/patologia , Teorema de Bayes , Prosencéfalo Basal/diagnóstico por imagem , Prosencéfalo Basal/patologia , Imageamento por Ressonância Magnética , Atrofia/patologia , Proteínas de Ligação a DNA/metabolismo , ColinérgicosRESUMO
PURPOSE OF REVIEW: Availability of possible disease modifying treatments and the recognition of predementia stages of Alzheimer's disease (AD) have raised awareness for the prognostic and predictive role of biomarkers, particularly imaging markers. RECENT FINDINGS: The positive predictive value of amyloid PET for the transition to prodromal AD or AD dementia in cognitively normal people is below 25%. Evidence for tau PET, FDG-PET and structural MRI is even more limited. In people with mild cognitive impairment (MCI), imaging markers yield positive predictive values above 60% with moderate advantages for amyloid PET over the other modalities and an added value for the combination of molecular with downstream neurodegeneration markers. SUMMARY: In cognitively normal people, imaging is not recommended for individual prognosis due to lack of sufficient predictive accuracy. Such measures should be restricted to risk enrichment in clinical trials. In people with MCI, amyloid PET and, to a somewhat lesser extent, tau PET, FDG-PET, and MRI yield relevant predictive accuracy for clinical counseling as part of a comprehensive diagnostic program in tertiary care units. Future studies should focus on the systematic and patient-centered implementation of imaging markers in evidence-based care-pathways for people with prodromal AD.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Fluordesoxiglucose F18 , Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Prognóstico , Tomografia por Emissão de Pósitrons/métodos , Biomarcadores , Imagem Molecular , Peptídeos beta-Amiloides , Proteínas tauRESUMO
We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A-) of amyloid pathology was defined by CSF amyloid-ß42 (Aß42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A- individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aß42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau (>700 pg/ml) and phospho-tau (>100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and Aß42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A- groups. After classifying this matched sample for phospho-tau pathology (T-/T+), individuals with A+/T+ were significantly more memory-impaired than A-/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer's disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer's disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function.
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Doença de Alzheimer , Amiloidose , Disfunção Cognitiva , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Proteínas Amiloidogênicas , Apolipoproteínas E/genética , Biomarcadores , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Estudos Transversais , Hipocampo/metabolismo , Humanos , Proteínas tau/metabolismoRESUMO
BACKGROUND: Alzheimer's disease (AD) is often preceded by stages of cognitive impairment, namely subjective cognitive decline (SCD) and mild cognitive impairment (MCI). While cerebrospinal fluid (CSF) biomarkers are established predictors of AD, other non-invasive candidate predictors include personality traits, anxiety, and depression, among others. These predictors offer non-invasive assessment and exhibit changes during AD development and preclinical stages. METHODS: In a cross-sectional design, we comparatively evaluated the predictive value of personality traits (Big Five), geriatric anxiety and depression scores, resting-state functional magnetic resonance imaging activity of the default mode network, apoliprotein E (ApoE) genotype, and CSF biomarkers (tTau, pTau181, Aß42/40 ratio) in a multi-class support vector machine classification. Participants included 189 healthy controls (HC), 338 individuals with SCD, 132 with amnestic MCI, and 74 with mild AD from the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). RESULTS: Mean predictive accuracy across all participant groups was highest when utilizing a combination of personality, depression, and anxiety scores. HC were best predicted by a feature set comprised of depression and anxiety scores and participants with AD were best predicted by a feature set containing CSF biomarkers. Classification of participants with SCD or aMCI was near chance level for all assessed feature sets. CONCLUSION: Our results demonstrate predictive value of personality trait and state scores for AD. Importantly, CSF biomarkers, personality, depression, anxiety, and ApoE genotype show complementary value for classification of AD and its at-risk stages.
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Doença de Alzheimer , Disfunção Cognitiva , Idoso , Humanos , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Ansiedade , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/psicologia , Estudos Transversais , Depressão , Aprendizado de Máquina , PersonalidadeRESUMO
INTRODUCTION: Aging has been associated with a decline in cognitive and motor performance, often expressed in multitasking situations, which could include wayfinding. A major challenge to successful wayfinding is spatial disorientation, occurring mostly at crossings. Although gait changes have been observed in various dual-task conditions, little is known about the effect of disorientation on gait and psychophysiological response among older adults during wayfinding. The study aimed at identifying the effect of spatial disorientation on gait variability and psychophysiological response among healthy older adults during wayfinding in a controlled environment. METHOD: We analyzed data of 28 participants (age 70.8 ± 4.6, 18 female), 14 experimental and 14 controls. Participants performed a wayfinding task consisting of 14 major decision points (7 intersections) within a virtual environment (VE) projected on a 180° screen while walking on a self-paced treadmill equipped with a marker-based optical motion-capture system. The VE was held constant for the controls and manipulated for the experimental participants. Disorientation was identified based on a customized annotation scheme. Variability in gait, including the coefficient of variation (CV), was measured as the primary endpoint. Psychophysiological response measures, including heart rate variability (RMSSD) and skin conductance response (SCR), were continuously monitored as secondary endpoints and estimates of cognitive effort. Linear Mixed Effects models were applied to hypothesis-driven outcome measures extracted from decision points. RESULTS: Walking speed and step length decreased when disoriented (p < 0.05), while stride time, stance time, walking speed CV, stance time CV, SCR amplitude, and SCR count increased when disoriented (p < 0.05). A higher RMSSD was associated with being disoriented at crossings (p < 0.05). SCR count was greater in the older experimental group (p < 0.001), including when disoriented (p < 0.001). DISCUSSION/CONCLUSION: The results provide evidence for the impact of spatial disorientation on changes in gait pattern and psychophysiological response among older adults during wayfinding. Location also had implications for the effect of disorientation on gait and cognitive effort. This gives further insight into the substrates of real-world navigation challenges among older adults, with an emphasis on viable features for designing situation-adaptive interventional devices aiding independent mobility.
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Marcha , Caminhada , Humanos , Feminino , Idoso , Marcha/fisiologia , Caminhada/fisiologia , Envelhecimento , Velocidade de Caminhada/fisiologia , ConfusãoRESUMO
BACKGROUND: Currently, there is a lack of interaction between research and healthcare practice. As a result, research findings reach healthcare practice only late, and topics relevant to practice are often not known in research. Involving people living with dementia (PlwD), their relatives and healthcare providers in dementia care research can accelerate this process. For inclusion, firm and reliable structures are needed, which are to be established with the help of the Translational Network for Dementia Care Research in Germany. However, there is only limited knowledge about the priorities, expectations and conditions of stakeholders (healthcare providers and dementia researchers) for such cooperation within a network. OBJECTIVES: The aim is to gather stakeholders' views on (i) future research topics to be addressed within the dementia care research network, (ii) the nature of collaboration within the network and (iii) the facilitating and hindering factors for establishing such a network. METHODS: Within an exploratory sequential mixed-method study, we interviewed 87 stakeholders within eleven semistructured focus group interviews. The interviews were transcribed, pseudonymized and analyzed using qualitative content analysis. The qualitative data were analyzed with MAXQDA. Based on the qualitative results found in the focus group interviews, a supplementary online questionnaire was developed to prioritise and rank these findings afterwards. RESULTS: Stakeholders prioritized a comprehensible transfer of research results into practice, increased involvement of PlwD and their relatives (additionally marginalized groups such as people with a migrant background) in research and exchange between researchers. Cooperation should preferably occur in a regional context with local contacts, and the latest research results should be made available via an online database. The stakeholders' time, finances and human resources should be considered. CONCLUSION: Stakeholders have partly similar preferences and goals for cooperation and involvement, emphasizing that such interaction in a network offers the possibility of long-term, effective collaboration and added value for practice and research. PATIENT OR PUBLIC CONTRIBUTION: For this study, dementia healthcare providers and dementia care researchers were asked about their perspectives. Their involvement is further elucidated in the manuscript text.
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Demência , Pessoal de Saúde , Humanos , Atenção à Saúde , Grupos Focais , Pesquisa Translacional Biomédica , Demência/terapia , Pesquisa QualitativaRESUMO
INTRODUCTION: This study aimed to analyze the impact of low-value medications (Lvm), that is, medications unlikely to benefit patients but to cause harm, on patient-centered outcomes over 24 months. METHODS: This longitudinal analysis was based on baseline, 12 and 24 months follow-up data of 352 patients with dementia. The impact of Lvm on health-related quality of life (HRQoL), hospitalizations, and health care costs were assessed using multiple panel-specific regression models. RESULTS: Over 24 months, 182 patients (52%) received Lvm at least once and 56 (16%) continuously. Lvm significantly increased the risk of hospitalization by 49% (odds ratio, confidence interval [CI] 95% 1.06-2.09; p = 0.022), increased health care costs by 6810 (CI 95% -707-14,27; p = 0.076), and reduced patients' HRQoL (b = -1.55; CI 95% -2.76 to -0.35; p = 0.011). DISCUSSION: More than every second patient received Lvm, negatively impacting patient-reported HRQoL, hospitalizations, and costs. Innovative approaches are needed to encourage prescribers to avoid and replace Lvm in dementia care. HIGHLIGHTS: Over 24 months, more than every second patient received low-value medications (Lvm). Lvm negatively impact physical, psychological, and financial outcomes. Appropriate measures are needed to change prescription behaviors.
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Demência , Qualidade de Vida , Humanos , Custos de Cuidados de Saúde , Hospitalização , Demência/tratamento farmacológicoRESUMO
INTRODUCTION: Limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is common in advanced age and can underlie a clinical presentation mimicking Alzheimer's disease (AD). We studied whether an autopsy-derived fluorodeoxyglucose positron emission tomography (FDG-PET) signature of LATE-NC provides clinical utility for differential diagnosis of amnestic dementia patients. METHODS: Ante mortem FDG-PET patterns from autopsy-confirmed LATE-NC (N = 7) and AD (N = 23) patients were used to stratify an independent cohort of clinically diagnosed AD dementia patients (N = 242) based on individual FDG-PET profiles. RESULTS: Autopsy-confirmed LATE-NC and AD groups showed markedly distinct temporo-limbic and temporo-parietal FDG-PET patterns, respectively. Clinically diagnosed AD dementia patients showing a LATE-NC-like FDG-PET pattern (N = 25, 10%) were significantly older, showed less abnormal AD biomarker levels, lower APOE ε4, and higher TMEM106B risk allele load. Clinically, they exhibited a more memory-predominant profile and a generally slower disease course. DISCUSSION: An autopsy-derived temporo-limbic FDG-PET signature identifies older amnestic patients whose clinical, genetic, and molecular biomarker features are consistent with underlying LATE-NC.
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Doença de Alzheimer , Fluordesoxiglucose F18 , Humanos , Autopsia , Diagnóstico Diferencial , Encéfalo/patologia , Tomografia por Emissão de Pósitrons/métodos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Biomarcadores , Proteínas de Membrana , Proteínas do Tecido NervosoRESUMO
INTRODUCTION: Standardized cognitive assessment would enhance diagnostic reliability across memory clinics. An expert consensus adapted the Uniform Dataset (UDS)-3 for European centers, the clinician's UDS (cUDS). This study assessed its implementation acceptability and feasibility. METHODS: We developed a survey investigating barriers, facilitators, and willingness to implement the cUDS. With a mixed-methods design, we analyzed data from academic memory clinics. RESULTS: Seventy-eight percent of responding clinicians were experienced neuropsychologists/psychologists and 22% were medical specialists coming from 18 European countries. Sixty-five percent clinicians were willing to implement cUDS. General barriers related to implementation (43%) and clinical-methodological domains (21%). Favorable clinicians reported finances (15%) and digitalization (9%) as facilitating, but unavailability of local norms (23%) as hindering. Unfavorable clinicians reported logistical (23%) and time issues (18%). DISCUSSION: Despite challenges, data showed moderate clinicians' acceptability and requirements to improve feasibility. Nonetheless, these results come from academic clinicians. The next steps will require feasibility evaluation in non-academic contexts.
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Cognição , Humanos , Estudos de Viabilidade , Reprodutibilidade dos Testes , Inquéritos e Questionários , Europa (Continente)RESUMO
BACKGROUND: Apathy is the most frequent neuropsychiatric symptom in patients with dementia of the Alzheimer's type (DAT). We analyzed the influence of apathy on the resource use of DAT patients and their caregivers. METHODS: Included were baseline data of 107 DAT patients from a randomized clinical trial on apathy treatment. The Resource Utilization in Dementia (RUD) instrument assessed costs over a 1-month period prior to baseline. Cost predictors were determined via a least absolute shrinkage and selection operator (LASSO). RESULTS: On average, total monthly costs were 3070, of which 2711 accounted for caregivers' and 359 for patients' costs. An increase of one point in the Apathy Evaluation Scale resulted in a 4.1% increase in total costs. DISCUSSION: Apathy is a significant cost driving factor for total costs in mild to moderate DAT. Effective treatment of apathy might be associated with reduced overall costs in DAT.
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Doença de Alzheimer , Apatia , Humanos , Doença de Alzheimer/diagnóstico , Cuidadores/psicologia , Resultado do TratamentoRESUMO
INTRODUCTION: It remains unclear whether functional brain networks are consistently altered in individuals with subjective cognitive decline (SCD) of diverse ethnic and cultural backgrounds and whether the network alterations are associated with an amyloid burden. METHODS: Cross-sectional resting-state functional magnetic resonance imaging connectivity (FC) and amyloid-positron emission tomography (PET) data from the Chinese Sino Longitudinal Study on Cognitive Decline and German DZNE Longitudinal Cognitive Impairment and Dementia cohorts were analyzed. RESULTS: Limbic FC, particularly hippocampal connectivity with right insula, was consistently higher in SCD than in controls, and correlated with SCD-plus features. Smaller SCD subcohorts with PET showed inconsistent amyloid positivity rates and FC-amyloid associations across cohorts. DISCUSSION: Our results suggest an early adaptation of the limbic network in SCD, which may reflect increased awareness of cognitive decline, irrespective of amyloid pathology. Different amyloid positivity rates may indicate a heterogeneous underlying etiology in Eastern and Western SCD cohorts when applying current research criteria. Future studies should identify culture-specific features to enrich preclinical Alzheimer's disease in non-Western populations. HIGHLIGHTS: Common limbic hyperconnectivity across Chinese and German subjective cognitive decline (SCD) cohorts was observed. Limbic hyperconnectivity may reflect awareness of cognition, irrespective of amyloid load. Further cross-cultural harmonization of SCD regarding Alzheimer's disease pathology is required.