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Objectives: This scoping review aims to summarize and synthesize research findings on the disparities between audiometrically diagnosed and aided hearing loss versus the individual's own experience of hearing loss. Methods: A systematic search strategy was employed across multiple databases to identify studies published between 1990 and October 2023 focusing on the experiences of hearing problems among individuals with aided hearing loss. The selected studies underwent screening based on predetermined inclusion and exclusion criteria. These criteria revolved around including papers featuring a population of adult (+18) individuals with audiometrically measured hearing loss who had undergone technological rehabilitation. Data charting was employed to provide an overview of the studies and was additionally utilized to identify key themes. Narrative analysis was used to identify subthemes within the data set. Results: A total of 11 articles met the inclusion criteria. The analysis identified five themes: "disability experience and discrepancy between measured and self-perceived hearing loss"; "listening effort"; "mental burden/psychological consequences"; "factors that alleviate the consequences of HL"; and "sociodemographic factors." Conclusions: The scoping review shows that, despite the proliferation of technological options, there is a pressing need for a more concentrated effort to identify and scrutinize the supplementary facets of hearing loss that remain inadequately addressed by current hearing technology. This includes subjective experiences associated with hearing loss that may not be effectively treated solely with hearing aids.
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BACKGROUND AND OBJECTIVES: CSF biomarkers have immense diagnostic and prognostic potential for Alzheimer disease (AD). However, AD is still diagnosed relatively late in the disease process, sometimes even years after the initial manifestation of cognitive symptoms. Thus, further identification of biomarkers is required to detect related pathology in the preclinical stage and predict cognitive decline. Our study aimed to assess the association of neurogranin and ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with cognitive decline in individuals with subjective cognitive decline (SCD). METHODS: We enrolled participants with available neurogranin and BACE1 measurements in CSF from the DELCODE (DZNE-Longitudinal Cognitive Impairment and Dementia, Germany) cohort. The longitudinal change of Preclinical Alzheimer's Cognitive Composite score was assessed as the primary outcome in participants with SCD and controls. The secondary outcome was defined as conversion of SCD to mild cognitive impairment (MCI) during follow-up. Levels of neurogranin, BACE1, and neurogranin/BACE1 ratio across groups were compared by analysis of covariance after adjustment for demographics. The linear mixed-effects model and Cox regression analysis were applied to evaluate their association with cognitive decline and progression of SCD to MCI, respectively. RESULTS: A total of 530 participants (mean age: 70.76 ± 6.01 years, 48.7% female) were analyzed in the study. The rate of cognitive decline was faster in individuals with SCD with higher neurogranin and neurogranin/BACE1 ratio (ß = -0.138, SE = 0.065, p = 0.037, and ß = -0.293, SE = 0.115, p = 0.013). Higher baseline neurogranin and neurogranin/BACE1 ratio were associated with an increased rate of conversion from SCD to MCI (hazard ratio [HR] 1.35 per SD, 95% CI 1.03-1.77, p = 0.028, and HR 1.53 per SD, 95% CI 1.13-2.07, p = 0.007). In addition, the impact of higher neurogranin levels on accelerating the rate of cognitive decline was more pronounced in the SCD group than in cognitively unimpaired controls (ß = -0.077, SE = 0.033, p = 0.020). DISCUSSION: Our findings suggest that CSF neurogranin and BACE1 begin to change in the preclinical stage of AD and they are associated with clinical progression in individuals with SCD.
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Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Biomarcadores , Disfunção Cognitiva , Progressão da Doença , Neurogranina , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Secretases da Proteína Precursora do Amiloide/líquido cefalorraquidiano , Ácido Aspártico Endopeptidases/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Estudos Longitudinais , Neurogranina/líquido cefalorraquidianoRESUMO
BACKGROUND: Multiple system atrophy (MSA), an atypical parkinsonian syndrome, is a rapidly progressive neurodegenerative disease with currently no established fluid biomarkers available. MSA is characterized by an oligodendroglial α-synucleinopathy, progressive neuronal cell loss and concomitant astrocytosis. Here, we investigate glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as fluid biomarkers for differential diagnosis, assessment of clinical disease severity and prediction of disease progression in MSA. METHODS: GFAP and NfL levels were analyzed in plasma and CSF samples of 47 MSA patients as well as 24 Parkinson's disease (PD) and 25 healthy controls (HC) as reference cohorts. In MSA, biomarker levels were correlated to baseline and longitudinal clinical disease severity (UMSARS scores). RESULTS: In MSA, GFAP levels in CSF and plasma predicted baseline clinical disease severity as indicated by UMSARS scores, while NfL levels predicted clinical disease progression as indicated by longitudinal changes in UMSARS scores. Cross-sectionally, NfL levels in CSF and plasma were significantly elevated in MSA compared to both PD and HC. Receiver operating curves (ROC) indicated high diagnostic accuracy of NfL for distinguishing MSA from PD (CSF: AUC = 0.97, 95% CI 0.90-1.00; plasma: AUC = 0.90, 95% CI 0.81-1.00). DISCUSSION: In MSA, GFAP shows promise as novel biomarker for assessing current clinical disease severity, while NfL might serve as biomarker for prediction of disease progression and differential diagnosis of MSA against PD.
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Biomarcadores , Progressão da Doença , Proteína Glial Fibrilar Ácida , Atrofia de Múltiplos Sistemas , Proteínas de Neurofilamentos , Índice de Gravidade de Doença , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/sangue , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Masculino , Feminino , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Pessoa de Meia-Idade , Idoso , Doença de Parkinson/diagnóstico , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Estudos Transversais , Diagnóstico Diferencial , Curva ROCRESUMO
This study extends the transferable anisotropic Mie potential (TAMie) to alkanethiols. The force field parameters are optimized by using an analytic equation of state as a surrogate model. Given the lack of experimental density data at elevated temperatures where Monte Carlo simulations have high statistical precision, the equation of state is supplemented by a linear multifidelity Gaussian process approach to bridge the temperature gap. Force field parameters are adjusted by minimizing squared deviations of calculated vapor pressures and liquid densities from experimental data of 1-propanethiol, 1-butanethiol and 1-pentanethiol leading to small mean absolute relative deviations in liquid densities and vapor pressures. The force field is transferable to higher 1-thiols, as shown for 1-hexanethiol and 1-octanethiol. Individual parameter sets are provided for methanethiol and ethanethiol. The shear viscosity of pure substances is predicted in fair agreement with experimental data, considering that it is not included in the parametrization. Further, the phase behavior of binary mixtures of alkanethiols with alkanes is studied, and predictions of the TAMie model are found in excellent agreement with experimental data.
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Accurate thermochemistry computations often require proper treatment of torsional modes. The one-dimensional hindered rotor model has proven to be a computationally efficient solution, given a sufficiently accurate potential energy surface. Methods that provide potential energies at various compromises of uncertainty and computational time demand can be optimally combined within a multifidelity treatment. In this study, we demonstrate how multifidelity modeling leads to (1) smooth interpolation along low-fidelity scan points with uncertainty estimates, (2) inclusion of high-fidelity data that change the energetic order of conformations, and (3) predicting best next-point calculations to extend an initial coarse grid. Our diverse application set comprises molecules, clusters, and transition states of alcohols, ethers, and rings. We discuss limitations for cases in which the low-fidelity computation is highly unreliable. Different features of the potential energy curve affect different quantities. To obtain "optimal" fits, we apply strategies ranging from simple minimization of deviations to developing an acquisition function tailored for statistical thermodynamics. Bayesian prediction of best next calculations can save a substantial amount of computation time for one- and multidimensional hindered rotors.
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INTRODUCTION: Subjective cognitive decline (SCD) in amyloid-positive (Aß+) individuals was proposed as a clinical indicator of Stage 2 in the Alzheimer's disease (AD) continuum, but this requires further validation across cultures, measures, and recruitment strategies. METHODS: Eight hundred twenty-one participants from SILCODE and DELCODE cohorts, including normal controls (NC) and individuals with SCD recruited from the community or from memory clinics, underwent neuropsychological assessments over up to 6 years. Amyloid positivity was derived from positron emission tomography or plasma biomarkers. Global cognitive change was analyzed using linear mixed-effects models. RESULTS: In the combined and stratified cohorts, Aß+ participants with SCD showed steeper cognitive decline or diminished practice effects compared with NC or Aß- participants with SCD. These findings were confirmed using different operationalizations of SCD and amyloid positivity, and across different SCD recruitment settings. DISCUSSION: Aß+ individuals with SCD in German and Chinese populations showed greater global cognitive decline and could be targeted for interventional trials. HIGHLIGHTS: SCD in amyloid-positive (Aß+) participants predicts a steeper cognitive decline. This finding does not rely on specific SCD or amyloid operationalization. This finding is not specific to SCD patients recruited from memory clinics. This finding is valid in both German and Chinese populations. Aß+ older adults with SCD could be a target population for interventional trials.
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A method for structure refinement of molecules based on residual dipolar coupling (RDC) data is proposed. It calculates RDC values using magnetic-field rotational sampling of the rotational degrees of freedom of a molecule in conjunction with molecule-internal configurational sampling. By applying rotational sampling, as is occurring in the experiment, leading to observable RDCs, the method stays close to the experiment. It avoids the use of an alignment tensor and, therefore, the assumptions that the overall rotation of the molecule is decoupled from its internal motions and that the molecule is rigid. Two simple molecules, a relatively rigid and a very flexible cyclo-octane molecule with eight aliphatic side chains containing 24 united atoms, serve as so-called "toy model" test systems. The method demonstrates the influence of molecular flexibility, force-field dominance, and the number of RDC restraints available on the outcome of structure refinement based on RDCs. Magnetic-field rotational sampling is basically equivalent but more efficient than explicitly sampling the rotational degrees of freedom of the molecule. In addition, the performance of the method is less dependent on the number NRDC of measured RDC-values available. The restraining forces bias the overall orientation distribution of the molecule correctly. This study suggests that the information content of RDCs with respect to molecular structure is limited.
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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
Aging is a multifaceted and highly varied process in the brain. Identifying aging biomarkers is one means of distinguishing pathological from physiological aging. The aim of this narrative review is to focus on two new developments in the field of fluid biomarkers and draw attention to this excellent tool for the early detection of potential brain pathologies that delay, alter, or enable physiological aging to become pathological. Pathological aging can lower the threshold for the development of specific diseases such as late-onset epilepsy. Fluid biomarkers can reveal pathological levels at an early stage and thus indicate disease processes in the brain that begin before symptoms develop; they thus differ from physiological aging.
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In NMR experiments, residual dipolar couplings (RDCs) in a molecule can be measured by averaging the dipolar couplings (DCs) over the rotational motion of a molecule in an environment that induces a slight anisotropic orientation distribution of the molecule. Since the shape of the anisotropic distribution cannot be measured, it is standard practice to use a particular orientation distribution of the molecule with respect to the magnetic field, in the form of a so-called alignment tensor (AT), to calculate RDC-values for the molecule. Since the same alignment tensor is commonly used to calculate the different RDCs of a molecule, this approach rests on the assumption that the rotational motion of the molecule is decoupled from its internal motions and that the molecule is rigid. The validity of these two assumptions is investigated for a small, simple molecule, using a relatively rigid atomic interaction function or force field and a more flexible one. By simulating the molecule using an orientation-biasing force an anisotropic rotational distribution can be generated, for which RDCs can be obtained. Using these RDCs as target RDCs when applying one of the two approaches of structure refinement based on RDCs, it can be investigated how well the target RDCs are approximated in the RDC restraining and whether the corresponding nonuniform orientation distribution is reproduced. For the relatively rigid version of the molecule, the AT approach reproduces the target RDC-values, although the nonuniform orientation distribution of the angle θab,H between the vector râab connecting two atoms a and b in the molecule and the vector representing the direction of the magnetic field Hâ as generated in the orientation-biasing simulation cannot be reproduced in the AT RDC-restraining simulation. For the relatively flexible version of the molecule, the AT approach fails to reproduce both the target RDC values and the nonuniform orientation distribution. For biomolecules with flexible parts, the application of the AT approach is thus not recommended. Instead, a method based on sampling of the rotational and internal degrees of freedom of the molecule should be applied in molecular structure determination or refinement based on measured RDCs.
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Modelos Moleculares , Rotação , Anisotropia , Espectroscopia de Ressonância Magnética/métodosRESUMO
Terpene synthesis stands at the forefront of modern synthetic chemistry and represents the state-of-the-art in the chemist's toolbox. Notwithstanding, these endeavors are inherently tied to the current availability of natural cyclic building blocks. Addressing this limitation, the stereocontrolled cyclization of abundant unbiased linear terpenes emerges as a valuable tool, which is still difficult to achieve with chemical catalysts. In this study, we showcase the remarkable capabilities of squalene-hopene cyclases (SHCs) in the chemoenzymatic synthesis of head-to-tail-fused terpenes. By combining engineered SHCs and a practical reaction setup, we generate ten chiral scaffolds with >99% ee and de, at up to decagram scale. Our mechanistic insights suggest how cyclodextrin encapsulation of terpenes may influence the performance of the membrane-bound enzyme. Moreover, we transform the chiral templates to valuable (mero)-terpenes using interdisciplinary synthetic methods, including a catalytic ring-contraction of enol-ethers facilitated by cooperative iodine/lipase catalysis.
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Biocatálise , Terpenos , Ciclização , Terpenos/metabolismo , Terpenos/química , Estereoisomerismo , Transferases Intramoleculares/metabolismo , Transferases Intramoleculares/genética , Transferases Intramoleculares/química , Ciclodextrinas/química , Ciclodextrinas/metabolismoRESUMO
Covalent organic frameworks (COFs) are a class of porous materials whose sorption properties have so far been studied primarily by physisorption. Quantifying the self-diffusion of guest molecules inside their nanometer-sized pores allows for a better understanding of confinement effects or transport limitations and is thus essential for various applications ranging from molecular separation to catalysis. Using a combination of pulsed field gradient nuclear magnetic resonance measurements and molecular dynamics simulations, we have studied the self-diffusion of acetonitrile and chloroform in the 1D pore channels of two imine-linked COFs (PI-3-COF) with different levels of crystallinity and porosity. The higher crystallinity and porosity sample exhibited anisotropic diffusion for MeCN parallel to the pore direction, with a diffusion coefficient of Dpar = 6.1(3) × 10-10 m2 s-1 at 300 K, indicating 1D transport and a 7.4-fold reduction in self-diffusion compared to the bulk liquid. This finding aligns with molecular dynamics simulations predicting 5.4-fold reduction, assuming an offset-stacked COF layer arrangement. In the low-porosity sample, more frequent diffusion barriers result in isotropic, yet significantly reduced diffusivities (DB = 1.4(1) × 10-11 m2 s-1). Diffusion coefficients for chloroform at 300 K in the pores of the high- (Dpar = 1.1(2) × 10-10 m2 s-1) and low-porosity (DB = 4.5(1) × 10-12 m2 s-1) samples reproduce these trends. Our multimodal study thus highlights the significant influence of real structure effects such as stacking faults and grain boundaries on the long-range diffusivity of molecular guest species while suggesting efficient intracrystalline transport at short diffusion times.
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Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.
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Esclerose Lateral Amiotrófica , Biomarcadores , Proteínas de Ligação a DNA , Vesículas Extracelulares , Demência Frontotemporal , Proteínas tau , Humanos , Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/genética , Proteínas tau/sangue , Proteínas tau/metabolismo , Vesículas Extracelulares/metabolismo , Demência Frontotemporal/sangue , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Biomarcadores/sangue , Proteínas de Ligação a DNA/sangue , Proteínas de Ligação a DNA/genética , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Paralisia Supranuclear Progressiva/sangue , Paralisia Supranuclear Progressiva/diagnóstico , Isoformas de Proteínas/sangueRESUMO
The development of force fields for polyfunctional molecules, such as alkanediols, requires a careful account of different average intramolecular conformations for gas states compared to dense liquid states, where intra- and intermolecular hydrogen bonds compete. In the present work, the transferable anisotropic Mie (TAMie) potential is extended to 1,n-alkanediols. Using the convention that intramolecular nonbonded interactions up to and including the third neighbor are excluded, all force field parameters developed previously for 1-alcohols were transferred to 1,5-pentanediol and beyond, with good agreement with experimental phase equilibrium data. To obtain trans-gauche ratios of 1,2-ethanediol and 1,3-propanediol that are consistent with experimental results, the propensities for intra- and intermolecular hydrogen bonds had to be balanced. This was achieved by parameterizing the intramolecular dihedral energy functions governing the O-C-C-O and O-C-C-C angles while intramolecular charge-charge interactions were active. All partial charges belonging to a functional group are collected in a charge group and all interactions among two charge groups are evaluated even if they are separated by less than three bonds. With this approach, it is possible to apply the nonbonded parameters from 1-alcohols to alkanediols without further refinement. The agreement with experimental phase equilibrium and shear viscosity data is of similar quality as for the 1-alcohols and the trans-gauche ratio agrees with literature results from spectroscopic measurements and ab initio calculations.
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Both music and language are found in all known human societies, yet no studies have compared similarities and differences between song, speech, and instrumental music on a global scale. In this Registered Report, we analyzed two global datasets: (i) 300 annotated audio recordings representing matched sets of traditional songs, recited lyrics, conversational speech, and instrumental melodies from our 75 coauthors speaking 55 languages; and (ii) 418 previously published adult-directed song and speech recordings from 209 individuals speaking 16 languages. Of our six preregistered predictions, five were strongly supported: Relative to speech, songs use (i) higher pitch, (ii) slower temporal rate, and (iii) more stable pitches, while both songs and speech used similar (iv) pitch interval size and (v) timbral brightness. Exploratory analyses suggest that features vary along a "musi-linguistic" continuum when including instrumental melodies and recited lyrics. Our study provides strong empirical evidence of cross-cultural regularities in music and speech.
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Idioma , Música , Fala , Humanos , Fala/fisiologia , Masculino , Percepção da Altura Sonora/fisiologia , Feminino , Adulto , Publicação Pré-RegistroRESUMO
OBJECTIVES: Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. MATERIALS AND METHODS: A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. RESULTS: Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD ( P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI ( P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups ( P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. CONCLUSIONS: The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.
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Doença de Alzheimer , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Masculino , Feminino , Idoso , Imageamento por Ressonância Magnética/métodos , Progressão da Doença , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Sistema Glinfático/diagnóstico por imagem , Idoso de 80 Anos ou maisRESUMO
INTRODUCTION: Soluble amyloid beta (Aß) oligomers have been suggested as initiating Aß related neuropathologic change in Alzheimer's disease (AD) but their quantitative distribution and chronological sequence within the AD continuum remain unclear. METHODS: A total of 526 participants in early clinical stages of AD and controls from a longitudinal cohort were neurobiologically classified for amyloid and tau pathology applying the AT(N) system. Aß and tau oligomers in the quantified cerebrospinal fluid (CSF) were measured using surface-based fluorescence intensity distribution analysis (sFIDA) technology. RESULTS: Across groups, highest Aß oligomer levels were found in A+ with subjective cognitive decline and mild cognitive impairment. Aß oligomers were significantly higher in A+T- compared to A-T- and A+T+. APOE ε4 allele carriers showed significantly higher Aß oligomer levels. No differences in tau oligomers were detected. DISCUSSION: The accumulation of Aß oligomers in the CSF peaks early within the AD continuum, preceding tau pathology. Disease-modifying treatments targeting Aß oligomers might have the highest therapeutic effect in these disease stages. Highlights: Using surface-based fluorescence intensity distribution analysis (sFIDA) technology, we quantified Aß oligomers in cerebrospinal fluid (CSF) samples of the DZNE-Longitudinal Cognitive Impairment and Dementia (DELCODE) cohortAß oligomers were significantly elevated in mild cognitive impairment (MCI)Amyloid-positive subjects in the subjective cognitive decline (SCD) group increased compared to the amyloid-negative control groupInterestingly, levels of Aß oligomers decrease at advanced stages of the disease (A+T+), which might be explained by altered clearing mechanisms.
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Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorders(SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta-analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta-analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI -0.55-0.22, p = 0.341). However, males with elevated CSF/serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05-0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17-0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptoms severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdownand sex-related differences in SSDs clinical trials and treatment strategies.
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Transtornos Psicóticos , Esquizofrenia , Humanos , Transtornos Psicóticos/líquido cefalorraquidiano , Esquizofrenia/líquido cefalorraquidiano , Masculino , Feminino , Barreira Hematoencefálica/metabolismo , Adulto , Índice de Gravidade de Doença , Fatores Sexuais , Biomarcadores/líquido cefalorraquidianoRESUMO
Background: Alzheimer's disease (AD) diagnosis is difficult, and new accurate tools based on peripheral biofluids are urgently needed. Extracellular vesicles (EVs) emerged as a valuable source of biomarker profiles for AD, since their cargo is disease-specific and these can be easily isolated from easily accessible biofluids, as blood. Fourier Transform Infrared (FTIR) spectroscopy can be employed to analyze EVs and obtain the spectroscopic profiles from different regions of the spectra, simultaneously characterizing carbohydrates, nucleic acids, proteins, and lipids. Objective: The aim of this study was to identify blood-derived EVs (bdEVs) spectroscopic signatures with AD discriminatory potential. Methods: Herein, FTIR spectra of bdEVs from two biofluids (serum and plasma) and distinct sets of Controls and AD cases were acquired, and EVs' spectra analyzed. Results: Analysis of bdEVs second derivative peaks area revealed differences between Controls and AD cases in distinct spectra regions, assigned to carbohydrates and nucleic acids, amides, and lipids. Conclusions: EVs' spectroscopic profiles presented AD discriminatory value, supporting the use of bdEVs combined with FTIR as a screening or complementary tool for AD diagnosis.