RESUMEN
Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.
Asunto(s)
Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Esclerosis Múltiple , Humanos , Estudio de Asociación del Genoma Completo , Enfermedades Inflamatorias del Intestino/genética , Sitios de Carácter Cuantitativo , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/genética , Inflamación/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Several studies have shown white matter (WM) abnormalities in Alzheimer's disease (AD) using diffusion tensor imaging (DTI). Nonetheless, robust characterization of WM changes has been challenging due to the methodological limitations of DTI. We applied fixel-based analyses (FBA) to examine microscopic differences in fiber density (FD) and macroscopic changes in fiber cross-section (FC) in early stages of AD (N = 393, 212 females). FBA was also compared with DTI, free-water corrected (FW)-DTI and diffusion kurtosis imaging (DKI). We further investigated the correlation of FBA and tensor-derived metrics with AD pathology and cognition. FBA metrics were decreased in the entire cingulum bundle, uncinate fasciculus and anterior thalamic radiations in Aß-positive patients with mild cognitive impairment compared to control groups. Metrics derived from DKI, and FW-DTI showed similar alterations whereas WM degeneration detected by DTI was more widespread. Tau-PET uptake in medial temporal regions was only correlated with reduced FC mainly in the parahippocampal cingulum in Aß-positive individuals. This tau-related WM alteration was also associated with impaired memory. Despite the spatially extensive between-group differences in DTI-metrics, the link between WM and tau aggregation was only revealed using FBA metrics implying high sensitivity but low specificity of DTI-based measures in identifying subtle tau-related WM degeneration. No relationship was found between amyloid load and any diffusion-MRI measures. Our results indicate that early tau-related WM alterations in AD are due to macrostructural changes specifically captured by FBA metrics. Thus, future studies assessing the effects of AD pathology in WM tracts should consider using FBA metrics.
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Enfermedad de Alzheimer , Imagen de Difusión Tensora , Sustancia Blanca , Proteínas tau , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Femenino , Masculino , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Anciano , Proteínas tau/metabolismo , Imagen de Difusión Tensora/métodos , Anciano de 80 o más Años , Persona de Mediana Edad , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patologíaRESUMEN
OBJECTIVE: We aimed to test whether region-specific factors, including spatial expression patterns of the tau-encoding gene MAPT and regional levels of amyloid positron emission tomography (PET), enhance connectivity-based modeling of the spatial variability in tau-PET deposition in the Alzheimer disease (AD) spectrum. METHODS: We included 685 participants (395 amyloid-positive participants within AD spectrum and 290 amyloid-negative controls) with tau-PET and amyloid-PET from 3 studies (Alzheimer's Disease Neuroimaging Initiative, 18 F-AV-1451-A05, and BioFINDER-1). Resting-state functional magnetic resonance imaging was obtained in healthy controls (n = 1,000) from the Human Connectome Project, and MAPT gene expression from the Allen Human Brain Atlas. Based on a brain-parcellation atlas superimposed onto all modalities, we obtained region of interest (ROI)-to-ROI functional connectivity, ROI-level PET values, and MAPT gene expression. In stepwise regression analyses, we tested connectivity, MAPT gene expression, and amyloid-PET as predictors of group-averaged and individual tau-PET ROI values in amyloid-positive participants. RESULTS: Connectivity alone explained 21.8 to 39.2% (range across 3 studies) of the variance in tau-PET ROI values averaged across amyloid-positive participants. Stepwise addition of MAPT gene expression and amyloid-PET increased the proportion of explained variance to 30.2 to 46.0% and 45.0 to 49.9%, respectively. Similarly, for the prediction of patient-level tau-PET ROI values, combining all 3 predictors significantly improved the variability explained (mean adjusted R2 range across studies = 0.118-0.148, 0.156-0.196, and 0.251-0.333 for connectivity alone, connectivity plus MAPT expression, and all 3 modalities combined, respectively). INTERPRETATION: Across 3 study samples, combining the functional connectome and molecular properties substantially enhanced the explanatory power compared to single modalities, providing a valuable tool to explain regional susceptibility to tau deposition in AD. ANN NEUROL 2024;95:274-287.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Conectoma , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Imagen por Resonancia Magnética/métodos , Proteínas tau/genética , Proteínas tau/metabolismo , Encéfalo/patología , Tomografía de Emisión de Positrones/métodos , Amiloide/metabolismo , Expresión Génica , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/patologíaRESUMEN
OBJECTIVE: We compared the accuracy of amyloid and [18F]Flortaucipir (FTP) tau positron emission tomography (PET) visual reads for distinguishing patients with mild cognitive impairment (MCI) or dementia with fluid biomarker support of Alzheimer's disease (AD). METHODS: Participants with FTP-PET, amyloid-PET, and diagnosis of dementia-AD (n = 102), MCI-AD (n = 41), non-AD diseases (n = 76), and controls (n = 20) were included. AD status was determined independent of PET by cerebrospinal fluid or plasma biomarkers. The mean age was 66.9 years, and 44.8% were women. Three readers interpreted scans blindly and independently. Amyloid-PET was classified as positive/negative using tracer-specific criteria. FTP-PET was classified as positive with medial temporal lobe (MTL) binding as the minimum uptake indicating AD tau (tau-MTL+), positive with posterolateral temporal or extratemporal cortical binding in an AD-like pattern (tau-CTX+), or negative. The majority of scan interpretations were used to calculate diagnostic accuracy of visual reads in detecting MCI/dementia with fluid biomarker support for AD (MCI/dementia-AD). RESULTS: Sensitivity of amyloid-PET for MCI/dementia-AD was 95.8% (95% confidence interval 91.1-98.4%), which was comparable to tau-CTX+ 92.3% (86.7-96.1%, p = 0.67) and tau-MTL+ 97.2% (93.0-99.2%, p = 0.27). Specificity of amyloid-PET for biomarker-negative healthy and disease controls was 84.4% (75.5-91.0%), which was like tau-CTX+ 88.5% (80.4-94.1%, p = 0.34), and trended toward being higher than tau-MTL+ 75.0% (65.1-83.3%, p = 0.08). Tau-CTX+ had higher specificity than tau-MTL+ (p = 0.0002), but sensitivity was lower (p = 0.02), driven by decreased sensitivity for MCI-AD (80.5% [65.1-91.2] vs. 95.1% [83.5-99.4], p = 0.03). INTERPRETATION: Amyloid- and tau-PET visual reads have similar sensitivity/specificity for detecting AD in cognitively impaired patients. Visual tau-PET interpretations requiring cortical binding outside MTL increase specificity, but lower sensitivity for MCI-AD. ANN NEUROL 2024;96:476-487.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Femenino , Tomografía de Emisión de Positrones/métodos , Masculino , Anciano , Proteínas tau/líquido cefalorraquídeo , Diagnóstico Diferencial , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico , Persona de Mediana Edad , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Carbolinas , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico , Péptidos beta-Amiloides/metabolismo , Biomarcadores/sangre , Anciano de 80 o más AñosRESUMEN
There is increased interest in developing markers reflecting microstructural changes that could serve as outcome measures in clinical trials. This is especially important after unexpected results in trials evaluating disease-modifying therapies targeting amyloid-ß (Aß), where morphological metrics from MRI showed increased volume loss despite promising clinical treatment effects. In this study, changes over time in cortical mean diffusivity, derived using diffusion tensor imaging, were investigated in a large cohort (n = 424) of non-demented participants from the Swedish BioFINDER study. Participants were stratified following the Aß/tau (AT) framework. The results revealed a widespread increase in mean diffusivity over time, including both temporal and parietal cortical regions, in Aß-positive but still tau-negative individuals. These increases were steeper in Aß-positive and tau-positive individuals and robust to the inclusion of cortical thickness in the model. A steeper increase in mean diffusivity was also associated with both changes over time in fluid markers reflecting astrocytic activity (i.e. plasma level of glial fibrillary acidic protein and CSF levels of YKL-40) and worsening of cognitive performance (all P < 0.01). By tracking cortical microstructural changes over time and possibly reflecting variations related to the astrocytic response, cortical mean diffusivity emerges as a promising marker for tracking treatments-induced microstructural changes in clinical trials.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Imagen de Difusión Tensora , Imagen de Difusión por Resonancia Magnética , Péptidos beta-Amiloides , Filamentos IntermediosRESUMEN
Cerebrovascular pathology often co-exists with Alzheimer's disease pathology and can contribute to Alzheimer's disease-related clinical progression. However, the degree to which vascular burden contributes to Alzheimer's disease pathological progression is still unclear. This study aimed to investigate interactions between vascular burden and amyloid-ß pathology on both baseline tau tangle load and longitudinal tau accumulation. We included 1229 participants from the Swedish BioFINDER-2 Study, including cognitively unimpaired and impaired participants with and without biomarker-confirmed amyloid-ß pathology. All underwent baseline tau-PET (18F-RO948), and a subset (n = 677) underwent longitudinal tau-PET after 2.5 ± 1.0â years. Tau-PET uptake was computed for a temporal meta-region-of-interest. We focused on four main vascular imaging features and risk factors: microbleeds; white matter lesion volume; stroke-related events (infarcts, lacunes and haemorrhages); and the Framingham Heart Study Cardiovascular Disease risk score. To validate our in vivo results, we examined 1610 autopsy cases from an Arizona-based neuropathology cohort on three main vascular pathological features: cerebral amyloid angiopathy; white matter rarefaction; and infarcts. For the in vivo cohort, primary analyses included age-, sex- and APOE É4-corrected linear mixed models between tau-PET (outcome) and interactions between time, amyloid-ß and each vascular feature (predictors). For the neuropathology cohort, age-, sex- and APOE É4-corrected linear models between tau tangle density (outcome) and an interaction between plaque density and each vascular feature (predictors) were performed. In cognitively unimpaired individuals, we observed a significant interaction between microbleeds and amyloid-ß pathology on greater baseline tau load (ß = 0.68, P < 0.001) and longitudinal tau accumulation (ß = 0.11, P < 0.001). For white matter lesion volume, we did not observe a significant independent interaction effect with amyloid-ß on tau after accounting for microbleeds. In cognitively unimpaired individuals, we further found that stroke-related events showed a significant negative interaction with amyloid-ß on longitudinal tau (ß = -0.08, P < 0.001). In cognitively impaired individuals, there were no significant interaction effects between cerebrovascular and amyloid-ß pathology at all. In the neuropathology dataset, the in vivo observed interaction effects between cerebral amyloid angiopathy and plaque density (ß = 0.38, P < 0.001) and between infarcts and plaque density (ß = -0.11, P = 0.005) on tau tangle density were replicated. To conclude, we demonstrated that cerebrovascular pathology-in the presence of amyloid-ß pathology-modifies tau accumulation in early stages of Alzheimer's disease. More specifically, the co-occurrence of microbleeds and amyloid-ß pathology was associated with greater accumulation of tau aggregates during early disease stages. This opens the possibility that interventions targeting microbleeds may attenuate the rate of tau accumulation in Alzheimer's disease.
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Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Accidente Cerebrovascular , Humanos , Tomografía Computarizada por Rayos X , Péptidos beta-Amiloides , Placa Amiloide , Infarto , Hemorragia Cerebral , Apolipoproteínas ERESUMEN
Synaptic dysfunction and degeneration is likely the key pathophysiology for the progression of cognitive decline in various dementia disorders. Synaptic status can be monitored by measuring synaptic proteins in CSF. In this study, both known and new synaptic proteins were investigated and compared as potential biomarkers of synaptic dysfunction, particularly in the context of Alzheimer's disease (AD). Seventeen synaptic proteins were quantified in CSF using two different targeted mass spectrometry assays in the prospective Swedish BioFINDER-2 study. The study included 958 individuals, characterized as having mild cognitive impairment (MCI, n = 205), AD dementia (n = 149) and a spectrum of other neurodegenerative diseases (n = 171), in addition to cognitively unimpaired individuals (CU, n = 443). Synaptic protein levels were compared between diagnostic groups and their associations with cognitive decline and key neuroimaging measures (amyloid-ß-PET, tau-PET and cortical thickness) were assessed. Among the 17 synaptic proteins examined, 14 were specifically elevated in the AD continuum. SNAP-25, 14-3-3 zeta/delta, ß-synuclein, and neurogranin exhibited the highest discriminatory accuracy in differentiating AD dementia from controls (areas under the curve = 0.81-0.93). SNAP-25 and 14-3-3 zeta/delta also had the strongest associations with tau-PET, amyloid-ß-PET and cortical thickness at baseline and were associated with longitudinal changes in these imaging biomarkers [ß(standard error, SE) = -0.056(0.0006) to 0.058(0.005), P < 0.0001]. SNAP-25 was the strongest predictor of progression to AD dementia in non-demented individuals (hazard ratio = 2.11). In contrast, neuronal pentraxins were decreased in all neurodegenerative diseases (except for Parkinson's disease), and NPTX2 showed the strongest associations with subsequent cognitive decline [longitudinal Mini-Mental State Examination: ß(SE) = 0.57(0.1), P ≤ 0.0001; and mPACC: ß(SE) = 0.095(0.024), P ≤ 0.001] across the AD continuum. Interestingly, utilizing a ratio of the proteins that displayed higher levels in AD, such as SNAP-25 or 14-3-3 zeta/delta, over NPTX2 improved the biomarkers' associations with cognitive decline and brain atrophy. We found 14-3-3 zeta/delta and SNAP-25 to be especially promising as synaptic biomarkers of pathophysiological changes in AD. Neuronal pentraxins were identified as general indicators of neurodegeneration and associated with cognitive decline across various neurodegenerative dementias. Cognitive decline and brain atrophy were best predicted by ratios of SNAP-25/NPTX2 and 14-3-3 zeta/delta/NPTX2.
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Enfermedad de Alzheimer , Biomarcadores , Disfunción Cognitiva , Enfermedades Neurodegenerativas , Sinapsis , Humanos , Masculino , Femenino , Anciano , Biomarcadores/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Persona de Mediana Edad , Sinapsis/patología , Anciano de 80 o más Años , Estudios Prospectivos , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Neurogranina/líquido cefalorraquídeoRESUMEN
Age-related white matter hyperintensities are a common feature and are known to be negatively associated with structural integrity, functional connectivity, and cognitive performance. However, this has yet to be fully understood mechanistically. We analyzed multiple MRI modalities acquired in 465 non-demented individuals from the Swedish BioFINDER study including 334 cognitively normal and 131 participants with mild cognitive impairment. White matter hyperintensities were automatically quantified using fluid-attenuated inversion recovery MRI and parameters from diffusion tensor imaging were estimated in major white matter fibre tracts. We calculated fMRI resting state-derived functional connectivity within and between predefined cortical regions structurally linked by the white matter tracts. How change in functional connectivity is affected by white matter lesions and related to cognition (in the form of executive function and processing speed) was explored. We examined the functional changes using a measure of sample entropy. As expected hyperintensities were associated with disrupted structural white matter integrity and were linked to reduced functional interregional lobar connectivity, which was related to decreased processing speed and executive function. Simultaneously, hyperintensities were also associated with increased intraregional functional connectivity, but only within the frontal lobe. This phenomenon was also associated with reduced cognitive performance. The increased connectivity was linked to increased entropy (reduced predictability and increased complexity) of the involved voxels' blood oxygenation level-dependent signal. Our findings expand our previous understanding of the impact of white matter hyperintensities on cognition by indicating novel mechanisms that may be important beyond this particular type of brain lesions.
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Disfunción Cognitiva , Imagen por Resonancia Magnética , Sustancia Blanca , Humanos , Masculino , Femenino , Anciano , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Imagen por Resonancia Magnética/métodos , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/patología , Imagen de Difusión Tensora/métodos , Anciano de 80 o más Años , Función Ejecutiva/fisiología , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Conectoma/métodos , Encéfalo/diagnóstico por imagenRESUMEN
Autopsy data indicate that the locus coeruleus (LC) is one of the first sites in the brain to accumulate hyperphosphorylated tau pathology, with the rostral part possibly being more vulnerable in the earlier stages of the disease. Taking advantage of recent developments in ultra-high field (7 T) imaging, we investigated whether imaging measures of the LC also reveal a specific anatomic correlation with tau using novel plasma biomarkers of different species of hyperphosphorylated tau, how early in adulthood these associations can be detected and if are associated with worse cognitive performance. To validate the anatomic correlations, we tested if a rostro-caudal gradient in tau pathology is also detected at autopsy in data from the Rush Memory and Aging Project (MAP). We found that higher plasma measures of phosphorylated tau, in particular ptau231, correlated negatively with dorso-rostral LC integrity, whereas correlations for neurodegenerative plasma markers (neurofilament light, total tau) were scattered throughout the LC including middle to caudal sections. In contrast, the plasma Aß42/40 ratio, associated with brain amyloidosis, did not correlate with LC integrity. These findings were specific to the rostral LC and not observed when using the entire LC or the hippocampus. Furthermore, in the MAP data, we observed higher rostral than caudal tangle density in the LC, independent of the disease stage. The in vivo LC-phosphorylated tau correlations became significant from midlife, with the earliest effect for ptau231, starting at about age 55. Finally, interactions between lower rostral LC integrity and higher ptau231 concentrations predicted lower cognitive performance. Together, these findings demonstrate a specific rostral vulnerability to early phosphorylated tau species that can be detected with dedicated magnetic resonance imaging measures, highlighting the promise of LC imaging as an early marker of AD-related processes.
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Enfermedad de Alzheimer , Locus Coeruleus , Humanos , Persona de Mediana Edad , Locus Coeruleus/metabolismo , Proteínas tau/metabolismo , Autopsia , Encéfalo/metabolismo , Imagen por Resonancia Magnética/métodos , Enfermedad de Alzheimer/patología , Péptidos beta-AmiloidesRESUMEN
Markers of downstream events are a key component of clinical trials of disease-modifying therapies for Alzheimer's disease. Morphological metrics like cortical thickness are established measures of atrophy but are not sensitive enough to detect amyloid-beta (Aß)- related changes that occur before overt atrophy become visible. We aimed to investigate to what extent diffusion MRI can provide sensitive markers of cortical microstructural changes and to test their associations with multiple aspects of the Alzheimer's disease pathological cascade, including both Aß and tau accumulation, astrocytic activation and cognitive deficits. We applied the mean apparent diffusion propagator model to diffusion MRI data from 492 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. Participants were stratified in Aß-negative/tau-negative, Aß-positive/tau-negative and Aß-positive/tau-positive based on Aß- and tau-PET uptake. Cortical regional values of diffusion MRI metrics and cortical thickness were compared across groups. Associations between regional values of diffusion MRI metrics and both Aß- and tau-PET uptake were also investigated along with the association with plasma level of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation (available in 292 participants). Mean squared displacement revealed widespread microstructural differences already between Aß-negative/tau-negative and Aß-positive/tau-negative participants with a spatial distribution that closely resembled the pattern of Aß accumulation. In contrast, differences in cortical thickness were clearly more limited. Mean squared displacement was also correlated with both Aß- and tau-PET uptake even independently from one another and from cortical thickness. Further, the same metric exhibited significantly stronger correlations with PET uptake than cortical thickness (P < 0.05). Mean squared displacement was also positively correlated with GFAP with a pattern that resembles Aß accumulation, and GFAP partially mediated the association between Aß accumulation and mean squared displacement. Further, impairments in executive functions were significantly more associated with mean squared displacement values extracted from a meta-region of interest encompassing regions accumulating Aß early in the disease process, than with cortical thickness (P < 0.05). Similarly, impairments in memory functions were significantly more associated with mean squared displacement values extracted from a temporal meta-region of interest than with cortical thickness (P < 0.05). Metrics of cortical microstructural alteration derived from diffusion MRI are highly sensitive to multiple aspects of the Alzheimer's disease pathological cascade. Of particular interest is the link with both Aß-PET and GFAP, suggesting diffusion MRI might reflects microstructural changes related to the astrocytic response to Aß aggregation. Therefore, metrics of cortical diffusion might be important outcome measures in anti-Aß treatments clinical trials for detecting drug-induced changes in cortical microstructure.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/patología , Proteínas tau/metabolismo , Encéfalo/patología , Tomografía de Emisión de Positrones , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/patología , Amiloide/metabolismo , Atrofia/patología , Biomarcadores/metabolismoRESUMEN
Different tau biomarkers become abnormal at different stages of Alzheimer's disease, with CSF phospho-tau typically becoming elevated at subthreshold levels of tau-PET binding. To capitalize on the temporal order of tau biomarker-abnormality and capture the earliest changes of tau accumulation, we implemented an observational study design to examine longitudinal changes in tau-PET, cortical thickness and cognitive decline in amyloid-ß-positive individuals with elevated CSF p-tau levels (P+) but subthreshold Tau-PET retention (T-). To this end, individuals without dementia (i.e. cognitively unimpaired or mild cognitive impairment, n = 231) were selected from the BioFINDER-2 study. Amyloid-ß-positive (A+) individuals were categorized into biomarker groups based on cut-offs for abnormal CSF p-tau217 and 18F-RO948 (Tau) PET, yielding groups of tau-concordant-negative (A+P-T-; n = 30), tau-discordant (i.e. A+P+T-; n = 48) and tau-concordant-positive (A+P+T+; n = 18) individuals. In addition, 135 amyloid-ß-negative, tau-negative, cognitively unimpaired individuals served as controls. Differences in annual change in regional tau-PET, cortical thickness and cognition between the groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures only) education. Mean follow-up time was â¼2 years. Longitudinal increase in tau-PET was faster in the A+P+T- group than in the control and A+P-T- groups across medial temporal and neocortical regions, with the highest accumulation rates in the medial temporal lobe. The A+P+T- group showed a slower rate of increase in tau-PET compared to the A+P+T+ group, primarily in neocortical regions. We did not detect differences in yearly change in cortical thickness or in cognitive decline between the A+P+T- and A+P-T- groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups. Altogether, these findings suggest that the A+P+T- biomarker profile in persons without dementia is associated with an isolated effect on increased tau-PET accumulation rates but not on cortical thinning and cognitive decline. While this suggests that the tau-discordant biomarker profile is not strongly associated with short-term clinical decline, this group does represent an interesting population for monitoring the effects of interventions with disease-modifying agents on tau accumulation in early Alzheimer's disease, and for examining the emergence of tau aggregates in Alzheimer's disease. Further, we suggest updating the AT(N) criteria for Alzheimer's disease biomarker classification to APT(N).
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/metabolismo , Proteínas tau/metabolismo , Tomografía de Emisión de Positrones , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Amiloide , Cognición , BiomarcadoresRESUMEN
TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterize TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n = 126), amyotrophic lateral sclerosis (ALS, n = 141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer's disease (n = 304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating individuals with and without Alzheimer's disease and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies.
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Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Proteinopatías TDP-43 , Humanos , Esclerosis Amiotrófica Lateral/genética , Demencia Frontotemporal/patología , Enfermedad de Alzheimer/patología , Proteinopatías TDP-43/patología , Degeneración Lobar Frontotemporal/patología , Proteínas de Unión al ADN/genéticaRESUMEN
Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-ß (Aß) status and predict future progression to Alzheimer's dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aß-status (i.e. abnormal CSF Aß42/40) at baseline; and 45 of these Aß-positive participants progressed to Alzheimer's dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aß status [area under curve (AUC) = 0.947; Pdiff < 0.015] or progression to Alzheimer's dementia (AUC = 0.932; Pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886-0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange 0.835-0.872; Pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUCrange 0.642-0.813; Pdiff ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; Pdiff = 0.003 versus p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange 0.320-0.669). In conclusion, our findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aß or those who will subsequently progress to Alzheimer's dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aß-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer's dementia in the future.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Femenino , Anciano , Masculino , Enfermedad de Alzheimer/diagnóstico , Proteínas tau , Péptidos beta-Amiloides , Disfunción Cognitiva/diagnóstico , Encéfalo , BiomarcadoresRESUMEN
Amyloid-ß (Aß) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aß, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aß-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aß in vivo. Immunohistochemistry was used to estimate Aß load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aß. This was also observed in individuals with low Aß load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aß. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aß pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aß-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aß-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aß density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aß pathology.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Tauopatías , Adulto , Humanos , Enfermedad de Alzheimer/patología , Proteínas tau , Disfunción Cognitiva/patología , Péptidos beta-Amiloides , Tomografía de Emisión de Positrones/métodos , Imagen por Resonancia MagnéticaRESUMEN
Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-ß-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stßinteraction = -0.062, P = 0.032), higher education level (Stßinteraction = -0.072, P = 0.011) and higher intracranial volume (Stßinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Estudios Longitudinales , Proteínas tau/metabolismo , Estudios Transversales , Adelgazamiento de la Corteza Cerebral/patología , Tomografía de Emisión de Positrones , Encéfalo/patología , Cognición , Apolipoproteínas ERESUMEN
OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.
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Enfermedad de Alzheimer , Trastorno Bipolar , Trastorno Depresivo Mayor , Demencia Frontotemporal , Trastornos Psicóticos , Humanos , Enfermedad de Alzheimer/diagnóstico , Biomarcadores , Trastorno Bipolar/diagnóstico , Trastorno Depresivo Mayor/diagnóstico , Demencia Frontotemporal/diagnóstico , Filamentos IntermediosRESUMEN
Importance: An accurate blood test for Alzheimer disease (AD) could streamline the diagnostic workup and treatment of AD. Objective: To prospectively evaluate a clinically available AD blood test in primary care and secondary care using predefined biomarker cutoff values. Design, Setting, and Participants: There were 1213 patients undergoing clinical evaluation due to cognitive symptoms who were examined between February 2020 and January 2024 in Sweden. The biomarker cutoff values had been established in an independent cohort and were applied to a primary care cohort (n = 307) and a secondary care cohort (n = 300); 1 plasma sample per patient was analyzed as part of a single batch for each cohort. The blood test was then evaluated prospectively in the primary care cohort (n = 208) and in the secondary care cohort (n = 398); 1 plasma sample per patient was sent for analysis within 2 weeks of collection. Exposure: Blood tests based on plasma analyses by mass spectrometry to determine the ratio of plasma phosphorylated tau 217 (p-tau217) to non-p-tau217 (expressed as percentage of p-tau217) alone and when combined with the amyloid-ß 42 and amyloid-ß 40 (Aß42:Aß40) plasma ratio (the amyloid probability score 2 [APS2]). Main Outcomes and Measures: The primary outcome was AD pathology (determined by abnormal cerebrospinal fluid Aß42:Aß40 ratio and p-tau217). The secondary outcome was clinical AD. The positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy, and area under the curve (AUC) values were calculated. Results: The mean age was 74.2 years (SD, 8.3 years), 48% were women, 23% had subjective cognitive decline, 44% had mild cognitive impairment, and 33% had dementia. In both the primary care and secondary care assessments, 50% of patients had AD pathology. When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 (95% CI, 0.95-0.99) when the APS2 was used, the PPV was 91% (95% CI, 87%-96%), and the NPV was 92% (95% CI, 87%-96%); in the secondary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 83%-93%), and the NPV was 87% (95% CI, 82%-93%). When the plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 81%-94%), and the NPV was 90% (95% CI, 84%-96%); in the secondary care cohort, the AUC was 0.97 (95% CI, 0.95-0.98) when the APS2 was used, the PPV was 91% (95% CI, 87%-95%), and the NPV was 91% (95% CI, 87%-95%). The diagnostic accuracy was high in the 4 cohorts (range, 88%-92%). Primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) for identifying clinical AD after clinical examination, cognitive testing, and a computed tomographic scan vs 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) vs 91% (95% CI, 88%-95%) using the APS2. In the overall population, the diagnostic accuracy using the APS2 (90% [95% CI, 88%-92%]) was not different from the diagnostic accuracy using the percentage of p-tau217 alone (90% [95% CI, 88%-91%]). Conclusions and Relevance: The APS2 and percentage of p-tau217 alone had high diagnostic accuracy for identifying AD among individuals with cognitive symptoms in primary and secondary care using predefined cutoff values. Future studies should evaluate how the use of blood tests for these biomarkers influences clinical care.
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INTRODUCTION: The recent introduction of seed amplification assays (SAAs) detecting misfolded α-synuclein, a pathology-specific marker for Lewy body disease (LBD), has allowed the in vivo identification and phenotypic characterization of patients with co-occurring Alzheimer's disease (AD) and LBD since the early clinical or even preclinical stage. METHODS: We reviewed studies with an in vivo biomarker-based diagnosis of AD-LBD copathology. RESULTS: Studies in large cohorts of cognitively impaired individuals have shown that cerebrospinal fluid (CSF) biomarkers detect the coexistence of AD and LB pathology in approximately 20%-25% of them, independently of the primary clinical diagnosis. Compared to those with pure AD, AD-LBD patients showed worse global cognition, especially in attentive/executive and visuospatial functions, and worse motor functions. In cognitively unimpaired individuals, concurrent AD-LBD pathologies predicted longitudinal cognitive progression with faster worsening of global cognition, memory, and attentive/executive functions. DISCUSSION: Future research studies aiming for a better precision medicine approach should develop SAAs further to reach a quantitative evaluation or staging of each underlying pathology using a single biofluid sample. HIGHLIGHTS: α-Synuclein seed amplification assays (SAAs) provide a specific marker for Lewy body disease (LBD). SAAs allow for the in vivo identification of co-occurring LBD in patients with Alzheimer's disease (AD). AD-LBD coexist in 20-25% of cognitively impaired elderly individuals, and â¼8% of those asymptomatic. Compared to pure AD, AD-LBD causes a faster worsening of cognitive functions. AD-LBD is associated with worse attentive/executive, memory, visuospatial and motor functions.
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Enfermedad de Alzheimer , Biomarcadores , Enfermedad por Cuerpos de Lewy , Humanos , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , alfa-Sinucleína/líquido cefalorraquídeo , Progresión de la EnfermedadRESUMEN
INTRODUCTION: Remote unsupervised cognitive assessments have the potential to complement and facilitate cognitive assessment in clinical and research settings. METHODS: Here, we evaluate the usability, validity, and reliability of unsupervised remote memory assessments via mobile devices in individuals without dementia from the Swedish BioFINDER-2 study and explore their prognostic utility regarding future cognitive decline. RESULTS: Usability was rated positively; remote memory assessments showed good construct validity with traditional neuropsychological assessments and were significantly associated with tau-positron emission tomography and downstream magnetic resonance imaging measures. Memory performance at baseline was associated with future cognitive decline and prediction of future cognitive decline was further improved by combining remote digital memory assessments with plasma p-tau217. Finally, retest reliability was moderate for a single assessment and good for an aggregate of two sessions. DISCUSSION: Our results demonstrate that unsupervised digital memory assessments might be used for diagnosis and prognosis in Alzheimer's disease, potentially in combination with plasma biomarkers. HIGHLIGHTS: Remote and unsupervised digital memory assessments are feasible in older adults and individuals in early stages of Alzheimer's disease. Digital memory assessments are associated with neuropsychological in-clinic assessments, tau-positron emission tomography and magnetic resonance imaging measures. Combination of digital memory assessments with plasma p-tau217 holds promise for prognosis of future cognitive decline. Future validation in further independent, larger, and more diverse cohorts is needed to inform clinical implementation.