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Blood-based biomarkers have been extensively evaluated for their diagnostic potential in Alzheimer's disease. However, their relative prognostic and monitoring capabilities for cognitive decline, amyloid-ß (Aß) accumulation and grey matter loss in cognitively unimpaired elderly require further investigation over extended time periods. This prospective cohort study in cognitively unimpaired elderly [n = 185, mean age (range) = 69 (53-84) years, 48% female] examined the prognostic and monitoring capabilities of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), Aß1-42/Aß1-40 and phosphorylated tau (pTau)181 through their quantification in serum. All participants underwent baseline Aß-PET, MRI and blood sampling as well as 2-yearly cognitive testing. A subset additionally underwent Aß-PET (n = 109), MRI (n = 106) and blood sampling (n = 110) during follow-up [median time interval (range) = 6.1 (1.3-11.0) years]. Matching plasma measurements were available for Aß1-42/Aß1-40 and pTau181 (both n = 140). Linear mixed-effects models showed that high serum GFAP and NfL predicted future cognitive decline in memory (ßGFAP×Time = -0.021, PFDR = 0.007 and ßNfL×Time = -0.031, PFDR = 0.002) and language (ßGFAP×Time = -0.021, PFDR = 0.002 and ßNfL×Time = -0.018, PFDR = 0.03) domains. Low serum Aß1-42/Aß1-40 equally but independently predicted memory decline (ßAß1-42/Aß1-40×Time = -0.024, PFDR = 0.02). Whole-brain voxelwise analyses revealed that low Aß1-42/Aß1-40 predicted Aß accumulation within the precuneus and frontal regions, high GFAP and NfL predicted grey matter loss within hippocampal regions and low Aß1-42/Aß1-40 predicted grey matter loss in lateral temporal regions. Serum GFAP, NfL and pTau181 increased over time, while Aß1-42/Aß1-40 decreased only in Aß-PET-negative elderly. NfL increases associated with declining memory (ßNfLchange×Time = -0.030, PFDR = 0.006) and language (ßNfLchange×Time = -0.021, PFDR = 0.02) function and serum Aß1-42/Aß1-40 decreases associated with declining language function (ßAß1-42/Aß1-40×Time = -0.020, PFDR = 0.04). GFAP increases associated with Aß accumulation within the precuneus and NfL increases associated with grey matter loss. Baseline and longitudinal serum pTau181 only associated with Aß accumulation in restricted occipital regions. In head-to-head comparisons, serum outperformed plasma Aß1-42/Aß1-40 (ΔAUC = 0.10, PDeLong, FDR = 0.04), while both plasma and serum pTau181 demonstrated poor performance to detect asymptomatic Aß-PET positivity (AUC = 0.55 and 0.63, respectively). However, when measured with a more phospho-specific assay, plasma pTau181 detected Aß-positivity with high performance (AUC = 0.82, PDeLong, FDR < 0.007). In conclusion, serum GFAP, NfL and Aß1-42/Aß1-40 are valuable prognostic and/or monitoring tools in asymptomatic stages providing complementary information in a time- and pathology-dependent manner.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Femenino , Anciano , Masculino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/metabolismo , Estudios Prospectivos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Amiloide/metabolismo , Disfunción Cognitiva/metabolismo , Biomarcadores , Cognición , Tomografía de Emisión de PositronesRESUMEN
INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aß]42), T+ (CSF phosphorylated tau181), and N+ or N- based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS: Only a few individuals were A+T+Ng-. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng- and A+T+NfL-, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV-, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. HIGHLIGHTS: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.
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The major neuropathological hallmarks of Alzheimer's disease (AD) are amyloid ß (Aß) plaques and neurofibrillary tangles (NFT), accompanied by neuroinflammation and neuronal loss. Increasing evidence is emerging for the activation of the canonical NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome in AD. However, the mechanisms leading to neuronal loss in AD and the involvement of glial cells in these processes are still not clear. The aim of this study was to investigate the contribution of pyroptosis, a pro-inflammatory mechanism of cell death downstream of the inflammasome, to neurodegeneration in AD. Immunohistochemistry and biochemical analysis of protein levels were performed on human post-mortem brain tissue. We investigated the presence of cleaved gasdermin D (GSDMD), the pyroptosis effector protein, as well as the NLRP3 inflammasome-forming proteins, in the medial temporal lobe of 23 symptomatic AD, 25 pathologically defined preclinical AD (p-preAD) and 21 non-demented control cases. Cleaved GSDMD was detected in microglia, but also in astrocytes and in few pyramidal neurons in the first sector of the cornu ammonis (CA1) of the hippocampus and the temporal cortex of Brodmann area 36. Only microglia expressed all NLRP3 inflammasome-forming proteins (i.e., ASC, NLRP3, caspase-1). Cleaved GSDMD-positive astrocytes and neurons exhibited caspase-8 and non-canonical inflammasome protein caspase-4, respectively, potentially indicating alternative pathways for GSDMD cleavage. Brains of AD patients exhibited increased numbers of cleaved GSDMD-positive cells. Cleaved GSDMD-positive microglia and astrocytes were found in close proximity to Aß plaques, while cleaved GSDMD-positive neurons were devoid of NFTs. In CA1, NLRP3-positive microglia and cleaved GSDMD-positive neurons were associated with local neuronal loss, indicating a possible contribution of NLRP3 inflammasome and pyroptosis activation to AD-related neurodegeneration. Taken together, our results suggest cell type-specific activation of pyroptosis in AD and extend the current knowledge about the contribution of neuroinflammation to the neurodegenerative process in AD via a direct link to neuron death by pyroptosis.
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Enfermedad de Alzheimer , Inflamasomas , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad de Alzheimer/patología , Piroptosis , Microglía/patología , Péptidos beta-Amiloides , Astrocitos/patología , Enfermedades Neuroinflamatorias , Neuronas/patologíaRESUMEN
Visual consciousness is shaped by the interplay between endogenous selection and exogenous capture. If stimulus saliency is aligned with a subject's attentional priorities, endogenous selection will be facilitated. In case of a misalignment, endogenous selection may be compromised as attentional capture is a strong and automatic process. We manipulated task-congruent versus -incongruent saliency in a functional magnetic resonance imaging change-detection task and analyzed brain activity patterns in the cortex surrounding the intraparietal sulcus (IPS) within the Julich-Brain probabilistic cytoarchitectonic mapping reference frame. We predicted that exogenous effects would be seen mainly in the posterior regions of the IPS (hIP4-hIP7-hIP8), whereas a conflict between endogenous and exogenous orienting would elicit activity from more anterior cytoarchitectonic areas (hIP1-hIP2-hIP3). Contrary to our hypothesis, a conflict between endogenous and exogenous orienting had an effect early in the IPS (mainly in hIP7 and hIP8). This is strong evidence for an endogenous component in hIP7/8 responses to salient stimuli beyond effects of attentional bottom-up sweep. Our results suggest that hIP7 and hIP8 are implicated in the individuation of attended locations based on saliency as well as endogenous instructions.
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Atención , Lóbulo Parietal , Atención/fisiología , Mapeo Encefálico/métodos , Corteza Cerebral/fisiología , Imagen por Resonancia Magnética , Lóbulo Parietal/fisiologíaRESUMEN
INTRODUCTION: Imaging studies indicated basal forebrain reduction in primary progressive aphasia (PPA), which might be a candidate marker for cholinergic treatment. Nucleus basalis of Meynert (nbM) neuronal loss has been reported, but a systematic quantitative neuropathological assessment including the three clinical PPA variants is lacking. METHODS: Quantitative assessment of neuronal density and pathology was performed on nbM tissue of 47 cases: 15 PPA, constituting the different clinicopathological phenotypes, 14 Alzheimer's disease (AD), and 18 cognitively normals. RESULTS: Group-wise, reduced nbM neuronal density was restricted to AD. At the individual level, semantic variant PPA with underlying AD neuropathological change (ADNC) had lower neuronal densities, while those with frontotemporal lobar degeneration (FTLD) transactive response DNA binding protein 43 kDa (TDP-43) type C pathology were unaffected. Higher Braak stages and increased numbers of nbM-related pretangles were associated with nbM neuronal loss. DISCUSSION: nbM neuronal loss in PPA is related to ADNC. This study cautions against overinterpreting MRI-based basal forebrain volumes in non-AD PPA as neuronal loss.
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Enfermedad de Alzheimer , Afasia Progresiva Primaria , Degeneración Lobar Frontotemporal , Humanos , Enfermedad de Alzheimer/patología , Núcleo Basal de Meynert/metabolismo , Núcleo Basal de Meynert/patología , Degeneración Lobar Frontotemporal/patología , Neuronas/metabolismo , Afasia Progresiva Primaria/diagnóstico por imagen , Afasia Progresiva Primaria/patologíaRESUMEN
PURPOSE: End-of-life studies have validated the binary visual reads of 18F-labeled amyloid PET tracers as an accurate tool for the presence or absence of increased neuritic amyloid plaque density. In this study, the performance of a support vector machine (SVM)-based classifier will be tested against pathological ground truths and its performance determined in cognitively healthy older adults. METHODS: We applied SVM with a linear kernel to an 18F-Flutemetamol end-of-life dataset to determine the regions with the highest feature weights in a data-driven manner and to compare between two different pathological ground truths: based on neuritic amyloid plaque density or on amyloid phases, respectively. We also trained and tested classifiers based on the 10% voxels with the highest amplitudes of feature weights for each of the two neuropathological ground truths. Next, we tested the classifiers' diagnostic performance in the asymptomatic Alzheimer's disease (AD) phase, a phase of interest for future drug development, in an independent dataset of cognitively intact older adults, the Flemish Prevent AD Cohort-KU Leuven (F-PACK). A regression analysis was conducted between the Centiloid (CL) value in a composite volume of interest (VOI), as index for amyloid load, and the distance to the hyperplane for each of the two classifiers, based on the two pathological ground truths. A receiver operating characteristic analysis was also performed to determine the CL threshold that optimally discriminates between neuritic amyloid plaque positivity versus negativity, or amyloid phase positivity versus negativity, within F-PACK. RESULTS: The classifiers yielded adequate specificity and sensitivity within the end-of-life dataset (neuritic amyloid plaque density classifier: specificity of 90.2% and sensitivity of 83.7%; amyloid phase classifier: specificity of 98.4% and sensitivity of 84.0%). The regions with the highest feature weights corresponded to precuneus, caudate, anteromedial prefrontal, and also posterior inferior temporal and inferior parietal cortex. In the cognitively normal cohort, the correlation coefficient between CL and distance to the hyperplane was -0.66 for the classifier trained with neuritic amyloid plaque density, and -0.88 for the classifier trained with amyloid phases. This difference was significant. The optimal CL cut-off for discriminating positive versus negative scans was CL = 48-51 for the different classifiers (area under the curve (AUC) = 99.9%), except for the classifier trained with amyloid phases and based on the 10% voxels with highest feature weights. There the cut-off was CL = 26 (AUC = 99.5%), which closely matched the CL threshold for discriminating phases 0-2 from 3-5 based on the end-of-life dataset and the neuropathological ground truth. DISCUSSION: Among a set of neuropathologically validated classifiers trained with end-of-life cases, transfer to a cognitively normal population works best for a classifier trained with amyloid phases and using only voxels with the highest amplitudes of feature weights.
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Enfermedad de Alzheimer , Placa Amiloide , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Amiloide , Compuestos de Anilina , Benzotiazoles , Muerte , Humanos , Aprendizaje Automático , Placa Amiloide/diagnóstico por imagen , Tomografía de Emisión de PositronesRESUMEN
Language dysfunction is common in Alzheimer's disease. There is increasing interest in the preclinical or asymptomatic phase of Alzheimer's disease. Here we examined in 35 cognitively intact older adults (age range 52-78 years at baseline, 17 male) in a longitudinal study design the association between accumulation of amyloid over a 5-6-year period, measured using PET, and functional changes in the language network measured over the same time period using task-related functional MRI. In the same participants, we also determined the association between the longitudinal functional MRI changes and a cross-sectional measure of tau load as measured with 18F-AV1451 PET. As predicted, the principal change occurred in posterior temporal cortex. In the cortex surrounding the right superior temporal sulcus, the response amplitude during the associative-semantic versus visuo-perceptual task increased over time as amyloid load accumulated (Pcorrected = 0.008). In a whole-brain voxel-wise analysis, amyloid accumulation was also associated with a decrease in response amplitude in the left inferior frontal sulcus (Pcorrected = 0.009) and the right dorsomedial prefrontal cortex (Pcorrected = 0.005). In cognitively intact older adults, cross-sectional tau load was not associated with longitudinal changes in functional MRI response amplitude. Our findings confirm the central role of the neocortex surrounding the posterior superior temporal sulcus as the area of predilection within the language network in the earliest stages of Alzheimer's disease. Amyloid accumulation has an impact on cognitive brain circuitry in the asymptomatic phase of Alzheimer's disease.
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Envejecimiento/patología , Péptidos beta-Amiloides , Lenguaje , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/fisiopatología , Anciano , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Lóbulo Temporal/patologíaRESUMEN
BACKGROUND: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. METHODS: Individuals were classified based on CSF amyloid beta (Aß)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. RESULTS: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. CONCLUSION: The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.
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PURPOSE: In vivo tau-PET tracer retention in the anterior temporal lobe of patients with semantic variant primary progressive aphasia (SV PPA) has consistently been reported. This is unexpected as the majority of these patients have frontotemporal lobar degeneration TDP (FTLD-TDP). METHODS: We conducted an in vitro [18F]AV1451 autoradiography binding study in five cases with a clinical diagnosis of SV PPA constituting the range of pathologies (i.e., three FTLD-TDP, one Alzheimer's disease (AD), and one Pick's disease (PiD)). Binding was compared with two controls without neurodegeneration, two typical AD, one corticobasal syndrome with underlying AD, and one frontotemporal dementia behavioral variant with FTLD-TDP. The effect of blocking with the authentic reference material and with the MAO-B inhibitor deprenyl was assessed. Immunohistochemistry was performed on adjacent cryosections. RESULTS: Absence of specific [18F]AV1451 binding was observed for all three SV PPA FTLD-TDP cases. The absence of binding in controls as well as the successful blocking with authentic AV1451 in cases with tauopathy demonstrated specificity of the [18F]AV1451 signal for tau. The specific [18F]AV1451 binding was highest in AD, followed by PiD. This binding colocalized with the respective tau lesions and could not be blocked by deprenyl. Similar pilot findings were obtained with [18F]THK5351. CONCLUSION: In vitro autoradiography showed no [18F]AV1451 binding in SV PPA due to FTLD-TDP, while specific binding was present in SV PPA due to AD and PiD. The discrepancy between in vitro and in vivo findings remains to be explained. The discordance is not related to [18F]AV1451 idiosyncrasies as [18F]THK5351 findings were similar.
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Afasia Progresiva Primaria , Degeneración Lobar Frontotemporal , Afasia Progresiva Primaria/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Carbolinas , Degeneración Lobar Frontotemporal/diagnóstico por imagen , Humanos , Semántica , Proteínas tau/metabolismoRESUMEN
The main pathophysiological alterations of Alzheimer's disease (AD) include loss of neuronal and synaptic integrity, amyloidogenic processing, and neuroinflammation. Similar alterations can, however, also be observed in cognitively intact older subjects and may prelude the clinical manifestation of AD. The objectives of this prospective cross-sectional study in a cohort of 38 cognitively intact older adults were twofold: (i) to investigate the latent relationship among cerebrospinal fluid (CSF) biomarkers reflecting the main pathophysiological processes of AD, and (ii) to assess the correlation between these biomarkers and gray matter volume as well as amyloid load. All subjects underwent extensive neuropsychological examinations, CSF sampling, [18 F]-flutemetamol amyloid positron emission tomography, and T1 -weighted magnetic resonance imaging. A factor analysis revealed one factor that explained most of the variance in the CSF biomarker dataset clustering t-tau, α-synuclein, p-tau181 , neurogranin, BACE1, visinin-like protein 1, chitinase-3-like protein 1 (YKL-40), Aß1-40 and Aß1-38 . Higher scores on this factor correlated with lower gray matter volume and with higher amyloid load in the precuneus. At the level of individual CSF biomarkers, levels of visinin-like protein 1, neurogranin, BACE1, Aß1-40 , Aß1-38, and YKL-40 all correlated inversely with gray matter volume of the precuneus. These findings demonstrate that in cognitively intact older subjects, CSF levels of synaptic and neuronal integrity biomarkers, amyloidogenic processing and measures of innate immunity (YKL-40) display a latent structure of common variance, which is associated with loss of structural integrity of brain regions implicated in the earliest stages of AD. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript, and for *Preregistration* because the study was pre-registered at https://osf.io/7qm9t/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
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Péptidos beta-Amiloides/análisis , Biomarcadores/líquido cefalorraquídeo , Sustancia Gris/patología , Lóbulo Parietal/patología , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , MasculinoRESUMEN
PURPOSE: To assess the binding of the PET tracer [18F]THK5351 in patients with different primary progressive aphasia (PPA) variants and its correlation with clinical deficits. The majority of patients with nonfluent variant (NFV) and logopenic variant (LV) PPA have underlying tauopathy of the frontotemporal lobar or Alzheimer disease type, respectively, while patients with the semantic variant (SV) have predominantly transactive response DNA binding protein 43-kDa pathology. METHODS: The study included 20 PPA patients consecutively recruited through a memory clinic (12 NFV, 5 SV, 3 LV), and 20 healthy controls. All participants received an extensive neurolinguistic assessment, magnetic resonance imaging and amyloid biomarker tests. [18F]THK5351 binding patterns were assessed on standardized uptake value ratio (SUVR) images with the cerebellar grey matter as the reference using statistical parametric mapping. Whole-brain voxel-wise regression analysis was performed to evaluate the association between [18F]THK5351 SUVR images and neurolinguistic scores. Analyses were performed with and without partial volume correction. RESULTS: Patients with NFV showed increased binding in the supplementary motor area, left premotor cortex, thalamus, basal ganglia and midbrain compared with controls and patients with SV. Patients with SV had increased binding in the temporal lobes bilaterally and in the right ventromedial frontal cortex compared with controls and patients with NFV. The whole-brain voxel-wise regression analysis revealed a correlation between agrammatism and motor speech impairment, and [18F]THK5351 binding in the left supplementary motor area and left postcentral gyrus. Analysis of [18F]THK5351 scans without partial volume correction revealed similar results. CONCLUSION: [18F]THK5351 imaging shows a topography closely matching the anatomical distribution of predicted underlying pathology characteristic of NFV and SV PPA. [18F]THK5351 binding correlates with the severity of clinical impairment.
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Aminopiridinas/metabolismo , Afasia Progresiva Primaria/metabolismo , Quinolinas/metabolismo , Anciano , Anciano de 80 o más Años , Afasia Progresiva Primaria/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Trazadores RadiactivosRESUMEN
The extent to which non-linguistic auditory processing deficits may contribute to the phenomenology of primary progressive aphasia is not established. Using non-linguistic stimuli devoid of meaning we assessed three key domains of auditory processing (pitch, timing and timbre) in a consecutive series of 18 patients with primary progressive aphasia (eight with semantic variant, six with non-fluent/agrammatic variant, and four with logopenic variant), as well as 28 age-matched healthy controls. We further examined whether performance on the psychoacoustic tasks in the three domains related to the patients' speech and language and neuropsychological profile. At the group level, patients were significantly impaired in the three domains. Patients had the most marked deficits within the rhythm domain for the processing of short sequences of up to seven tones. Patients with the non-fluent variant showed the most pronounced deficits at the group and the individual level. A subset of patients with the semantic variant were also impaired, though less severely. The patients with the logopenic variant did not show any significant impairments. Significant deficits in the non-fluent and the semantic variant remained after partialling out effects of executive dysfunction. Performance on a subset of the psychoacoustic tests correlated with conventional verbal repetition tests. In sum, a core central auditory impairment exists in primary progressive aphasia for non-linguistic stimuli. While the non-fluent variant is clinically characterized by a motor speech deficit (output problem), perceptual processing of tone sequences is clearly deficient. This may indicate the co-occurrence in the non-fluent variant of a deficit in working memory for auditory objects. Parsimoniously we propose that auditory timing pathways are altered, which are used in common for processing acoustic sequence structure in both speech output and acoustic input.
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Afasia Progresiva Primaria/fisiopatología , Percepción Auditiva/fisiología , Psicoacústica , Anciano , Afasia Progresiva Primaria/diagnóstico , Afasia Progresiva Primaria/diagnóstico por imagen , Estudios de Casos y Controles , Señales (Psicología) , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas NeuropsicológicasRESUMEN
Posterior cortical atrophy (PCA) is a rare focal neurodegenerative syndrome characterized by progressive visuoperceptual and visuospatial deficits, most often due to atypical Alzheimer's disease (AD). We applied insights from basic visual neuroscience to analyze 3D shape perception in humans affected by PCA. Thirteen PCA patients and 30 matched healthy controls participated, together with two patient control groups with diffuse Lewy body dementia (DLBD) and an amnestic-dominant phenotype of AD, respectively. The hierarchical study design consisted of 3D shape processing for 4 cues (shading, motion, texture, and binocular disparity) with corresponding 2D and elementary feature extraction control conditions. PCA and DLBD exhibited severe 3D shape-processing deficits and AD to a lesser degree. In PCA, deficient 3D shape-from-shading was associated with volume loss in the right posterior inferior temporal cortex. This region coincided with a region of functional activation during 3D shape-from-shading in healthy controls. In PCA patients who performed the same fMRI paradigm, response amplitude during 3D shape-from-shading was reduced in this region. Gray matter volume in this region also correlated with 3D shape-from-shading in AD. 3D shape-from-disparity in PCA was associated with volume loss slightly more anteriorly in posterior inferior temporal cortex as well as in ventral premotor cortex. The findings in right posterior inferior temporal cortex and right premotor cortex are consistent with neurophysiologically based models of the functional anatomy of 3D shape processing. However, in DLBD, 3D shape deficits rely on mechanisms distinct from inferior temporal structural integrity. SIGNIFICANCE STATEMENT: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visuoperceptual dysfunction and most often an atypical presentation of Alzheimer's disease (AD) affecting the ventral and dorsal visual streams rather than the medial temporal system. We applied insights from fundamental visual neuroscience to analyze 3D shape perception in PCA. 3D shape-processing deficits were affected beyond what could be accounted for by lower-order processing deficits. For shading and disparity, this was related to volume loss in regions previously implicated in 3D shape processing in the intact human and nonhuman primate brain. Typical amnestic-dominant AD patients also exhibited 3D shape deficits. Advanced visual neuroscience provides insight into the pathogenesis of PCA that also bears relevance for vision in typical AD.
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Corteza Cerebral/patología , Percepción de Forma/fisiología , Enfermedades Neurodegenerativas/fisiopatología , Anciano , Agnosia/fisiopatología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Atrofia , Ceguera/etiología , Ceguera/fisiopatología , Mapeo Encefálico , Corteza Cerebral/fisiopatología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Enfermedad por Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Percepción de Movimiento/fisiología , Corteza Motora/patología , Corteza Motora/fisiopatología , Enfermedades Neurodegenerativas/patología , Pruebas Neuropsicológicas , Tamaño de los Órganos , Tomografía de Emisión de Positrones , Lóbulo Temporal/patología , Lóbulo Temporal/fisiopatologíaRESUMEN
PURPOSE: Preclinical, or asymptomatic, Alzheimer's disease (AD) refers to the presence of positive AD biomarkers in the absence of cognitive deficits. This research concept is being applied to define target populations for clinical drug development. In a prospective community-recruited cohort of cognitively intact older adults, we compared two amyloid imaging markers within subjects: (18)F-flutemetamol and (11)C-Pittsburgh compound B (PIB). METHODS: In 32 community-recruited cognitively intact older adults aged between 65 and 80 years, we determined the concordance between binary classification based on (18)F-flutemetamol versus (11)C-PIB according to semiquantitative assessment (standardized uptake value ratio in composite cortical volume, SUVRcomp) and, alternatively, according to visual reads. We also determined the correlation between (18)F-flutemetamol and (11)C-PIB SUVR and evaluated how this was affected by the reference region chosen (cerebellar grey matter versus pons) and the use of partial volume correction (PVC) in this population. RESULTS: Binary classification based on semiquantitative assessment was concordant between (18)F-flutemetamol and (11)C-PIB in 94 % of cases. Concordance of blinded binary visual reads between tracers was 84 %. The Spearman correlation between (18)F-flutemetamol and (11)C-PIB SUVRcomp with cerebellar grey matter as reference region was 0.84, with a slope of 0.98. Correlations in neocortical regions were significantly lower with the pons as reference region. PVC improved the correlation in striatum and medial temporal cortex. CONCLUSION: For the definition of preclinical AD based on (18)F-flutemetamol, concordance with (11)C-PIB was highest using semiquantitative assessment with cerebellar grey matter as reference region.
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Amiloide/metabolismo , Compuestos de Anilina , Benzotiazoles , Cognición , Tomografía de Emisión de Positrones/métodos , Tiazoles , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , MasculinoRESUMEN
The dynamic phase of preclinical Alzheimer's disease, as characterized by accumulating cortical amyloid-ß, is a window of opportunity for amyloid-ß-lowering therapies to have greater efficacy. Biomarkers that accurately predict amyloid-ß accumulation may be of critical importance for participant inclusion in secondary prevention trials and thus enhance development of early Alzheimer's disease therapies. We compared the abilities of baseline plasma pTau181, pTau217 and amyloid-ß PET load to predict future amyloid-ß accumulation in asymptomatic elderly. In this longitudinal cohort study, baseline plasma pTau181 and pTau217 were quantified using single molecule array assays in cognitively unimpaired elderly selected from the community-recruited F-PACK cohort based on the availability of baseline plasma samples and longitudinal amyloid-ß PET data (median time interval = 5 years, range 2-10 years). The predictive abilities of pTau181, pTau217 and PET-based amyloid-ß measures for PET-based amyloid-ß accumulation were investigated using receiver operating characteristic analyses, correlations and stepwise regression analyses. We included 75 F-PACK subjects (mean age = 70 years, 48% female), of which 16 were classified as amyloid-ß accumulators [median (interquartile range) Centiloid rate of change = 3.42 (1.60) Centiloids/year). Plasma pTau181 [area under the curve (95% confidence interval) = 0.72 (0.59-0.86)] distinguished amyloid-ß accumulators from non-accumulators with similar accuracy as pTau217 [area under the curve (95% confidence interval) = 0.75 (0.62-0.88) and amyloid-ß PET [area under the curve (95% confidence interval) = 0.72 (0.56-0.87)]. Plasma pTau181 and pTau217 strongly correlated with each other (r = 0.93, Pfalse discovery rate < 0.001) and, together with amyloid-ß PET, similarly correlated with amyloid-ß rate of change (r pTau181 = 0.33, r pTau217 = 0.36, r amyloid-ß PET = 0.35, all Pfalse discovery rate ≤ 0.01). Addition of plasma pTau181, plasma pTau217 or amyloid-ß PET to a linear demographic model including age, sex and APOE-ε4 carriership similarly improved the prediction of amyloid-ß accumulation (ΔAkaike information criterion ≤ 4.1). In a multimodal biomarker model including all three biomarkers, each biomarker lost their individual predictive ability. These findings indicate that plasma pTau181, plasma pTau217 and amyloid-ß PET convey overlapping information and therefore predict the dynamic phase of asymptomatic amyloid-ß accumulation with comparable performances. In clinical trial recruitment, confirmatory PET scans following blood-based prescreening might thus not provide additional value for detecting participants in these early disease stages who are destined to accumulate cortical amyloid-ß. Given the moderate performances, future studies should investigate whether integrating plasma pTau species with other factors can improve performance and thus enhance clinical and research utility.
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BACKGROUND: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer's disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. METHODS: We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD. RESULTS: ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways. CONCLUSIONS: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.
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Enfermedad de Alzheimer , Plexo Coroideo , Modelos Animales de Enfermedad , Ratones Transgénicos , Proteómica , Plexo Coroideo/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Animales , Humanos , Ratones , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Proteoma/metabolismo , Masculino , Femenino , Ratones Endogámicos C57BLRESUMEN
PURPOSE: Measuring longitudinal changes in amyloid load in the asymptomatic stage of Alzheimer's disease is of high relevance for clinical research and progress towards more efficacious, timely treatments. Apolipoprotein E ε4 (APOE4) has a well-established effect on the rate of amyloid accumulation. Here we investigated which region of interest and which reference region perform best at detecting the effect of APOE4 on longitudinal amyloid load in individuals participating in the Flemish Prevent Alzheimer's Disease Cohort KU Leuven (F-PACK). METHODS: Ninety cognitively intact F-PACK participants (baseline age: 68 (52-80) years, 46 males, 42 APOE4 carriers) received structural MRI and 18F-Flutemetamol PET scans at baseline and follow-up (6.2 (3.4-10.9) year interval). Standardised uptake value ratios (SUVRs) and Centiloids (CLs) were calculated in a composite cortical volume of interest (SUVRcomp/CL) and in the precuneus (SUVRprec), and amyloid rate of change derived: (follow-up amyloid load - baseline amyloid load) / time interval (years). Four reference regions were used to derive amyloid load: whole cerebellum, cerebellar grey matter, eroded subcortical white matter, and pons. RESULTS: When using whole cerebellum or cerebellar grey matter as reference region, APOE4 carriers had a significantly higher SUVRcomp amyloid rate of change than non-carriers (pcorr = 0.004, t = 3.40 (CI 0.005-0.018); pcorr = 0.036, t = 2.66 (CI 0.003-0.018), respectively). Significance was not observed for eroded subcortical white matter or pons (pcorr = 0.144, t = 2.13 (CI 0.0003-0.008); pcorr = 0.116, t = 2.22 (CI 0.005-0.010), respectively). When using CLs as the amyloid measurement, and whole cerebellum, APOE4 carriers had a higher amyloid rate of change than non-carriers (pcorr = 0.012, t = 3.05 (CI 0.499-2.359)). Significance was not observed for the other reference regions. No significance was observed with any of the reference regions and amyloid rate of change in the precuneus (SUVRprec). CONCLUSION: In this cognitively intact cohort, a composite neocortical volume of interest together with whole cerebellum or cerebellar grey matter as reference region are the methods of choice for detecting APOE4-dependent differences in amyloid rate of change.
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Enfermedad de Alzheimer , Masculino , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Benzotiazoles , Amiloide/metabolismo , Compuestos de Anilina , Tomografía de Emisión de Positrones/métodos , Proteínas Amiloidogénicas , Péptidos beta-Amiloides , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismoRESUMEN
BACKGROUND: Gene expression is dysregulated in Alzheimer's disease (AD) patients, both in peripheral blood and post mortem brain. We investigated peripheral whole-blood gene (co)expression to determine molecular changes prior to symptom onset. METHODS: RNA was extracted and sequenced for 65 cognitively healthy F-PACK participants (65 (56-80) years, 34 APOE4 non-carriers, 31 APOE4 carriers), at baseline and follow-up (interval: 5.0 (3.4-8.6) years). Participants received amyloid PET at both time points and amyloid rate of change derived. Accumulators were defined with rate of change ≥ 2.19 Centiloids. We performed differential gene expression and weighted gene co-expression network analysis to identify differentially expressed genes and networks of co-expressed genes, respectively, with respect to traits of interest (APOE4 status, amyloid accumulation (binary/continuous)), and amyloid positivity status, followed by Gene Ontology annotation. RESULTS: There were 166 significant differentially expressed genes at follow-up compared to baseline in APOE4 carriers only, whereas 12 significant differentially expressed genes were found only in APOE4 non-carriers, over time. Among the significant genes in APOE4 carriers, several had strong evidence for a pathogenic role in AD based on direct association scores generated from the DISQOVER platform: NGRN, IGF2, GMPR, CLDN5, SMIM24. Top enrichment terms showed upregulated mitochondrial and metabolic pathways, and an exacerbated upregulation of ribosomal pathways in APOE4 carriers compared to non-carriers. Similarly, there were 33 unique significant differentially expressed genes at follow-up compared to baseline in individuals classified as amyloid negative at baseline and positive at follow-up or amyloid positive at both time points and 32 unique significant differentially expressed genes over time in individuals amyloid negative at both time points. Among the significant genes in the first group, the top five with the highest direct association scores were as follows: RPL17-C18orf32, HSP90AA1, MBP, SIRPB1, and GRINA. Top enrichment terms included upregulated metabolism and focal adhesion pathways. Baseline and follow-up gene co-expression networks were separately built. Seventeen baseline co-expression modules were derived, with one significantly negatively associated with amyloid accumulator status (r2 = - 0.25, p = 0.046). This was enriched for proteasomal protein catabolic process and myeloid cell development. Thirty-two follow-up modules were derived, with two significantly associated with APOE4 status: one downregulated (r2 = - 0.27, p = 0.035) and one upregulated (r2 = 0.26, p = 0.039) module. Top enrichment processes for the downregulated module included proteasomal protein catabolic process and myeloid cell homeostasis. Top enrichment processes for the upregulated module included cytoplasmic translation and rRNA processing. CONCLUSIONS: We show that there are longitudinal gene expression changes that implicate a disrupted immune system, protein removal, and metabolism in cognitively intact individuals who carry APOE4 or who accumulate in cortical amyloid. This provides insight into the pathophysiology of AD, whilst providing novel targets for drug and therapeutic development.
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Enfermedad de Alzheimer , Apolipoproteína E4 , Anciano , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Proteínas Amiloidogénicas , Apolipoproteína E4/genética , Perfilación de la Expresión Génica , Factores de Transcripción , Transcriptoma , Persona de Mediana Edad , Anciano de 80 o más AñosRESUMEN
Recent mechanistic models argue for a key role of rhythm processing in both speech production and speech perception. Patients with the non-fluent variant (NFV) of primary progressive aphasia (PPA) with apraxia of speech (AOS) represent a specific study population in which this link can be examined. Previously, we observed impaired rhythm processing in NFV with AOS. We hypothesized that a shared neurocomputational mechanism structures auditory input (sound and speech) and output (speech production) in time, a "temporal scaffolding" mechanism. Since considerable white matter damage is observed in NFV, we test here whether white matter changes are related to impaired rhythm processing. Forty-seven participants performed a psychoacoustic test battery: 12 patients with NFV and AOS, 11 patients with the semantic variant of PPA, and 24 cognitively intact age- and education-matched controls. Deformation-based morphometry was used to test whether white matter volume correlated to rhythmic abilities. In 34 participants, we also obtained tract-based metrics of the left Aslant tract, which is typically damaged in patients with NFV. Nine out of 12 patients with NFV displayed impaired rhythmic processing. Left frontal white matter atrophy adjacent to the supplementary motor area (SMA) correlated with poorer rhythmic abilities. The structural integrity of the left Aslant tract also correlated with rhythmic abilities. A colocalized and perhaps shared white matter substrate adjacent to the SMA is associated with impaired rhythmic processing and motor speech impairment. Our results support the existence of a temporal scaffolding mechanism structuring perceptual input and speech output.