Explore the vast range of titles available.

Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Genes that are aberrantly expressed and/or mutated that lead to the dysplastic erythroid morphology seen in −7/del(7q) MDS have not been identified. In this study, we show that reduced expression of dedicator of cytokinesis 4 ( DOCK4 ) causes dysplasia by disrupting the actin cytoskeleton in developing red blood cells. In addition, our identification of the molecular pathway that leads to morphological defects in this type of MDS provides potential therapeutic targets downstream of DOCK4 that can be exploited to reverse the dysplasia in the erythroid lineage. Furthermore, we developed a novel single-cell multispectral flow cytometry assay for evaluation of disrupted F-actin filaments, which can be used for potential early detection of dysplastic cells in MDS. Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in −7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.

Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate thatDOCK4is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion ofDOCK4levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression ofDOCK4leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in −7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed thatDOCK4knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identifyDOCK4as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.

Purpose [ 18 F]MK-6240, a second-generation tau PET tracer, is increasingly used for the detection and the quantification of in vivo cerebral tauopathy in Alzheimer’s disease (AD). Given that neurological symptoms are better explained by the topography rather than by the nature of brain lesions, our study aimed to evaluate whether cognitive impairment would be more closely associated with the spatial extent than with the intensity of tau-PET signal, as measured by the standard uptake value ratio (SUVr). Methods [ 18 F]MK6240 tau-PET data from 82 participants in the AD spectrum were quantified in three different brain regions ( Braak  ≤  2 , Braak  ≤  4 , and Braak  ≤  6 ) using SUVr and the extent of tauopathy (EOT, percentage of voxels with SUVr ≥ 1.3). PET data were first compared between diagnostic categories, and ROC curves were computed to evaluate sensitivity and specificity. PET data were then correlated to cognitive performances and cerebrospinal fluid (CSF) tau values. Results The EOT in the Braak  ≤  2 region provided the highest diagnostic accuracies, distinguishing between amyloid-negative and positive clinically unimpaired individuals (threshold = 9%, sensitivity = 79%, specificity = 82%) as well as between prodromal AD and preclinical AD (threshold = 38%, sensitivity = 81%, specificity = 93%). The EOT better correlated with cognition than SUVr (∆R 2  + 0.08–0.09) with the best correlation observed for EOT in the Braak  ≤  4 region ( R 2  = 0.64). Cognitive performances were more closely associated with PET metrics than with CSF values. Conclusions Quantifying [ 18 F]MK-6240 tau PET in terms of EOT rather than SUVr significantly increases the correlation with cognitive performances. Quantification in the mesiotemporal lobe is the most useful to diagnose preclinical AD or prodromal AD.

Background Early Alzheimer’s disease diagnosis is crucial for preventive therapy development. Standard neuropsychological evaluation does not identify clinically normal individuals with brain amyloidosis, the first stage of the pathology, defined as preclinical Alzheimer’s disease. Spatial navigation assessment, in particular path integration, appears promising to detect preclinical symptoms, as the medial temporal lobe plays a key role in navigation and is the first cortical region affected by tau pathology. Methods We have conducted a cross-sectional study. We related the path integration performance of 102 individuals without dementia, aged over 50, to amyloid and tau pathologies, measured using positron emission tomography. We included 75 clinically normal individuals (19 with brain amyloidosis, 56 without) and 27 individuals with mild cognitive impairment (18 with brain amyloidosis, 9 without). We fitted linear mixed models to predict the path integration performances according to amyloid status or tau pathology in the medial temporal lobal, adjusting for age, gender, cognitive status, education, and video game experience. We decomposed the error into rotation and distance errors. Results We observed that clinically normal adults with brain amyloidosis (preclinical Alzheimer’s disease) had spatial navigation deficits when relying only on self-motion cues. However, they were able to use a landmark to reduce their errors. Individuals with mild cognitive impairment had deficits in path integration that did not improve when a landmark was added in the environment. The amyloid status did not influence performance among individuals with mild cognitive impairment. Among all individuals, rotation, but not distance, errors increased with the level of tau pathology in the medial temporal lobe. Conclusion Our results suggest that path integration performance in an environment without external cues allows identifying individuals with preclinical Alzheimer’s disease, before overt episodic memory impairment is noticeable. Specifically, we demonstrated that poor angular estimation is an early cognitive marker of tau pathology, whereas distance estimation relates to older ages, not to Alzheimer’s disease. Trial registration Eudra-CT 2018–003473-94.

Background There is good evidence that elevated amyloid-β (Aβ) positron emission tomography (PET) signal is associated with cognitive decline in clinically normal (CN) individuals. However, it is less well established whether there is an association between the Aβ burden and decline in daily living activities in this population. Moreover, Aβ-PET Centiloids (CL) thresholds that can optimally predict functional decline have not yet been established. Methods Cross-sectional and longitudinal analyses over a mean three-year timeframe were performed on the European amyloid-PET imaging AMYPAD-PNHS dataset that phenotypes 1260 individuals, including 1032 CN individuals and 228 participants with questionable functional impairment. Amyloid-PET was assessed continuously on the Centiloid (CL) scale and using Aβ groups (CL < 12 = Aβ-, 12 ≤ CL ≤ 50 = Aβ-intermediate/Aβ± , CL > 50 = Aβ+). Functional abilities were longitudinally assessed using the Clinical Dementia Rating (Global-CDR, CDR-SOB) and the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). The Global-CDR was available for the 1260 participants at baseline, while baseline CDR-SOB and A-IADL-Q scores and longitudinal functional data were available for different subsamples that had similar characteristics to those of the entire sample. Results Participants included 765 Aβ- (61%, Mdn age  = 66.0, IQR age  = 61.0–71.0; 59% women), 301 Aβ± (24%; Mdn age  = 69.0, IQR age  = 64.0–75.0; 53% women) and 194 Aβ+ individuals (15% , Mdn age  = 73.0, IQR age  = 68.0–78.0; 53% women). Cross-sectionally, CL values were associated with CDR outcomes. Longitudinally, baseline CL values predicted prospective changes in the CDR-SOB ( b CL*Time  = 0.001/CL/year, 95% CI [0.0005,0.0024], p  = .003) and A-IADL-Q ( b CL*Time  =  - 0.010/CL/year, 95% CI [-0.016,-0.004], p  = .002) scores in initially CN participants. Increased clinical progression (Global-CDR > 0) was mainly observed in Aβ+ CN individuals ( HR Aβ+ vs Aβ-  = 2.55, 95% CI [1.16,5.60], p  = .020). Optimal thresholds for predicting decline were found at 41 CL using the CDR-SOB ( b Aβ+  vs  Aβ-  = 0.137/year, 95% CI [0.069,0.206], p  < .001) and 28 CL using the A-IADL-Q ( b Aβ+  vs  Aβ-  = -0.693/year, 95% CI [-1.179,-0.208], p  = .005). Conclusions Amyloid-PET quantification supports the identification of CN individuals at risk of functional decline. Trial registration The AMYPAD PNHS is registered at www.clinicaltrialsregister.eu with the EudraCT Number: 2018-002277-22.

Introduction Second‐generation tau‐PET tracers like [18F]MK‐6240 are increasingly used both for diagnosing and quantifying Alzheimer's Disease (AD) tauopathy. However, while [18F]MK‐6240 tau‐PET has demonstrated excellent sensitivity for AD tauopathy, data assessing its specificity and binding in non‐AD tauopathies are still scarce. Methods Participants were assigned to exclusive categorical diagnoses based on their amyloid (Aβ) and cognitive status. We quantified mesiotemporal (MTL) and neocortical [18F]MK‐6240 tau‐PET signal in 28 Aβ− cognitively impaired (CI) patients presenting various non‐AD neurodegenerative disorders. Tau‐PET quantifications were compared with Aβ− cognitively unimpaired (CU) subjects (n = 51) and Aβ+ CI patients (n = 77). Results Among the 28 Aβ− impaired subjects, only five presented significant and isolated mesiotemporal signal, most of them being suspected of primary age‐related tauopathy (PART). Only two Aβ− impaired patients (7%) presented positive neocortical signal, both being diagnosed with fronto‐temporal degeneration (FTD). The Tau‐PET results of all the remaining Aβ− patients were comparable to the CU population, including eight other FTD patients. Importantly, 4R‐only tauopathies (CBD and PSP) and sv‐PPA were negative. Conclusion [18F]MK‐6240 tau‐PET has a special affinity for tauopathies involving 3R/4R paired helical filaments: AD, PART (Aβ− subjects with MTL‐restricted tau‐PET signal) and some forms of FTD while most primary tauopathies do not exhibit significant cortical signal. Positive neocortical scans are therefore highly specific for AD tauopathy. Based on those and previous results, we propose a diagnostic flowchart for MCI subjects suspected of AD or another tauopathy which may significantly reduce the need for amyloid PET or CSF measurement.

INTRODUCTION Magnetic resonance imaging (MRI) segmentation algorithms make it possible to study detailed medial temporal lobe (MTL) substructures as hippocampal subfields and amygdala subnuclei, offering opportunities to develop biomarkers for preclinical Alzheimer's disease (AD). METHODS We identified the MTL substructures significantly associated with tau‐positron emission tomography (PET) signal in 581 non‐demented individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI‐3). We confirmed our results in our UCLouvain cohort including 110 non‐demented individuals by comparing volumes between individuals with different visual Braak's stages and clinical diagnosis. RESULTS Four amygdala subnuclei (cortical, central, medial, and accessory basal) were associated with tau in amyloid beta‐positive (Aβ+) clinically normal (CN) individuals, while the global amygdala and hippocampal volumes were not. Using UCLouvain data, we observed that both Braak I‐II and Aβ+ CN individuals had smaller volumes in these subnuclei, while no significant difference was observed in the global structure volumes or other subfields. CONCLUSION Measuring specific amygdala subnuclei, early atrophy may serve as a marker of temporal tauopathy in preclinical AD, identifying individuals at risk of progression. Highlights Amygdala atrophy is not homogeneous in preclinical Alzheimer's disease (AD). Tau pathology is associated with atrophy of specific amygdala subnuclei, specifically, the central, medial, cortical, and accessory basal subnuclei. Hippocampal and amygdala volume is not associated with tau in preclinical AD. Hippocampus and CA1‐3 volume is reduced in preclinical AD, regardless of tau.

[18F]MK-6240, a second-generation tau PET tracer, is increasingly used for the detection and the quantification of in vivo cerebral tauopathy in Alzheimer's disease (AD). Given that neurological symptoms are better explained by the topography rather than by the nature of brain lesions, our study aimed to evaluate whether cognitive impairment would be more closely associated with the spatial extent than with the intensity of tau-PET signal, as measured by the standard uptake value ratio (SUVr).PURPOSE[18F]MK-6240, a second-generation tau PET tracer, is increasingly used for the detection and the quantification of in vivo cerebral tauopathy in Alzheimer's disease (AD). Given that neurological symptoms are better explained by the topography rather than by the nature of brain lesions, our study aimed to evaluate whether cognitive impairment would be more closely associated with the spatial extent than with the intensity of tau-PET signal, as measured by the standard uptake value ratio (SUVr).[18F]MK6240 tau-PET data from 82 participants in the AD spectrum were quantified in three different brain regions (Braak ≤ 2, Braak ≤ 4, and Braak ≤ 6) using SUVr and the extent of tauopathy (EOT, percentage of voxels with SUVr ≥ 1.3). PET data were first compared between diagnostic categories, and ROC curves were computed to evaluate sensitivity and specificity. PET data were then correlated to cognitive performances and cerebrospinal fluid (CSF) tau values.METHODS[18F]MK6240 tau-PET data from 82 participants in the AD spectrum were quantified in three different brain regions (Braak ≤ 2, Braak ≤ 4, and Braak ≤ 6) using SUVr and the extent of tauopathy (EOT, percentage of voxels with SUVr ≥ 1.3). PET data were first compared between diagnostic categories, and ROC curves were computed to evaluate sensitivity and specificity. PET data were then correlated to cognitive performances and cerebrospinal fluid (CSF) tau values.The EOT in the Braak ≤ 2 region provided the highest diagnostic accuracies, distinguishing between amyloid-negative and positive clinically unimpaired individuals (threshold = 9%, sensitivity = 79%, specificity = 82%) as well as between prodromal AD and preclinical AD (threshold = 38%, sensitivity = 81%, specificity = 93%). The EOT better correlated with cognition than SUVr (∆R2 + 0.08-0.09) with the best correlation observed for EOT in the Braak ≤ 4 region (R2 = 0.64). Cognitive performances were more closely associated with PET metrics than with CSF values.RESULTSThe EOT in the Braak ≤ 2 region provided the highest diagnostic accuracies, distinguishing between amyloid-negative and positive clinically unimpaired individuals (threshold = 9%, sensitivity = 79%, specificity = 82%) as well as between prodromal AD and preclinical AD (threshold = 38%, sensitivity = 81%, specificity = 93%). The EOT better correlated with cognition than SUVr (∆R2 + 0.08-0.09) with the best correlation observed for EOT in the Braak ≤ 4 region (R2 = 0.64). Cognitive performances were more closely associated with PET metrics than with CSF values.Quantifying [18F]MK-6240 tau PET in terms of EOT rather than SUVr significantly increases the correlation with cognitive performances. Quantification in the mesiotemporal lobe is the most useful to diagnose preclinical AD or prodromal AD.CONCLUSIONSQuantifying [18F]MK-6240 tau PET in terms of EOT rather than SUVr significantly increases the correlation with cognitive performances. Quantification in the mesiotemporal lobe is the most useful to diagnose preclinical AD or prodromal AD.

Background The medial temporal lobe (MTL) is the first cortical region affected by tauopathy in Alzheimer’s disease (AD) and is implicated in spatial orientation. In early AD stages, navigation deficits, including path integration deficits, could be present, even before memory deficits. We investigated whether these deficits were related to AD pathology (amyloidosis and/or tauopathy) using a path integration task, the “Apple Game”. Method During the task, participants navigated through a virtual arena and were asked to return to a starting location after visiting one intermediate location. Two subtasks were tested: with a proximal cue (landmark‐supported path integration, LPI), and without (pure path integration, PPI). We recruited 90 participants (mean age: 69): 66 clinically normal (CN) and 24 patients with mild cognitive impairment (MCI). We classified them according to amyloid status: Aβ+ (n = 34) or Aβ‐ (n = 56) based on amyloid‐PET or CSF measurements. All participants underwent [18F]MK‐6240 Tau‐PET to disclose tau pathology in the MTL (entorhinal cortex and hippocampus). Task performances were analyzed in relation to amyloid status and MTL tauopathy using linear‐mixed‐effect models. First, we evaluated the error according to amyloid status, neuropsychological status, subtask, and their interactions. Then, we evaluated the error and its components (rotation and distance errors) according to MTL tauopathy, and amyloid status for each subtask. Education, gender, and video game experiences were adjusted for. Result Preclinical AD individuals (CN, Aβ+) had a deficit in pure path integration (p = 0.02) compared to CN Aβ‐ individuals, but not in landmark‐supported path integration (Fig. 1). The amyloid status did not influence performances among MCI patients. Rotation errors depended on MTL tauopathy in PPI (p = 0.02) and LPI (p = 0.0004) (Fig. 2), whereas distance errors depended on age in PPI (p = 0.004), and on the age (p = 0.015) and MTL tauopathy (p = 0.02) in LPI. Conclusion We detected a specific deficit in pure path integration in a virtual environment, in preclinical AD, suggesting a deficit to integrate self‐motion cues. Furthermore, we decomposed the path integration performances into rotation and distance errors, and found that rotation errors were associated with MTL tauopathy, possibly reflecting impairment of grid cells; whereas distance errors mainly increased with older ages.

Second-generation tau-PET tracers like [18F]MK-6240 are increasingly used both for diagnosing and quantifying Alzheimer's Disease (AD) tauopathy. However, while [18F]MK-6240 tau-PET has demonstrated excellent sensitivity for AD tauopathy, data assessing its specificity and binding in non-AD tauopathies are still scarce.INTRODUCTIONSecond-generation tau-PET tracers like [18F]MK-6240 are increasingly used both for diagnosing and quantifying Alzheimer's Disease (AD) tauopathy. However, while [18F]MK-6240 tau-PET has demonstrated excellent sensitivity for AD tauopathy, data assessing its specificity and binding in non-AD tauopathies are still scarce.Participants were assigned to exclusive categorical diagnoses based on their amyloid (Aβ) and cognitive status. We quantified mesiotemporal (MTL) and neocortical [18F]MK-6240 tau-PET signal in 28 Aβ- cognitively impaired (CI) patients presenting various non-AD neurodegenerative disorders. Tau-PET quantifications were compared with Aβ- cognitively unimpaired (CU) subjects (n = 51) and Aβ+ CI patients (n = 77).METHODSParticipants were assigned to exclusive categorical diagnoses based on their amyloid (Aβ) and cognitive status. We quantified mesiotemporal (MTL) and neocortical [18F]MK-6240 tau-PET signal in 28 Aβ- cognitively impaired (CI) patients presenting various non-AD neurodegenerative disorders. Tau-PET quantifications were compared with Aβ- cognitively unimpaired (CU) subjects (n = 51) and Aβ+ CI patients (n = 77).Among the 28 Aβ- impaired subjects, only five presented significant and isolated mesiotemporal signal, most of them being suspected of primary age-related tauopathy (PART). Only two Aβ- impaired patients (7%) presented positive neocortical signal, both being diagnosed with fronto-temporal degeneration (FTD). The Tau-PET results of all the remaining Aβ- patients were comparable to the CU population, including eight other FTD patients. Importantly, 4R-only tauopathies (CBD and PSP) and sv-PPA were negative.RESULTSAmong the 28 Aβ- impaired subjects, only five presented significant and isolated mesiotemporal signal, most of them being suspected of primary age-related tauopathy (PART). Only two Aβ- impaired patients (7%) presented positive neocortical signal, both being diagnosed with fronto-temporal degeneration (FTD). The Tau-PET results of all the remaining Aβ- patients were comparable to the CU population, including eight other FTD patients. Importantly, 4R-only tauopathies (CBD and PSP) and sv-PPA were negative.[18F]MK-6240 tau-PET has a special affinity for tauopathies involving 3R/4R paired helical filaments: AD, PART (Aβ- subjects with MTL-restricted tau-PET signal) and some forms of FTD while most primary tauopathies do not exhibit significant cortical signal. Positive neocortical scans are therefore highly specific for AD tauopathy. Based on those and previous results, we propose a diagnostic flowchart for MCI subjects suspected of AD or another tauopathy which may significantly reduce the need for amyloid PET or CSF measurement.CONCLUSION[18F]MK-6240 tau-PET has a special affinity for tauopathies involving 3R/4R paired helical filaments: AD, PART (Aβ- subjects with MTL-restricted tau-PET signal) and some forms of FTD while most primary tauopathies do not exhibit significant cortical signal. Positive neocortical scans are therefore highly specific for AD tauopathy. Based on those and previous results, we propose a diagnostic flowchart for MCI subjects suspected of AD or another tauopathy which may significantly reduce the need for amyloid PET or CSF measurement.