US-Guided Interventional Procedures for Total Hip Arthroplasty.

In patients with total hip arthroplasty (THA) with recurrent pain, symptoms may be caused by several conditions involving not just the joint, but also the surrounding soft tissues including tendons, muscles, bursae, and peripheral nerves. US and US-guided interventional procedures are important tools in the diagnostic work-up of patients with painful THA given that it is possible to reach a prompt diagnosis both directly identifying the pathological changes of periprosthetic structures and indirectly evaluating the response and pain relief to local injection of anesthetics under US monitoring. Then, US guidance can be used for the aspiration of fluid from the joint or periarticular collections, or alternatively to follow the biopsy needle to collect samples for culture analysis in the suspicion of prosthetic joint infection. Furthermore, US-guided percutaneous interventions may be used to treat several conditions with well-established minimally invasive procedures that involve injections of corticosteroid, local anesthetics, and platelet-rich plasma or other autologous products. In this review, we will discuss the clinical and technical applications of US-guided percutaneous interventional procedures in painful THA that can be used in routine daily practice for diagnostic and therapeutic purposes.

Finding the limits of deep learning clinical sensitivity with fractional anisotropy (FA) microstructure maps.

Background: Quantitative maps obtained with diffusion weighted (DW) imaging, such as fractional anisotropy (FA) -calculated by fitting the diffusion tensor (DT) model to the data,-are very useful to study neurological diseases. To fit this map accurately, acquisition times of the order of several minutes are needed because many noncollinear DW volumes must be acquired to reduce directional biases. Deep learning (DL) can be used to reduce acquisition times by reducing the number of DW volumes. We already developed a DL network named "one-minute FA," which uses 10 DW volumes to obtain FA maps, maintaining the same characteristics and clinical sensitivity of the FA maps calculated with the standard method using more volumes. Recent publications have indicated that it is possible to train DL networks and obtain FA maps even with 4 DW input volumes, far less than the minimum number of directions for the mathematical estimation of the DT. Methods: Here we investigated the impact of reducing the number of DW input volumes to 4 or 7, and evaluated the performance and clinical sensitivity of the corresponding DL networks trained to calculate FA, while comparing results also with those using our one-minute FA. Each network training was performed on the human connectome project open-access dataset that has a high resolution and many DW volumes, used to fit a ground truth FA. To evaluate the generalizability of each network, they were tested on two external clinical datasets, not seen during training, and acquired on different scanners with different protocols, as previously done. Results: Using 4 or 7 DW volumes, it was possible to train DL networks to obtain FA maps with the same range of values as ground truth - map, only when using HCP test data; pathological sensitivity was lost when tested using the external clinical datasets: indeed in both cases, no consistent differences were found between patient groups. On the contrary, our "one-minute FA" did not suffer from the same problem. Conclusion: When developing DL networks for reduced acquisition times, the ability to generalize and to generate quantitative biomarkers that provide clinical sensitivity must be addressed.

Predicting functional decline in aging and Alzheimer's disease with PET-based Braak staging.

The progression of PET-based Braak stages correlates with cognitive deterioration in aging and Alzheimer's disease. Here, we investigate the association between PET-based Braak stages and functional impairment and assess whether PET-based Braak staging predicts a longitudinal decline in the performance of activities of daily living. In this cohort study, we evaluated cognitively unimpaired individuals and individuals with mild cognitive impairment or Alzheimer's disease dementia. Participants underwent [18F]MK6240 tau-PET, were assigned a PET-based Braak stage at baseline and were followed for a mean (SD) of 1.97 (0.66) years. Functional performance was evaluated with the Functional Activities Questionnaire, Everyday Cognition and functional Clinical Dementia Rating sum of boxes. Multiple linear regressions assessed the association of PET-based Braak stages with baseline functionality and with the longitudinal rate of change in functional scores, adjusting for age, sex and amyloid-ß load. We employed voxel-based regression models to investigate the association between functionality and tau-PET signal and assessed the voxel overlap with Braak regions of interest. We included 291 individuals (181 cognitively unimpaired, 56 amyloid-ß+ mild cognitive impairment and 54 amyloid-ß+ Alzheimer's disease) aged 70.60 (7.48) years. At baseline, PET-based Braak stages III-IV (ß = 0.43, P = 0.03) and V-VI (ß = 1.20, P < 0.0001) showed associations with poorer Functional Activities Questionnaire scores. Similarly, stages III-IV (ß = 0.43, P = 0.02) and V-VI (ß = 1.15, P < 0.0001) were associated with worse Everyday Cognition scores. Only stages V-VI were associated with higher functional Clinical Dementia Rating sum of boxes (ß = 1.17, P < 0.0001) scores. Increased tau-PET signals in all Braak regions of interest were linked to worse performance in all tools. The voxelwise analysis showed widespread cortical associations between functional impairment and tau-PET and high voxel overlap with Braak regions of interest. Baseline PET-based Braak stages V-VI predicted significant longitudinal functional decline as assessed by the Functional Activities Questionnaire (ß = 1.69, P < 0.0001), the Everyday Cognition (ß = 1.05, P = 0.001) and the functional Clinical Dementia Rating sum of boxes (ß = 1.29, P < 0.0001). Our results suggest that functional impairment increases with the severity of tau accumulation. These findings also indicate that PET-based Braak staging is a good predictor of functional impairment in the Alzheimer's disease continuum. Finally, our study provides evidence for the clinical significance of the PET-based Braak staging framework.

CT Arthrography of the Elbow: What Radiologists Should Know.

Computed tomography (CT) arthrography is a quickly available imaging modality to investigate elbow disorders. Its excellent spatial resolution enables the detection of subtle pathologic changes of intra-articular structures, which makes this technique extremely valuable in a joint with very tiny chondral layers and complex anatomy of articular capsule and ligaments. Radiation exposure has been widely decreased with the novel CT scanners, thereby increasing the indications of this examination. The main applications of CT arthrography of the elbow are the evaluation of capsule, ligaments, and osteochondral lesions in both the settings of acute trauma, degenerative changes, and chronic injury due to repeated microtrauma and overuse. In this review, we discuss the normal anatomic findings, technical tips for injection and image acquisition, and pathologic findings that can be encountered in CT arthrography of the elbow, shedding light on its role in the diagnosis and management of different orthopedic conditions. We aspire to offer a roadmap for the integration of elbow CT arthrography into routine clinical practice, fostering improved patient outcomes and a deeper understanding of elbow pathologies.

Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer's disease pathology.

BACKGROUND: Antibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau181, p-tau217 and p-tau231 with established immunoassay techniques. METHODS: We measured p-tau181, p-tau217 and p-tau231 concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods. All subjects were clinically evaluated by dementia specialists and had amyloid-PET and tau-PET assessments. Bland-Altman analyses evaluated the agreement between immunoassay and mass spectrometry p-tau181, p-tau217 and p-tau231. P-tau associations with amyloid-PET and tau-PET uptake were also compared. Receiver Operating Characteristic (ROC) analyses compared the performance of mass spectrometry and immunoassays p-tau concentrations to identify amyloid-PET positivity. RESULTS: Mass spectrometry and immunoassays of p-tau217 were highly comparable in terms of diagnostic performance, between-group effect sizes and associations with PET biomarkers. In contrast, p-tau181 and p-tau231 concentrations measured using antibody-free mass spectrometry had lower performance compared with immunoassays. CONCLUSIONS: Our results suggest that while similar overall, immunoassay-based p-tau biomarkers are slightly superior to antibody-free mass spectrometry-based p-tau biomarkers. Future work is needed to determine whether the potential to evaluate multiple biomarkers within a single run offsets the slightly lower performance of antibody-free mass spectrometry-based p-tau quantification.

Hippocampal subfield associations with memory depend on stimulus modality and retrieval mode.

Hippocampal atrophy is a well-known feature of age-related memory decline, and hippocampal subfields may contribute differently to this decline. In this cross-sectional study, we investigated the associations between hippocampal subfield volumes and performance in free recall and recognition memory tasks in both verbal and visual modalities in older adults without dementia. We collected MRIs from 97 (41 males) right-handed participants aged over 60. We segmented the right and left hippocampi into (i) dentate gyrus and cornu ammonis 4 (DG/CA4); (ii) CA2 and CA3 (CA2/CA3); (iii) CA1; (iv) strata radiatum, lacunosum and moleculare; and (v) subiculum. Memory was assessed with verbal free recall and recognition tasks, as well as visual free recall and recognition tasks. Amyloid-ß and hippocampal tau positivity were assessed using [18F]AZD4694 and [18F]MK6240 PET tracers, respectively. The verbal free recall and verbal recognition performances were positively associated with CA1 and strata radiatum, lacunosum and moleculare volumes. The verbal free recall and visual free recall were positively correlated with the right DG/CA4. The visual free recall, but not verbal free recall, was also associated with the right CA2/CA3. The visual recognition was not significantly associated with any subfield volume. Hippocampal tau positivity, but not amyloid-ß positivity, was associated with reduced DG/CA4, CA2/CA3 and strata radiatum, lacunosum and moleculare volumes. Our results suggest that memory performances are linked to specific subfields. CA1 appears to contribute to the verbal modality, irrespective of the free recall or recognition mode of retrieval. In contrast, DG/CA4 seems to be involved in the free recall mode, irrespective of verbal or visual modalities. These results are concordant with the view that DG/CA4 plays a primary role in encoding a stimulus' distinctive attributes, and that CA2/CA3 could be instrumental in recollecting a visual memory from one of its fragments. Overall, we show that hippocampal subfield segmentation can be useful for detecting early volume changes and improve our understanding of the hippocampal subfields' roles in memory.

Amyloid beta plaque accumulation with longitudinal [18F]AZD4694 PET.

Introduction: [18F]AZD4694 is an amyloid beta (Aß) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aß accumulation measured with [18F]AZD4694. Methods: We assessed 146 individuals who were evaluated with [18F]AZD4694 at baseline and 2-year follow-up. We calculated annual rates of [18F]AZD4694 change for clinically defined and biomarker-defined groups. Results: Cognitively unimpaired (CU) older adults displayed subtle [18F]AZD4694 standardized uptake value ratio (SUVR) accumulation over the follow-up period. In contrast, Aß positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aß positive mild cognitive impairment (MCI) and dementia was modest across the neocortex. Discussion: Larger increases in [18F]AZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. [18F]AZD4694 can be used to monitor Aß levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti-amyloid therapies.

Case report: Chorea and cognitive decline in a young woman: instrumental and genetic assessment of a case originally diagnosed as multiple sclerosis.

We describe the case of a young woman affected by debilitating chorea and rapidly progressive cognitive decline. While her original diagnosis was multiple sclerosis, we performed a full instrumental and genetic assessement, though which we identified multiple genetic variants, including a novel variant of the APP gene. We propose some possible mechanisms by which such variants may contribute to neuroinflammation and ultimately lead to this devastating clinical course.

The Use of Tau PET to Stage Alzheimer Disease According to the Braak Staging Framework.

Amyloid-ß plaques and neurofibrillary tangles (NFTs) are the 2 histopathologic hallmarks of Alzheimer disease (AD). On the basis of the pattern of NFT distribution in the brain, Braak and Braak proposed a histopathologic staging system for AD. Braak staging provides a compelling framework for staging and monitoring of NFT progression in vivo using PET imaging. Because AD staging remains based on clinical features, there is an unmet need to translate neuropathologic staging to a biologic clinical staging system. Such a biomarker staging system might play a role in staging preclinical AD or in improving recruitment strategies for clinical trials. Here, we review the literature regarding AD staging with the Braak framework using tau PET imaging, here called PET-based Braak staging. Our aim is to summarize the efforts of implementing Braak staging using PET and assess correspondence with the Braak histopathologic descriptions and with AD biomarkers. Methods: We conducted a systematic literature search in May 2022 on PubMed and Scopus combining the terms "Alzheimer" AND "Braak" AND ("positron emission tomography" OR "PET"). Results: The database search returned 262 results, and after assessment for eligibility, 21 studies were selected. Overall, most studies indicate that PET-based Braak staging may be an efficient method to stage AD since it presents an adequate ability to discriminate between phases of the AD continuum and correlates with clinical, fluid, and imaging biomarkers of AD. However, the translation of the original Braak descriptions to tau PET was done taking into account the limitations of this imaging technique. This led to important interstudy variability in the anatomic definitions of Braak stage regions of interest. Conclusion: Refinements in this staging system are necessary to incorporate atypical variants and Braak-nonconformant cases. Further studies are needed to understand the possible applications of PET-based Braak staging to clinical practice and research. Furthermore, there is a need for standardization in the topographic definitions of Braak stage regions of interest to guarantee reproducibility and methodologic homogeneity across studies.

Verbal memory formation across PET-based Braak stages of tau accumulation in Alzheimer's disease.

A classical early sign of typical Alzheimer's disease is memory decline, which has been linked to the aggregation of tau in the medial temporal lobe. Verbal delayed free recall and recognition tests have consistently probed useful to detect early memory decline, and there is substantial debate on how performance, particularly in recognition tests, is differentially affected through health and disease in older adults. Using in vivo PET-Braak staging, we investigated delayed recall and recognition memory dysfunction across the Alzheimer's disease spectrum. Our cross-sectional study included 144 cognitively unimpaired elderly, 39 amyloid-ß+ individuals with mild cognitive impairment and 29 amyloid-ß+ Alzheimer's disease patients from the Translational Biomarkers in Aging and Dementia cohort, who underwent [18F]MK6240 tau and [18F]AZD4694 amyloid PET imaging, structural MRI and memory assessments. We applied non-parametric comparisons, correlation analyses, regression models and voxel-wise analyses. In comparison with PET-Braak Stage 0, we found that reduced, but not clinically significant, delayed recall starts at PET-Braak Stage II (adjusted P < 0.0015), and that recognition (adjusted P = 0.011) displayed a significant decline starting at PET-Braak Stage IV. While performance in both delayed recall and recognition related to tau in nearly the same cortical areas, further analyses showed that delayed recall rendered stronger associations in areas of early tau accumulation, whereas recognition displayed stronger correlations in mostly posterior neocortical regions. Our results support the notion that delayed recall and recognition deficits are predominantly associated with tau load in allocortical and neocortical areas, respectively. Overall, delayed recall seems to be more dependent on the integrity of anterior medial temporal lobe structures, while recognition appears to be more affected by tau accumulation in cortices beyond medial temporal regions.

Equivalence of plasma p-tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease.

INTRODUCTION: Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established biomarkers are needed. METHODS: We assessed the diagnostic performance of p-tau181 , p-tau217 , and p-tau231 in plasma and CSF in 174 individuals evaluated by dementia specialists and assessed with amyloid-PET and tau-PET. Receiver operating characteristic (ROC) analyses assessed the performance of plasma and CSF biomarkers to identify amyloid-PET and tau-PET positivity. RESULTS: Plasma p-tau biomarkers had lower dynamic ranges and effect sizes compared to CSF p-tau. Plasma p-tau181 (AUC = 76%) and p-tau231 (AUC = 82%) assessments performed inferior to CSF p-tau181 (AUC = 87%) and p-tau231 (AUC = 95%) for amyloid-PET positivity. However, plasma p-tau217 (AUC = 91%) had diagnostic performance indistinguishable from CSF (AUC = 94%) for amyloid-PET positivity. DISCUSSION: Plasma and CSF p-tau217 had equivalent diagnostic performance for biomarker-defined AD. Our results suggest that plasma p-tau217 may help reduce the need for invasive lumbar punctures without compromising accuracy in the identification of AD. HIGHLIGHTS: p-tau217 in plasma performed equivalent to p-tau217 in CSF for the diagnosis of AD, suggesting the increased accessibility of plasma p-tau217 is not offset by lower accuracy. p-tau biomarkers in plasma had lower mean fold-changes between amyloid-PET negative and positive groups than p-tau biomarkers in CSF. CSF p-tau biomarkers had greater effect sizes than plasma p-tau biomarkers when differentiating between amyloid-PET positive and negative groups. Plasma p-tau181 and plasma p-tau231 performed worse than p-tau181 and p-tau231 in CSF for AD diagnosis.

Cardiorespiratory Fitness Moderates the Age-Related Association Between Executive Functioning and Mobility: Evidence From Remote Assessments.

Background and Objectives: In older adults, executive functions are important for daily-life function and mobility. Evidence suggests that the relationship between cognition and mobility is dynamic and could vary according to individual factors, but whether cardiorespiratory fitness reduces the age-related increase of interdependence between mobility and cognition remains unexplored. Research Design and Methods: One hundred eighty-nine participants (aged 50-87) were divided into 3 groups according to their age: middle-aged (MA; <65), young older adults (YOA; 65-74), and old older adults (OOA; ≥75). Participants performed Timed Up and Go and executive functioning assessments (Oral Trail Making Test and Phonologic verbal fluency) remotely by videoconference. Participants completed the Matthews questionnaire to estimate their cardiorespiratory fitness (VO2 max in ml/min/kg). A 3-way moderation was used to address whether cardiorespiratory fitness interacts with age to moderate the relationship between cognition and mobility. Results: Results showed that the cardiorespiratory fitness × age interaction moderated the association between executive functioning and mobility (ß = -0.05; p = .048; R 2 = 17.6; p < .001). At lower levels of physical fitness (<19.16 ml/min/kg), executive functioning significantly influenced YOA's mobility (ß = -0.48, p = .004) and to a greater extent OOA's mobility (ß = -0.96, p = .002). Discussion and Implications: Our results support the idea of a dynamic relationship between mobility and executive functioning during aging and suggest that physical fitness could play a significant role in reducing their interdependency.

Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography.

Importance: The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-ß plaques and tau neurofibrillary tangles. Objective: To determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral ß-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET). Design, Setting, and Participants: This was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded. Exposures: Amyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay. Main Outcomes and Measures: Associations between p-tau biomarkers with amyloid PET and tau PET. Results: A total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts. Conclusions and Relevance: Results of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-ß accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

Discordance and Concordance Between Cerebrospinal and [18F]FDG-PET Biomarkers in Assessing Atypical and Early-Onset AD Dementia Cases.

BACKGROUND AND OBJECTIVES: To assess the concordance and discordance between the core Alzheimer disease (AD) CSF biomarkers and [18F]fluorodeoxyglucose (FDG)-PET patterns evaluated clinically in memory clinic patients who meet appropriate use criteria for AD biomarker investigations. METHODS: We retrospectively assessed participants with atypical and/or early-onset dementia evaluated at a tertiary care memory clinic. All individuals underwent CSF evaluations for Aß42, phosphorylated tau (P-tau181) and total tau, and brain [18F]FDG-PET. [18F]FDG-PET data were visually interpreted by 2 nuclear medicine experts as being consistent with AD or non-AD. CSF biomarker results were similarly grouped into AD biomarker positive/negative. Contingency tables and Kappa coefficients were used to establish the level of agreement and disagreement between CSF and [18F]FDG-PET results in all individuals. RESULTS: One hundred thirty-six individuals had both [18F]FDG-PET and lumbar puncture performed as part of the early-onset and/or atypical dementia assessments. [18F]FDG-PET showed a pattern suggestive of AD in 43% of patients, while CSF biomarkers showed results consistent with AD in 57% of participants. In patients who met criteria for AD biomarker investigations, we found that [18F]FDG-PET was discordant with CSF AD biomarkers in nearly 20% of cases; 12% of individuals with [18F]FDG-PET scans consistent with AD had AD-negative CSF results; and 7% of individuals with [18F]FDG-PET scans not consistent with AD had AD-positive CSF results, potentially suggesting atypical AD variants or less advanced neurodegeneration. [18F]FDG-PET discriminated patients with an AD-positive CSF profile from patients with an AD-negative profile with a sensitivity and specificity higher than 80% (sensitivity: 81%, 95% CI = 71-88%, SP: 81%, 95% CI = 68-89%). Furthermore, [18F]FDG-PET had a positive predictive value of 87% (95% CI = 78-93%) and a negative predictive value of 72% (95% CI = 60-82%). DISCUSSION: CSF and [18F]FDG-PET disagreed in nearly 20% of the cases studied in this clinical series. While CSF Aß42 and P-tau181 biomarkers are specific for AD, the topographical information from [18F]FDG-PET may provide complementary information.

Computation of contrast-enhanced perfusion using only two CT scan phases: a proof-of-concept study on abdominal organs.

BACKGROUND: Computed tomography perfusion imaging (CTPI) by repeated scanning has clinical relevance but implies relatively high radiation exposure. We present a method to measure perfusion from two CT scan phases only, considering tissue enhancement, feeding vessel (aortic) peak enhancement, and bolus shape. METHODS: CTPI scans (each with 40 frames acquired every 1.5 s) of 11 patients with advanced hepatocellular carcinoma (HCC) enrolled between 2012 and 2016 were retrospectively analysed (aged 69 ± 9 years, 8/11 males). Perfusion was defined as the maximal slope of the time-enhancement curve divided by the peak enhancement of the feeding vessel (aorta). Perfusion was computed two times, first using the maximum slope derived from all data points and then using the peak tissue enhancement and the bolus shape obtained from the aortic curve. RESULTS: Perfusion values from the two methods were linearly related (r2 = 0.92, p < 0.001; Bland-Altman analysis bias -0.12). The mathematical model showed that the perfusion ratio of two ROIs with the same feeding vessel (aorta) corresponds to their peak enhancement ratio (r2 = 0.55, p < 0.001; Bland-Altman analysis bias -0.68). The relationship between perfusion and tissue enhancement is predicted to be linear in the clinical range of interest, being only function of perfusion, peak feeding vessel enhancement, and bolus shape. CONCLUSIONS: This proof-of-concept study showed that perfusion values of HCC, kidney, and pancreas could be computed using enhancement measured only with two CT scan phases, if aortic peak enhancement and bolus shape are known.

A generalized deep learning network for fractional anisotropy reconstruction: Application to epilepsy and multiple sclerosis.

Fractional anisotropy (FA) is a quantitative map sensitive to microstructural properties of tissues in vivo and it is extensively used to study the healthy and pathological brain. This map is classically calculated by model fitting (standard method) and requires many diffusion weighted (DW) images for data quality and unbiased readings, hence needing the acquisition time of several minutes. Here, we adapted the U-net architecture to be generalized and to obtain good quality FA from DW volumes acquired in 1 minute. Our network requires 10 input DW volumes (hence fast acquisition), is robust to the direction of application of the diffusion gradients (hence generalized), and preserves/improves map quality (hence good quality maps). We trained the network on the human connectome project (HCP) data using the standard model-fitting method on the entire set of DW directions to extract FA (ground truth). We addressed the generalization problem, i.e., we trained the network to be applicable, without retraining, to clinical datasets acquired on different scanners with different DW imaging protocols. The network was applied to two different clinical datasets to assess FA quality and sensitivity to pathology in temporal lobe epilepsy and multiple sclerosis, respectively. For HCP data, when compared to the ground truth FA, the FA obtained from 10 DW volumes using the network was significantly better (p <10-4) than the FA obtained using the standard pipeline. For the clinical datasets, the network FA retained the same microstructural characteristics as the FA calculated with all DW volumes using the standard method. At the subject level, the comparison between white matter (WM) ground truth FA values and network FA showed the same distribution; at the group level, statistical differences of WM values detected in the clinical datasets with the ground truth FA were reproduced when using values from the network FA, i.e., the network retained sensitivity to pathology. In conclusion, the proposed network provides a clinically available method to obtain FA from a generic set of 10 DW volumes acquirable in 1 minute, augmenting data quality compared to direct model fitting, reducing the possibility of bias from sub-sampled data, and retaining FA pathological sensitivity, which is very attractive for clinical applications.

Subject-specific features of excitation/inhibition profiles in neurodegenerative diseases.

Brain pathologies are characterized by microscopic changes in neurons and synapses that reverberate into large scale networks altering brain dynamics and functional states. An important yet unresolved issue concerns the impact of patients' excitation/inhibition profiles on neurodegenerative diseases including Alzheimer's Disease, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis. In this work, we used The Virtual Brain (TVB) simulation platform to simulate brain dynamics in healthy and neurodegenerative conditions and to extract information about the excitatory/inhibitory balance in single subjects. The brain structural and functional connectomes were extracted from 3T-MRI (Magnetic Resonance Imaging) scans and TVB nodes were represented by a Wong-Wang neural mass model endowing an explicit representation of the excitatory/inhibitory balance. Simulations were performed including both cerebral and cerebellar nodes and their structural connections to explore cerebellar impact on brain dynamics generation. The potential for clinical translation of TVB derived biophysical parameters was assessed by exploring their association with patients' cognitive performance and testing their discriminative power between clinical conditions. Our results showed that TVB biophysical parameters differed between clinical phenotypes, predicting higher global coupling and inhibition in Alzheimer's Disease and stronger N-methyl-D-aspartate (NMDA) receptor-dependent excitation in Amyotrophic Lateral Sclerosis. These physio-pathological parameters allowed us to perform an advanced analysis of patients' conditions. In backward regressions, TVB-derived parameters significantly contributed to explain the variation of neuropsychological scores and, in discriminant analysis, the combination of TVB parameters and neuropsychological scores significantly improved the discriminative power between clinical conditions. Moreover, cluster analysis provided a unique description of the excitatory/inhibitory balance in individual patients. Importantly, the integration of cerebro-cerebellar loops in simulations improved TVB predictive power, i.e., the correlation between experimental and simulated functional connectivity in all pathological conditions supporting the cerebellar role in brain function disrupted by neurodegeneration. Overall, TVB simulations reveal differences in the excitatory/inhibitory balance of individual patients that, combined with cognitive assessment, can promote the personalized diagnosis and therapy of neurodegenerative diseases.

Intrinsic connectivity of the human brain provides scaffold for tau aggregation in clinical variants of Alzheimer's disease.

Alzheimer's disease (AD) phenotypes might result from differences in selective vulnerability. Evidence from preclinical models suggests that tau pathology has cell-to-cell propagation properties. Therefore, here, we tested the cell-to-cell propagation framework in the amnestic, visuospatial, language, and behavioral/dysexecutive phenotypes of AD. We report that each AD phenotype is associated with a distinct network-specific pattern of tau aggregation, where tau aggregation is concentrated in brain network hubs. In all AD phenotypes, regional tau load could be predicted by connectivity patterns of the human brain. Furthermore, regions with greater connectivity displayed similar rates of longitudinal tau accumulation in an independent cohort. Connectivity-based tau deposition was not restricted to a specific vulnerable network but was rather a general property of brain organization, linking selective vulnerability and transneuronal spreading models of neurodegeneration. Together, this study indicates that intrinsic brain connectivity provides a framework for tau aggregation across diverse phenotypic manifestations of AD.

Vascular Lesions and Brain Atrophy in Alzheimer's, Vascular and Mixed Dementia: An Optimized 3T MRI Protocol Reveals Distinctive Radiological Profiles.

BACKGROUND: Vascular lesions may be a common finding also in Alzheimer's dementia, but their role on cognitive status is uncertain. OBJECTIVE: The study aims to investigate their distribution in patients with Alzheimer's, vascular or mixed dementia and detect any distinctive neuroradiological profiles. METHODS: Seventy-six subjects received a diagnosis of Alzheimer's (AD=32), vascular (VD=26) and mixed (MD=18) dementia. Three independent raters assessed the brain images acquired with an optimized 3T MRI protocol (including (3D FLAIR, T1, SWI, and 2D coronal T2 sequences) using semiquantitative scales for vascular lesions (periventricular lesions (PVL), deep white matter lesions (DWML), deep grey matter lesions (DGML), enlarged perivascular spaces (PVS), and microbleeds (MB)) and brain atrophy (medial temporal atrophy (MTA), posterior atrophy (PA), global cortical atrophy- frontal (GCA-F) and Evans' index). RESULTS: Raters reached a good-to-excellent agreement for all scales (ICC ranging from 0.78-0.96). A greater number of PVL (p<0.001), DWML (p<0.001), DGML (p=0.010), and PVS (p=0.001) was observed in VD compared to AD, while MD showed a significant greater number of PVL (p=0.001), DWML (p=0.002), DGML (p=0.018), and deep and juxtacortical MB (p=0.006 and p<0.001, respectively). Comparing VD and MD, VD showed a higher number of PVS in basal ganglia and centrum semiovale (p=0.040), while MD showed more deep and juxtacortical MB (p=0.042 and p=0.022, respectively). No significant difference was observed in scores of cortical atrophy scales and Evans' index among the three groups. CONCLUSION: The proposed MRI protocol represents a useful advancement in the diagnostic assessment of patients with cognitive impairment by more accurately detecting vascular lesions, mainly microbleeds, without a significant increase in time and resource expenditure. Our findings confirm that white and grey matter lesions predominate in vascular and mixed dementia, whereas deep and juxtacortical microbleeds predominate in mixed dementia, suggesting that cerebral amyloid angiopathy could be the main underlying pathology.

Adults with tetralogy of Fallot show specific features of cerebral small vessel disease: the BACH San Donato study.

Life expectancy in adults with congenital heart disease (ACHD) has increased. As these patients grow older, they experience aging-related diseases more than their healthy peers. To better characterize this field, we launched the multi-disciplinary BACH (Brain Aging in Congenital Heart disease) San Donato study, that aimed at investigating signs of brain injury in ACHD. Twenty-three adults with repaired tetralogy of Fallot and 23 age- and sex-matched healthy controls were prospectively recruited and underwent brain magnetic resonance imaging. White matter hyperintensities (WMHs) were segmented using a machine-learning approach and automatically split into periventricular and deep. Cerebral microbleeds were manually counted. A subset of 14 patients were also assessed with an extensive neuropsychological battery. Age was 41.78 ± 10.33 years (mean ± standard deviation) for patients and 41.48 ± 10.28 years for controls (p = 0.921). Albeit not significantly, total brain (p = 0.282) and brain tissue volumes (p = 0.539 for cerebrospinal fluid, p = 0.661 for grey matter, p = 0.793 for white matter) were lower in ACHD, while total volume (p = 0.283) and sub-classes of WMHs (p = 0.386 for periventricular WMHs and p = 0.138 for deep WMHs) were higher in ACHD than in controls. Deep WMHs were associated with poorer performance at the frontal assessment battery (r = -0.650, p = 0.012). Also, patients had a much larger number of microbleeds than controls (median and interquartile range 5 [3-11] and 0 [0-0] respectively; p < 0.001). In this study, adults with tetralogy of Fallot showed specific signs of brain injury, with some clinical implications. Eventually, accurate characterization of brain health using neuroimaging and neuropsychological data would aid in the identification of ACHD patients at risk of cognitive deterioration.