Cross-sectional Associations of Fatigue with Cerebral β-Amyloid in Older Adults at Risk of Dementia

Fatigue is a common symptom in the elderly and has also been associated with impaired cognition in older adults. Hence, we sought to explore the cross-sectional relationship between fatigue and cerebral \u3b2-amyloid (A\u3b2) in 269 elderly individuals reporting subjective memory complaints from the Multidomain Alzheimer Preventive Trial. Standard uptake value ratios (SUVRs) were generated by [18F] florbetapir positron emission tomography (PET) using the cerebellum as a reference. Cortical-to-cerebellar SUVRs (cortical-SUVRs) were obtained using the mean signal from the frontal cortex, temporal cortex, parietal cortex, precuneus, anterior cingulate, and posterior cingulate. Other brain regions independently assessed were the anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval center, and temporal cortex. Fatigue was defined according to two questions retrieved from the Center for Epidemiological Studies-Depression scale. Chronic fatigue was defined as meeting fatigue criteria at two consecutive clinical visits 6 months apart between study baseline and 1 year (visits were performed at baseline, 6 months and 1 year then annually). Cross-sectional associations between fatigue variables and cerebral A\u3b2 were explored using fully adjusted multiple linear regression models. We found no statistically significant cross-sectional associations between fatigue assessed at the clinical visit closest to PET and A\u3b2 in any brain region. Similarly, chronic fatigue was not significantly associated with A\u3b2 load. Sensitivity analysis in subjects with a Clinical Dementia Rating of 0.5 showed that fatigue reported at the clinical visit closest to PET was, however, weakly associated with increased A\u3b2 in the hippocampus (B-coefficient: 0.07, 95% CI: 0.01, 0.12, p\u2009=\u20090.016). These preliminary results suggest that fatigue might be associated with A\u3b2 in brain regions associated with Alzheimer's disease in subjects in the early stages of disease

Intracranial fluids dynamics alterations and cortical thickness

Objectives: The issue of cortical atrophy is important in normal aging and disease since it is associated with cognitive and physical impairments. Cortical atrophy is potentially a relevant biomarker for the early diagnosis of Alzheimer’s disease (AD). The vascular component is also an integral part of AD and other late-life neurodegenerative diseases. Abnormalities in blood flow appear before accumulation of abnormal proteins in AD. The occlusion of capillaries by neutrophils are significantly higher in AD animal models than control and reduction of those occlusions with an antibody increases both blood flow and cognitive capacities. Vascular alterations lead to hypoperfusion, oxidative stress and inflammation, which in turn lead to damage of neurons, glia and myelin, predominantly in the white mater. Implication of vascular pathologies for gray matter remains unclear. A recent study showed that altered cerebral hemodyamics in asymptomatic carotid artery stenosis is associated with cortical thinning. However there is no proven link between vascular pathologies and cortical thinning. We propose to explore brain aging with a combined biomechanical and imaging approach in order to assess both fluid dynamics alterations and brain structural modifications. We hypothesize that there is a link between altered cerebral hemodynamics and loss of cortical thickness during brain aging. Methods: 80 patients suspected of hydrocephalus were prospectively involved. All patients complain of gait alteration, urinary difficulties, mild apathy and ventriculomegaly on brain imaging. They all underwent brain MRI with T1 weighted images to quantify cortical thickness and phase contrast images to measure arterial, venous and CSF velocities. Lumbar infusion test was also performed to gauge lumbar pressure, a surrogate marker of intracranial pressure (ICP), and CSF dynamics. The cortical volumetric segmentation was done by an automatic post-processing analysis with FREESURFER and local thicknesses were assessed with CorThiZon. Venous, arterial and CSF velocities were measured from PCMRI with BIOFLOWIMAGE software. ICP and CSF dynamics were extracted form infusion tests. Pearson correlations were calculated between cortical thickness and arterial, venous and CSF velocities, but also ICP and derived indices. Results: Mean cortical thickness is positively correlated with mean ICP (r=0.48, p=0.001), ICP pulse amplitude (r=0.43, p=0.001), arterial flow (r=0.44, p=0.001), aqueductal CSF flow(r=046, p=0.001), but negatively correlates with venous flow (r=-0.44, p=0.001). Conclusions: We demonstrate that cortical thickness is correlated with arterial and CSF pulsatility. The causality is more complex since it involves local microcirculation that could not be directly measured. However the association between intracranial pulsatility and gray matter thickness suggests that there is a relationship between vascular alterations at the macroscale level and the pathobiology of cortical atrophy

The Story of the Dopamine Transporter PET Tracer LBT-999: From Conception to Clinical Use

The membrane dopamine transporter (DAT) is involved in a number of brain disorders and its exploration by positron emission tomography (PET) imaging is highly relevant for the early and differential diagnosis, follow-up and treatment assessment of these diseases. A number of carbon-11 and fluor-18 labeled tracers are to date available for this aim, the majority of them being derived from the chemical structure of cocaine. The development of such a tracer, from its conception to its use, is a long process, the expected result being to obtain the best radiopharmaceutical adapted for clinical protocols. In this context, the cocaine derivative (E)-N-(4-fluorobut-2-enyl)2β-carbomethoxy-3β-(4′-tolyl)nortropane, or LBT-999, has passed all the required stages of the development that makes it now a highly relevant imaging tool, particularly in the context of Parkinson's disease. This review describes the different steps of the development of LBT-999 which initially came from its non-fluorinated derivative (E)-N-(3-iodoprop-2-enyl)-2-carbomethoxy-3-(4-methylphenyl) nortropane, or PE2I, because of its high promising properties. [18F]LBT-999 has been extensively characterized in rodent and non-human primate models, in which it demonstrated its capability to explore in vivo the DAT localized at the dopaminergic nerve endings as well as at the mesencephalic cell bodies, in physiological conditions. In lesion-induced rat models of Parkinson's disease, [18F]LBT-999 was able to precisely quantify in vivo the dopaminergic neuron loss, and to assess the beneficial effects of therapeutic approaches such as pharmacological treatment and cell transplantation. Finally recent clinical data demonstrated the efficiency of [18F]LBT-999 in the diagnosis of Parkinson's disease

Toksikološke metode otkrivanja opojnih droga u tragovima: kromatografska, spektroskopska i biološka karakterizacija derivata ecstasyja

Analysis often reveals variability in the composition of ecstasy pills from pure 3,4-methylenedioxymethamphetamine (MDMA) to mixtures of MDMA derivatives, amphetamine, and other unidentifi ed substances. For a comprehensive toxicological analysis one needs to know all steps to MDMA synthesis which may originate impurities. The aim of this study was to synthesise and determine the chemical-physical and in vitro biological properties of a series of MDMA derivatives. 3,4-methylendioxyphenyl-2-nitropropene (MDNP) was obtained by condensation of piperonal with an excess of nitroethane in the presence of ammonium acetate. MDNP was then reduced to methylenedioxyamphetamine (MDA) by LiAlH3. All compounds were analysed using HPLC and spectroscopic technique [Raman, nuclear magnetic resonance (NMR), or infrared (IR)] at all the steps of synthesis. In addition, we assessed the biological potentials of these compounds by measuring in vitro their (i) blood cell/whole blood partition coeffi cient, (ii) binding to plasmatic proteins (Fbp), and (iii) membrane adsorption. Chemical structure was determined with antibody fl uorescence polarisation immunoassay (FPIA). This study showed the presence of solid impurities, particularly of a neurotoxic compound of Al3+ in the fi nal products. FPIA identifi ed the aminoethane group close to the substituted benzene ring, but did not detect the two major precursors of MDMA: MDNP and piperonal. Raman spectroscopy is an attractive alternative technique to characterise ecstasy pills and it can identify stereoisomeric forms such as cis-MDNP and trans-MDNP, which exhibit signals at 1650 cm-1 and 1300 cm-1, respectively.Analize često otkriju neujednačenost sastava tableta ecstasyja od čistoga 3,4-metilendioksimetamfetamina (MDMA) do mješavina njegovih derivata, amfetamina i drugih neutvrđenih tvari. Stoga je za kvalitetnu toksikološku analizu potreban uvid u sve korake sinteze MDMA, s obzirom na to da se ondje vjerojatno kriju izvori nečistoće (prekursori, katalizatori). Cilj ovog ispitivanja bio je sintetizirati derivate MDMA te napraviti njihovu kemijsko-fi zikalnu i biološku in vitro karakterizaciju. 3,4-metilendioksifenil-2-nitropropen (MDNP) dobiven je kondenzacijom piperonala u suvišku nitroetana uz dodatak amonijeva acetata. Njegovom redukcijom s pomoću LiAlH3 dobiven je 3,4-metilendioksiamfetamin (MDA). Svi spojevi iz pojedinih koraka sinteze karakterizirani su s pomoću tekućinske kromatografi je visoke djelotvornosti (HPLC) i spektroskopskih tehnika [Ramanove spektroskopije, nuklearne magnetske rezonancije (NMR-a) te infracrvene spektroskopije (IR-a)]. Usto je ocijenjen i njihov biološki učinak in vitro mjerenjem (i) koefi cijenta raspodjele krvna stanica/puna krv, (ii) vezanja za bjelančevine u plazmi (Fbp) te (iii) adsorpcije na membranu. Kemijska je struktura utvrđena s pomoću fl uorescentnoga polarizacijskog imunokemijskog testa (FPIA). Analiza je u konačnim proizvodima utvrdila prisutnost krutih nečistoća, napose spojeva neurotoksičnog aluminija (Al3+). FPIA je prepoznao aminoetansku skupinu blizu supstituiranoga benzenskog prstena, ali ne i dva glavna prekursora za MDMA: MDNP i piperonal. Posebno je zanimljiva Ramanova spektroskopija budući da (i) pruža privlačnu alternativu za karakterizaciju sastava tableta ecstasyja te (ii) može otkriti stereoizomerne cis/trans-oblike spoja poput cis-MDNP-a odnosno trans-MDNP-a, čiji se signal vidi na 1650 cm-1 odnosno 1300 cm-1

Eigenvector centrality dynamics are related to Alzheimer’s disease pathological changes in non-demented individuals

Amyloid-β accumulation starts in highly connected brain regions and is associated with functional connectivity alterations in the early stages of Alzheimer's disease. This regional vulnerability is related to the high neuronal activity and strong fluctuations typical of these regions. Recently, dynamic functional connectivity was introduced to investigate changes in functional network organization over time. High dynamic functional connectivity variations indicate increased regional flexibility to participate in multiple subnetworks, promoting functional integration. Currently, only a limited number of studies have explored the temporal dynamics of functional connectivity in the pre-dementia stages of Alzheimer's disease. We study the associations between abnormal cerebrospinal fluid amyloid and both static and dynamic properties of functional hubs, using eigenvector centrality, and their relationship with cognitive performance, in 701 non-demented participants from the European Prevention of Alzheimer's Dementia cohort. Voxel-wise eigenvector centrality was computed for the whole functional magnetic resonance imaging time series (static), and within a sliding window (dynamic). Differences in static eigenvector centrality between amyloid positive (A+) and negative (A-) participants and amyloid-tau groups were found in a general linear model. Dynamic eigenvector centrality standard deviation and range were compared between groups within clusters of significant static eigenvector centrality differences, and within 10 canonical resting-state networks. The effect of the interaction between amyloid status and cognitive performance on dynamic eigenvector centrality variability was also evaluated with linear models. Models were corrected for age, sex, and education level. Lower static centrality was found in A+ participants in posterior brain areas including a parietal and an occipital cluster; higher static centrality was found in a medio-frontal cluster. Lower eigenvector centrality variability (standard deviation) occurred in A+ participants in the frontal cluster. The default mode network and the dorsal visual networks of A+ participants had lower dynamic eigenvector centrality variability. Centrality variability in the default mode network and dorsal visual networks were associated with cognitive performance in the A- and A+ groups, with lower variability being observed in A+ participants with good cognitive scores. Our results support the role and timing of eigenvector centrality alterations in very early stages of Alzheimer's disease and show that centrality variability over time adds relevant information on the dynamic patterns that cause static eigenvector centrality alterations. We propose that dynamic eigenvector centrality is an early biomarker of the interplay between early Alzheimer's disease pathology and cognitive decline

Clinical heterogeneity of neuro-inflammatory PET profiles in early Alzheimer’s disease

The relationship between neuroinflammation and cognition remains uncertain in early Alzheimer’s disease (AD). We performed a cross-sectional study to assess how neuroinflammation is related to cognition using TSPO PET imaging and a multi-domain neuropsychological assessment. A standard uptake value ratio (SUVR) analysis was performed to measure [18F]-DPA-714 binding using the cerebellar cortex or the whole brain as a (pseudo)reference region. Among 29 patients with early AD, the pattern of neuroinflammation was heterogeneous and exhibited no correlation with cognition at voxel-wise, regional or whole-brain level. The distribution of the SUVR values was independent of sex, APOE phenotype, early and late onset of symptoms and the presence of cerebral amyloid angiopathy. However, we were able to demonstrate a complex dissociation as some patients with similar PET pattern had opposed neuropsychological profiles while other patients with opposite PET profiles had similar neuropsychological presentation. Further studies are needed to explore how this heterogeneity impacts disease progression

The Open-Access European Prevention of Alzheimer's Dementia (EPAD) MRI dataset and processing workflow

The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer's Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI preprocessing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features - i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia. The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features - Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) - were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses

Singular nonlinear (n-1,1) conjugate boundary value problems

Solutions are obtained for the boundary value problem, y (n) + f(x,y) = 0, y (i)(0) = y(1) = 0, 0 i n – 2, where f(x,y) is singular at y = 0. An application is made of a fixed point theorem for operators that are decreasing with respect to a cone

Clinical Effect of Early vs Late Amyloid Positron Emission Tomography in Memory Clinic Patients: The AMYPAD-DPMS Randomized Clinical Trial

IMPORTANCE: Amyloid positron emission tomography (PET) allows the direct assessment of amyloid deposition, one of the main hallmarks of Alzheimer disease. However, this technique is currently not widely reimbursed because of the lack of appropriately designed studies demonstrating its clinical effect. OBJECTIVE: To assess the clinical effect of amyloid PET in memory clinic patients. DESIGN, SETTING, AND PARTICIPANTS: The AMYPAD-DPMS is a prospective randomized clinical trial in 8 European memory clinics. Participants were allocated (using a minimization method) to 3 study groups based on the performance of amyloid PET: arm 1, early in the diagnostic workup (within 1 month); arm 2, late in the diagnostic workup (after a mean [SD] 8 [2] months); or arm 3, if and when the managing physician chose. Participants were patients with subjective cognitive decline plus (SCD+; SCD plus clinical features increasing the likelihood of preclinical Alzheimer disease), mild cognitive impairment (MCI), or dementia; they were assessed at baseline and after 3 months. Recruitment took place between April 16, 2018, and October 30, 2020. Data analysis was performed from July 2022 to January 2023. INTERVENTION: Amyloid PET. MAIN OUTCOME AND MEASURE: The main outcome was the difference between arm 1 and arm 2 in the proportion of participants receiving an etiological diagnosis with a very high confidence (ie, ≥90% on a 50%-100% visual numeric scale) after 3 months. RESULTS: A total of 844 participants were screened, and 840 were enrolled (291 in arm 1, 271 in arm 2, 278 in arm 3). Baseline and 3-month visit data were available for 272 participants in arm 1 and 260 in arm 2 (median [IQR] age: 71 [65-77] and 71 [65-77] years; 150/272 male [55%] and 135/260 male [52%]; 122/272 female [45%] and 125/260 female [48%]; median [IQR] education: 12 [10-15] and 13 [10-16] years, respectively). After 3 months, 109 of 272 participants (40%) in arm 1 had a diagnosis with very high confidence vs 30 of 260 (11%) in arm 2 (P < .001). This was consistent across cognitive stages (SCD+: 25/84 [30%] vs 5/78 [6%]; P < .001; MCI: 45/108 [42%] vs 9/102 [9%]; P < .001; dementia: 39/80 [49%] vs 16/80 [20%]; P < .001). CONCLUSION AND RELEVANCE: In this study, early amyloid PET allowed memory clinic patients to receive an etiological diagnosis with very high confidence after only 3 months compared with patients who had not undergone amyloid PET. These findings support the implementation of amyloid PET early in the diagnostic workup of memory clinic patients. TRIAL REGISTRATION: EudraCT Number: 2017-002527-21

Description of a European memory clinic cohort undergoing amyloid-PET: The AMYPAD Diagnostic and Patient Management Study

INTRODUCTION: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort. METHODS: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid-PET; ARM2, late amyloid-PET; and ARM3, free-choice. RESULTS: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms. DISCUSSION: The features of AMYPAD-DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results