Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification. HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

Participatory community action research in homeless shelters: Outcomes for shelter residents and service-learning research assistants.

The article reports empirical outcomes of an ongoing transdisciplinary participatory community action research project that implements behavioral activation in homeless shelters. The overall goal of this Project is twofold: (1) to improve psychosocial functioning of shelter residents and enhance their opportunities to overcome homelessness; and (2) to enhance civic development of service-learning students who assist in Project implementation. Two studies are reported, representing these goals. Study 1 found that residents of a men's shelter (n = 892), women's shelter (n = 433), and transitional housing (n = 40) perceived behavioral activation sessions as immediately beneficial (i.e., important, meaningful, worthy of repeating, and enjoyable), and over the course of shelter stay, they perceived behavioral activation as contributing to their hope, empowerment/self-sufficiency, quality of life, purpose/meaning in life, wellbeing, social support, shelter social climate, and relationships with staff. Quantitative findings are supported by qualitative data (comments by residents on forms). Study 2, which replicates and extends past research on civic-development in service-learning students, used a new quasi-experimental design to compare service-learning students (n = 41) in an interdisciplinary course on homelessness versus non-service-learning students (n = 16) in a psychology course. Service-learning students showed pre- to post-semester improvements in community service self-efficacy, decreases in stigmatizing attitudes, and increases in awareness of privilege and oppression, but students not engaged in service-learning did not show these civic-related changes. These quantitative results are supported by qualitative data (written reflections by students). Results and implications are discussed within the context of the concept of psychopolitical validity.

Benefits of a health advocacy intervention intended to improve self-efficacy for self-care in residents of a homeless shelter.

Despite a great need for healthcare, unhoused individuals encounter significant barriers to utilizing public healthcare systems. Given the inequities in access to healthcare, accompanied by disabilities and health risks associated with homelessness, self-efficacy for self-care is particularly critical. As a primary purpose of this article, we describe a self-care intervention (Health Advocacy Behavioral Activation), which was implemented within a long-standing participatory community action research project for homeless shelters, and report evidence of the intervention's effectiveness in enhancing self-efficacy for self-care. Participants included 62 residents of the St. Vincent de Paul Gateway Shelter for Men (Dayton, Ohio). Shelter residents with disabilities and those without disability benefited approximately equally from the intervention and both showed statistically significant pre- to post-intervention improvements in self-efficacy for self-care. Recommendations for future research examining the effectiveness of the intervention are provided. As a secondary (supplementary) purpose, we report preliminary evidence of psychometric validation for a new instrument (Scale of Self-Efficacy for Self-Care), which was developed in service of our primary purpose (i.e., to examine the effects of intervention on self-efficacy for self-care) because a literature search did not identify an appropriate measure. Because this new instrument fills a void in the literature, we anticipate that it will be useful in practice and research, and so we delineate research recommendations for additional psychometric validation of this measure. Because of the barriers that unhoused people encounter with regard to access to healthcare in the community, self-care interventions provided (and evaluated) on-site (e.g., in homeless shelters) are necessary.

Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of SV2A.

BACKGROUND: The synaptic hypothesis is an influential theory of the pathoetiology of schizophrenia (SCZ), which is supported by the finding that there is lower uptake of the synaptic terminal density marker [11C]UCB-J in patients with chronic SCZ than in control participants. However, it is unclear whether these differences are present early in the illness. To address this, we investigated [11C]UCB-J volume of distribution (VT) in antipsychotic-naïve/free patients with SCZ who were recruited from first-episode services compared with healthy volunteers. METHODS: Forty-two volunteers (SCZ n = 21, healthy volunteers n = 21) underwent [11C]UCB-J positron emission tomography to index [11C]UCB-J VT and distribution volume ratio in the anterior cingulate, frontal, and dorsolateral prefrontal cortices; the temporal, parietal and occipital lobes; and the hippocampus, thalamus, and amygdala. Symptom severity was assessed in the SCZ group using the Positive and Negative Syndrome Scale. RESULTS: We found no significant effects of group on [11C]UCB-J VT or distribution volume ratio in most regions of interest (effect sizes from d = 0.0-0.7, p > .05), with two exceptions: we found lower distribution volume ratio in the temporal lobe (d = 0.7, uncorrected p < .05) and lower VT/fp in the anterior cingulate cortex in patients (d = 0.7, uncorrected p < .05). The Positive and Negative Syndrome Scale total score was negatively associated with [11C]UCB-J VT in the hippocampus in the SCZ group (r = -0.48, p = .03). CONCLUSIONS: These findings indicate that large differences in synaptic terminal density are not present early in SCZ, although there may be more subtle effects. When taken together with previous evidence of lower [11C]UCB-J VT in patients with chronic illness, this may indicate synaptic density changes during the course of SCZ.

Estimation of target occupancy in repeated dosing design studies using positron emission tomography: Biases due to target upregulation.

Positron emission tomography (PET) has become indispensable in the quantification of target engagement by brain targeting medications. The relationship between the drug plasma concentration (or drug dose administered) and target occupancy determined during a PET occupancy study has provided valuable information for the assessment of novel pharmaceuticals in the early phases of drug development. Such information is also critical for the understanding of the mechanisms of action and side-effect profile of approved medication commonly used in the clinic. Occupancy studies conducted following repeated drug dosing (RD) can produce systematic differences from those conducted following single drug dose (SD), differences that have not been adequately explored. We have hypothesised that when differences are observed between RD and SD studies, they are related to changes in target density induced by repeated drug accumulation. We have developed a modified occupancy model to account for potential changes in target density and tested it on a sample dataset. We found that target upregulation can parsimoniously explain the differences in drug affinity estimated in SD and RD studies. Our findings have implications for the interpretation of RD occupancy data in the literature and the relationship between specific target occupancy levels and drug efficacy and tolerability.

Investigating Europa's Habitability with the Europa Clipper.

The habitability of Europa is a property within a system, which is driven by a multitude of physical and chemical processes and is defined by many interdependent parameters, so that its full characterization requires collaborative investigation. To explore Europa as an integrated system to yield a complete picture of its habitability, the Europa Clipper mission has three primary science objectives: (1) characterize the ice shell and ocean including their heterogeneity, properties, and the nature of surface-ice-ocean exchange; (2) characterize Europa's composition including any non-ice materials on the surface and in the atmosphere, and any carbon-containing compounds; and (3) characterize Europa's geology including surface features and localities of high science interest. The mission will also address several cross-cutting science topics including the search for any current or recent activity in the form of thermal anomalies and plumes, performing geodetic and radiation measurements, and assessing high-resolution, co-located observations at select sites to provide reconnaissance for a potential future landed mission. Synthesizing the mission's science measurements, as well as incorporating remote observations by Earth-based observatories, the James Webb Space Telescope, and other space-based resources, to constrain Europa's habitability, is a complex task and is guided by the mission's Habitability Assessment Board (HAB).

Terminal organization of the corticospinal projection from the arm/hand region of the rostral primary motor cortex (M1r or old M1) to the cervical enlargement (C5-T1) in rhesus monkey.

High-resolution anterograde tracers and stereology were used to study the terminal organization of the corticospinal projection (CSP) from the rostral portion of the primary motor cortex (M1r) to spinal levels C5-T1. Most of this projection (90%) terminated contralaterally within laminae V-IX, with the densest distribution in lamina VII. Moderate bouton numbers occurred in laminae VI, VIII, and IX with few in lamina V. Within lamina VII, labeling occurred over the distal-related dorsolateral subsectors and proximal-related ventromedial subsectors. Within motoneuron lamina IX, most terminations occurred in the proximal-related dorsomedial quadrant, followed by the distal-related dorsolateral quadrant. Segmentally, the contralateral lamina VII CSP gradually declined from C5-T1 but was consistently distributed at C5-C7 in lamina IX. The ipsilateral CSP ended in axial-related lamina VIII and adjacent ventromedial region of lamina VII. These findings demonstrate the M1r CSP influences distal and proximal/axial-related spinal targets. Thus, the M1r CSP represents a transitional CSP, positioned between the caudal M1 (M1c) CSP, which is 98% contralateral and optimally organized to mediate distal upper extremity movements (Morecraft et al., 2013), and dorsolateral premotor (LPMCd) CSP being 79% contralateral and optimally organized to mediate proximal/axial movements (Morecraft et al., 2019). This distal to proximal CSP gradient corresponds to the clinical deficits accompanying caudal to rostral motor cortex injury. The lamina IX CSP is considered in the light of anatomical and neurophysiological evidence which suggests M1c gives rise to the major proportion of the cortico-motoneuronal (CM) projection, while there is a limited M1r CM projection.

A PET-CT study on neuroinflammation in Huntington's disease patients participating in a randomized trial with laquinimod.

Microglia activation, an indicator of central nervous system inflammation, is believed to contribute to the pathology of Huntington's disease. Laquinimod is capable of regulating microglia. By targeting the translocator protein, 11C-PBR28 PET-CT imaging can be used to assess the state of regional gliosis in vivo and explore the effects of laquinimod treatment. This study relates to the LEGATO-HD, multi-centre, double-blinded, Phase 2 clinical trial with laquinimod (US National Registration: NCT02215616). Fifteen patients of the UK LEGATO-HD cohort (mean age: 45.2 ± 7.4 years; disease duration: 5.6 ± 3.0 years) were treated with laquinimod (0.5 mg, N = 4; 1.0 mg, N = 6) or placebo (N = 5) daily. All participants had one 11C-PBR28 PET-CT and one brain MRI scan before laquinimod (or placebo) and at the end of treatment (12 months apart). PET imaging data were quantified to produce 11C-PBR28 distribution volume ratios. These ratios were calculated for the caudate and putamen using the reference Logan plot with the corpus callosum as the reference region. Partial volume effect corrections (Müller-Gartner algorithm) were applied. Differences were sought in Unified Huntington's Disease Rating Scale scores and regional distribution volume ratios between baseline and follow-up and between the two treatment groups (laquinimod versus placebo). No significant change in 11C-PBR28 distribution volume ratios was found post treatment in the caudate and putamen for both those treated with laquinimod (N = 10) and those treated with placebo (N = 5). Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the 11C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period.

Glial cell transcriptome analyses in 3xTg-AD mice: Effects of aging, disease progression, and anti-Aß immunotherapy.

Background: To investigate how changes in expression of glial genes relate to a progression of Alzheimer's disease (AD) pathology, and how anti-Aß immunotherapy impact these changes, we conducted a transcriptomic analysis for brains from cohorts of 2-, 10-, and 20 month old 3xTg-AD mice, and a cross-sectional study in groups of 20 month-old mice treated with active DNA Aß42 immunization, passive immunotherapy, untreated, and wild-type (wt) controls. Methods: Twenty-four Formalin-Fixed Paraffin-Embedded (FFPE) mouse brain sections were used for the gene expression analyses (nanostring). Adjacent sections from these and additional mouse brains were stained for microglia using antibodies detecting IbaI and Gal3. For a semi-quantitative analysis of increased tau and amyloid pathology with aging and disease progression, a comparison of ELISA results from brains of 12 and 20 months old 3xTg-AD mice were shown. Results: Based on the different comparisons of transcript numbers found the 3xTg-AD age groups with the senescent 20 months old wt control mouse brains, and the 20 months old 3xTg-AD mouse brains with the 20 months old wt control mouse brains, genes were assigned as upregulated due to aging, or due to disease progression, or due to both. The immunohistochemistry of microglia markers revealed that Gal3 might be an important marker for phagocytosing microglia around amyloid plaques. The comparison of the two anti-Aß immunotherapy approaches showed a differential downregulation of inflammatory glial genes. Conclusion: These results are relevant for future clinical trials using active anti-amyloid immunotherapy.

DNA Aß42 immunization via needle-less Jet injection in mice and rabbits as potential immunotherapy for Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia found in the elderly and disease progression is associated with accumulation of Amyloid beta 1-42 (Aß42) in brain. An immune-mediated approach as a preventive intervention to reduce amyloid plaques without causing brain inflammation is highly desirable for future clinical use. Genetic immunization, in which the immunizing agent is DNA encoding Aß42, has great potential because the immune response to DNA delivered into the skin is generally non-inflammatory, and thus differs quantitatively and qualitatively from immune responses elicited by peptides, which are inflammatory with production of IFNγ and IL-17 cytokines by activated T cells. DNA immunization has historically been proven difficult to apply to larger mammals. A potential barrier to use DNA immunization in large mammals is the method for delivery of the DNA antigen. We tested jet injection in mice and rabbits and found good antibody production and safe immune responses (no inflammatory cytokines). We found significant reduction of amyloid plaques and Aß peptides in brains of the DNA Aß42 immunized 3xTg-AD mouse model. This study was designed to optimize DNA delivery for possible testing of the DNA Aß42 vaccine for AD prevention in a clinical trial.

Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge.

BACKGROUND: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. METHODS: Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16-30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [11C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region. RESULTS: Following d-amphetamine administration, frontal nondisplaceable binding potential (BPND) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBPND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041). CONCLUSIONS: This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE.

The evidence against somatotopic organization of function in the primate corticospinal tract.

We review the spatial organization of corticospinal outputs from different cortical areas and how this reflects the varied functions mediated by the corticospinal tract. A long-standing question is whether the primate corticospinal tract shows somatotopical organization. Although this has been clearly demonstrated for corticofugal outputs passing through the internal capsule and cerebral peduncle, there is accumulating evidence against somatotopy in the pyramidal tract in the lower brainstem and in the spinal course of the corticospinal tract. Answering the question on somatotopy has important consequences for understanding the effects of incomplete spinal cord injury. Our recent study in the macaque monkey, using high-resolution dextran tracers, demonstrated a great deal of intermingling of fibres originating from primary motor cortex arm/hand, shoulder and leg areas. We quantified the distribution of fibres belonging to these different projections and found no significant difference in their distribution across different subsectors of the pyramidal tract or lateral corticospinal tract, arguing against somatotopy. We further demonstrated intermingling with corticospinal outputs derived from premotor and supplementary motor arm areas. We present new evidence against somatotopy for corticospinal projections from rostral and caudal cingulate motor areas and from somatosensory areas of the parietal cortex. In the pyramidal tract and lateral corticospinal tract, fibres from the cingulate motor areas overlap with each other. Fibres from the primary somatosensory cortex arm area completely overlap those from the leg area. There is also substantial overlap of both these outputs with those from posterior parietal sensorimotor areas. We argue that the extensive intermingling of corticospinal outputs from so many different cortical regions must represent an organizational principle, closely related to its mediation of many different functions and its large range of fibre diameters. The motor sequelae of incomplete spinal injury, such as central cord syndrome and 'cruciate paralysis', include much greater deficits in upper than in lower limb movement. Current teaching and text book explanations of these symptoms are still based on a supposed corticospinal somatotopy or 'lamination', with greater vulnerability of arm and hand versus leg fibres. We suggest that such explanations should now be finally abandoned. Instead, the clinical and neurobiological implications of the complex organization of the corticospinal tract need now to be taken into consideration. This leads us to consider the evidence for a greater relative influence of the corticospinal tract on upper versus lower limb movements, the former best characterized by skilled hand and digit movements.

The Effect of Antiplatelet Agents on Thromboelastography.

BACKGROUND: Thomboelastography (TEG) is a point of care viscoelastic test that provides an assessment of clot formation and kinetics. Antiplatelet agents are commonly used but there is limited literature evaluating their possible effects on overall clot kinetics. We aimed to evaluate the relationship between antiplatelet agents and clot kinetics as defined by TEG. METHODS: This is a retrospective study of adult patients who underwent TEG from February 2018 to July 2020. Patients who received anticoagulants or blood transfusions within 72 hours, had an incomplete TEG, were diagnosed with COVID-19, or had liver failure were excluded. Patients were stratified based on antiplatelet status. RESULTS: Of 1060 patients, 119 were included (50 controls, 69 antiplatelet agents-37 aspirin monotherapy, 26 dual antiplatelet therapy). Between the control and antiplatelet therapy groups, there was no significant difference in clot time, maximal clot strength, or fibrinogen level. When compared to control patients, patients on dual antiplatelets had significantly higher fibrinogen levels (408.1 mg/dL vs 481.5 mg/dL, P = .013) but no significant differences in clot time or maximal clot strength. In our subgroup analysis, patients on dual antiplatelets had increased maximal clot strength (58.8° vs 63°, P = .005) and fibrinogen levels (384.1 mg/dL vs 481.5 mg/dL, P = .005) compared to those on aspirin alone. DISCUSSION: Compared to control patients and those on aspirin alone, patients on dual antiplatelets have increased maximal clot strength and increased fibrinogen levels. These results can help physicians better target product resuscitation in patients who are on antiplatelet agents.

A Visual Interpretation Algorithm for Assessing Brain Tauopathy with 18F-MK-6240 PET.

In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials of Alzheimer disease (AD). 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (18F-MK-6240) is a radiotracer with high selectivity and subnanomolar affinity for neurofibrillary tangles that shows favorable nonspecific brain penetration and excellent kinetic properties. The purpose of the present investigation was to develop a visual assessment method that provides both an overall assessment of brain tauopathy and regional characterization of abnormal tau deposition. Methods: 18F-MK-6240 scans from 102 participants (including cognitively normal volunteers and patients with AD or other neurodegenerative disorders) were reviewed by an expert nuclear medicine physician masked to each participant's diagnosis to identify common patterns of brain uptake. This initial visual read method was field-tested in a separate, nonoverlapping cohort of 102 participants, with 2 additional naïve readers trained on the method. Visual read outcomes were compared with semiquantitative assessments using volume-of-interest SUV ratio. Results: For the visual read, the readers assessed 8 gray-matter regions per hemisphere as negative (no abnormal uptake) or positive (1%-25% of the region involved, 25%-75% involvement, or >75% involvement) and then characterized the tau binding pattern as positive or negative for evidence of tau and, if positive, whether brain uptake was in an AD pattern. The readers demonstrated agreement 94% of the time for overall positivity or negativity. Concordance on the determination of regional binary outcomes (negative or positive) showed agreement of 74.3% and a Fleiss κ of 0.912. Using clinical diagnosis as the ground truth, the readers demonstrated a sensitivity of 73%-79% and specificity of 91%-93%, with a combined reader-concordance sensitivity of 80% and specificity of 93%. The average SUV ratio in cortical regions showed a robust correlation with visually derived ratings of regional involvement (r = 0.73, P < 0.0001). Conclusion: We developed a visual read algorithm for 18F-MK-6240 PET offering determination of both scan positivity and the regional degree of cortical involvement. These cross-sectional results show strong interreader concordance on both binary and regional assessments of tau deposition, as well as good sensitivity and excellent specificity supporting use as a tool for clinical trials.

Seven new genera and thirty-four new species of buccinoid gastropods (Neogastropoda: Buccinidae) from the Aleutian Islands, Alaska.

Seven new genera and thirty-four new species of gastropods in the in the family Buccinidae, are described from the Aleutian Islands. The new taxa represent five subfamilies: Parancistrolepidinae Habe, 1972: Boreancistrolepis excelsus n. gen. & n. sp. Beringiinae Golikov & Starabogatov, 1975: Aleutijapelion mirandus n. gen. & n. sp.; Beringius nearensis n. sp., B. amliensis n. sp., B. bisulcatus n. sp., B. kiskensis n. sp., B. stanchfieldi n. sp., B. frausseni n. sp., B. aurulentus n. sp., B. maristempestus n. sp., B. undataformis n. sp.; Exiloberingius exiguus n. gen. & n. sp. Neptuneinae Stimpson, 1865: Aulacofusus canaliculatus n. sp., A. tanagaensis n. sp.; Neptunea aleutica n. sp., N. baxteri n. sp., N. dominator n. sp., N. petrelensis n. sp., N. quhmax n. sp., N. vesteraalen n. sp.; N. harrisoni n. sp., N. jewetti n. sp., Laevisipho galaxaios n. gen & n. sp., L. kessleri n. sp.; Volutopsiinae: Volutopsius nanus n. sp., Volutopsius gracilis n. sp.; Crebrivolutopsius labidentatus n. gen. & n. sp. Buccininae Rafinesque, 1815: Aleutibuccinum n. gen.; Castaneobuccinum orri n. gen. & n. sp., C. lauthi, n. sp., C. clinopsis n. sp., C. pagodaformis n. sp.; Sulcosinus carinatus n. sp.; Buccinum lanatum n. sp.; and Buccinum katharinae n. gen. & n. sp. The new genera and species are distinguished by the morphological characters of the shells and radulae.

Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability.

Establishing preclinical models of Alzheimer's disease that predict clinical outcomes remains a critically important, yet to date not fully realized, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-individual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer's disease where we sought a match between individual disease characteristics in the cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-ß burden in life, as measured by cognitive decline and brain activity levels, varies between individuals and this vulnerability rating correlates with the individual cellular vulnerability to extrinsic amyloid-ß in vitro as measured by synapse loss and function. Our findings indicate that patient-induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer's disease pathology but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an individual's in-life clinical vulnerability thus represent a tractable method of Alzheimer's disease modelling using clinical data in combination with cellular phenotypes.

Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance.

Recent insight in the genomic landscape of newly diagnosed multiple myeloma (NDMM) and its precursor conditions, monoclonal gammopathy of uncertain significance (MGUS), and smoldering myeloma have allowed the identification of patients with precursor conditions with a high risk of progression. These cases with "progressor" MGUS/SMM have a higher average mutation burden, have higher rates of mutations in specific genes such as MAPK, DNA repair, MYC, DIS3, and are enriched for specific mutational signatures when compared to non-progressors and are comparable to those found in NDMM. The highly preserved clonal heterogeneity seen upon progression of SMM, combined with the importance of these early variables, suggests that the identification of progressors based on these findings could complement and enhance the currently available clinical models based on tumor burden. Mechanisms leading to relapse/refractory multiple myeloma (RRMM) are of clinical interest given worse overall survival in this population. An Increased mutational burden is seen in patients with RRMM when compared to NDMM, however, there is evidence of branching evolution with many of these mutations being present at the subclonal level. Likewise, alterations in proteins associated with proteosome inhibitor and immunomodulatory drugs activity could partially explain clinical resistance to these agents. Evidence of chromosomal events leading to copy number changes is seen, with the presence of TP53 deletion, mutation, or a combination of both being present in many cases. Additional chromosomal events such as 1q gain and amplification may also interact and lead to resistance.

Astrogliosis in aging and Parkinson's disease dementia: a new clinical study with 11C-BU99008 PET.

The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites represent a possible target to map the distribution of reactive astrocytes. In this study, we use 11C-BU99008, an imidazoline-2 binding sites-specific PET radioligand, to image reactive astrocytes in vivo in healthy controls and patients with established Parkinson's disease dementia. Eighteen healthy controls (age: 45-78 years) and six patients with Parkinson's disease dementia (age: 64-77 years) had one 11C-BU99008 PET-CT scan with arterial input function. All subjects underwent one 3 T MRI brain scan to facilitate the analysis of the PET data and to capture individual cerebral atrophy. Regional 11C-BU99008 volumes of distribution were calculated for each subject by the two-tissue compartmental modelling. Positive correlations between 11C-BU99008 volumes of distribution values and age were found for all tested regions across the brain within healthy controls (P < 0.05); furthermore, multiple regression indicated that aging affects 11C-BU99008 volumes of distribution values in a region-specific manner. Independent samples t-test indicated that there was no significant group difference in 11C-BU99008 volumes of distribution values between Parkinson's disease dementia (n = 6; mean age = 71.97 ± 4.66 years) and older healthy controls (n = 9; mean age = 71.90 ± 5.51 years). Our data set shows that astrogliosis is common with aging in a region-specific manner. However, in this set-up, 11C-BU99008 PET cannot differentiate patients with Parkinson's disease dementia from healthy controls of similar age.