Patterns of Amygdala Region Pathology in LATE-NC: Subtypes that Differ with Regard to TDP-43 Histopathology, Genetic Risk Factors, and Comorbid Pathologies

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant agerelated TDP-43 encephalopathy (LATE). The amygdala is afected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age=85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, and the TMEM106B risk allele. Pathologically, LATE-NC was associated with comorbid hippocampal sclerosis (HS), myelin loss, and vascular disease in white matter (WM). Unbiased hierarchical clustering of TDP-43 inclusion morphologies revealed discernable subtypes of LATE-NC with distinct clinical, genetic, and pathologic associations. The most common patterns were: Pattern 1, with lamina II TDP-43+processes and preinclusion pathology in cortices of the amygdala region, and frequent LATE-NC Stage 3 with HS; Pattern 2, previously described as type-β, with neurofbrillary tangle-like TDP-43 neuronal cytoplasmic inclusions (NCIs), high Alzheimer’s disease neuropathologic change (ADNC), frequent APOE ε4, and usually LATE-NC Stage 2; Pattern 3, with round NCIs and thick neurites in amygdala, younger age at death, and often comorbid Lewy body disease; and Pattern 4 (the most common pattern), with tortuous TDP43 processes in subpial and WM regions, low ADNC, rare HS, and lower dementia probability. TDP-43 pathology with features of patterns 1 and 2 were often comorbid in the same brains. Early and mild TDP-43 pathology was often best described to be localized in the “amygdala region” rather than the amygdala proper. There were also important shared attributes across patterns. For example, all four patterns were associated with the TMEM106B risk allele. Each pattern also demonstrated the potential to progress to higher LATE-NC stages with confuent anatomical and pathological patterns, and to contribute to dementia. Although LATE-NC showed distinct patterns of initiation in amygdala region, there was also apparent shared genetic risk and convergent pathways of clinico-pathological evolution

Investigating white matter hyperintensities in a multicenter COVID-19 study using 7T MRI

Background: Emerging evidence indicates that COVID-19 can negatively impact patient’s brain health (Douaud et al., 2022) (Cecchetti et al., 2022). Common clinical symptoms include brain fog, headaches, difficulty concentrating, and loss of sense of smell or taste. Some studies suggest that SARS-CoV-2 infection can damage the blood brain barrier either directly or through immune-inflammatory mechanisms (Zhang, et al. 2021). White matter hyperintensities (WMH) are imaging biomarkers of brain vascular or inflammatory injury. We investigated the association between severity of COVID-19 infection and burden of white matter hyperintensity volumes within a diverse multi-nation, multi-racial cohort using 7 Tesla (7T) MRI that can detect more subtle injury than conventional 1.5 or 3T MRI. Method: Participants were recruited at 4 sites: Pittsburgh, San Antonio and Houston, USA, and Nottingham, UK. To date, we have scanned and included the following participants in our analysis (Table 1). Detailed cognitive, neurological, mood and functional assessments and high-resolution MRI scans were collected. Subsequent WMH segmentation was performed using our in-house built deep learning based model (Figure 1). All segmentations were visually inspected and manually corrected before statistical analysis. Normalized WMH is calculated as a ratio of the WMH volume and the intracranial volume (WMH/ICV). Imaging data for an additional 36 age-matched controls were retrieved from the 7 Tesla Bioengineering Research Program (7TBRP) imaging bank at Pittsburgh. Result: Figure 1 shows the WMH segmentation outputs from our deep learning based model on images acquired at the 3 sites. Our Linear regression models along with our non-parametric Kruskal-Wallis test result suggests that compared to mild COVID cases and healthy control, COVID infected individuals that were ICU admitted show elevated WMH burden (Figure 2). Conclusion: Our results demonstrate that white matter hyperintensity volumes were higher among patients who had severe acute COVID infection that required ICU admission, compared to healthy age-matched controls. In contrast, no difference in white matter burden was observed in patients with mild COVID infection compared to healthy controls. Additional data (both cross-sectional and longitudinal), including more sensitive MRI measures is being collected to define the full spectrum of brain injury associated with sequelae of COVID infection

Clinical Findings in a Multicenter MRI Study of Mild TBI

Background: Uncertainty continues to surround mild traumatic brain injury (mTBI) diagnosis, symptoms, prognosis, and outcome due in part to a lack of objective biomarkers of injury and recovery. As mTBI gains recognition as a serious public health epidemic, there is need to identify risk factors, diagnostic tools, and imaging biomarkers to help guide diagnosis and management. Methods: One hundred and eleven patients (15-50 years old) were enrolled acutely after mTBI and followed with up to four standardized serial assessments over 3 months. Each encounter included a clinical exam, neuropsychological assessment, and magnetic resonance imaging (MRI). Chi-square and linear mixed models were used to assess changes over time and determine potential biomarkers of mTBI severity and outcome. Results: The symptoms most frequently endorsed after mTBI were headache (91%), not feeling right (89%), fatigue (86%), and feeling slowed down (84%). Of the 104 mTBI patients with a processed MRI scan, 28 (27%) subjects had white matter changes which were deemed unrelated to age, and 26 of these findings were deemed unrelated to acute trauma. Of the neuropsychological assessments tested, 5- and 6-Digit Backward Recall, the modified Balance Error Scoring System (BESS), and Immediate 5-Word Recall significantly improved longitudinally in mTBI subjects and differentiated between mTBI subjects and controls. Female sex was found to increase symptom severity scores (SSS) at every time point. Age \u3e/= 25 years was correlated with increased SSS. Subjects aged \u3e/= 25 also did not improve longitudinally on 5-Digit Backward Recall, Immediate 5-Word Recall, or Single-Leg Stance of the BESS, whereas subjects \u3c 25 years improved significantly. Patients who reported personal history of depression, anxiety, or other psychiatric disorder had higher SSS at each time point. Conclusions: The results of this study show that 5- and 6-Digit Backward Recall, the modified BESS, and Immediate 5-Word Recall should be considered useful in demonstrating cognitive and vestibular improvement during the mTBI recovery process. Clinicians should take female sex, older age, and history of psychiatric disorder into account when managing mTBI patients. Further study is necessary to determine the true prevalence of white matter changes in people with mTBI

Clinical Findings in a Multicenter MRI Study of Mild TBI

Background: Uncertainty continues to surround mild traumatic brain injury (mTBI) diagnosis, symptoms, prognosis, and outcome due in part to a lack of objective biomarkers of injury and recovery. As mTBI gains recognition as a serious public health epidemic, there is need to identify risk factors, diagnostic tools, and imaging biomarkers to help guide diagnosis and management.Methods: One hundred and eleven patients (15–50 years old) were enrolled acutely after mTBI and followed with up to four standardized serial assessments over 3 months. Each encounter included a clinical exam, neuropsychological assessment, and magnetic resonance imaging (MRI). Chi-square and linear mixed models were used to assess changes over time and determine potential biomarkers of mTBI severity and outcome.Results: The symptoms most frequently endorsed after mTBI were headache (91%), not feeling right (89%), fatigue (86%), and feeling slowed down (84%). Of the 104 mTBI patients with a processed MRI scan, 28 (27%) subjects had white matter changes which were deemed unrelated to age, and 26 of these findings were deemed unrelated to acute trauma. Of the neuropsychological assessments tested, 5- and 6-Digit Backward Recall, the modified Balance Error Scoring System (BESS), and Immediate 5-Word Recall significantly improved longitudinally in mTBI subjects and differentiated between mTBI subjects and controls. Female sex was found to increase symptom severity scores (SSS) at every time point. Age ≥ 25 years was correlated with increased SSS. Subjects aged ≥ 25 also did not improve longitudinally on 5-Digit Backward Recall, Immediate 5-Word Recall, or Single-Leg Stance of the BESS, whereas subjects < 25 years improved significantly. Patients who reported personal history of depression, anxiety, or other psychiatric disorder had higher SSS at each time point.Conclusions: The results of this study show that 5- and 6-Digit Backward Recall, the modified BESS, and Immediate 5-Word Recall should be considered useful in demonstrating cognitive and vestibular improvement during the mTBI recovery process. Clinicians should take female sex, older age, and history of psychiatric disorder into account when managing mTBI patients. Further study is necessary to determine the true prevalence of white matter changes in people with mTBI

P1‐349: Advancing Clinical And Biomarker Research In Ad: The Lead Study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152716/1/alzjjalz201906904.pd

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Neuroimaging.

Neuroimaging, Part One, a text from The Handbook of Clinical Neurology illustrates how neuroimaging is rapidly expanding its reach and applications in clinical neurology. It is an ideal resource for anyone interested in the study of the nervous system, and is useful to both beginners in various related fields and to specialists who want to update or refresh their knowledge base on neuroimaging. This first volume specifically covers a description of imaging techniques used in the adult brain, aiming to bring a comprehensive view of the field of neuroimaging to a varying audience. It brings broad coverage of the topic using many color images to illustrate key points. Contributions from leading global experts are collated, providing the broadest view of neuroimaging as it currently stands. For a number of neurological disorders, imaging is not only critical for diagnosis, but also for monitoring the effect of therapies, and the entire field is moving from curing diseases to preventing them. Most of the information contained in this volume reflects the newness of this approach, pointing to this new horizon in the study of neurological disorders.Includes bibliographical references and index.Neuroimaging methods. Computed tomography imaging and angiography -- principles / Shervin Kamalian, Michael H. Lev, Rajiv Gupta -- MR imaging: deconstructing timing diagrams and demystifying k-space / Andrew J.M. Kiruluta, R. Gilberto González -- Volumetric and fiber-tracing MRI methods for gray and white matter / Mykol Larvie, Bruce Fischl -- Functional magnetic resonance imaging / Bradley R. Buchbinder -- Clinical magnetic resonance spectroscopy of the central nervous system / Eva-Maria Ratai, R. Gilberto González -- Brain perfusion: computed tomography and magnetic resonance techniques / William A. Copen, Michael H. Lev, Otto Rapalino -- Magnetic resonance angiography: physical principles and applications / Andrew J.M. Kiruluta, R. Gilberto González -- Diagnostic angiography of the cerebrospinal vasculature / James D. Rabinov, Thabele M. Leslie-Mazwi, Joshua A. Hirsch -- Neurosonology and noninvasive imaging of the carotid arteries / Raffaella Pizzolato, Javier M. Romero -- Myelography: modern technique and indications / Stuart R. Pomerantz -- Positron emission tomography / Katherine Lameka, Michael D. Farwell, Masanori Ichise -- Positron emission tomography: ligand imaging / Mateen Moghbel, Andrew Newberg, Abass Alavi -- Single-photon emission tomography / Karolien Goffin, Koen van Laere -- Brain diseases. Intra-axial brain tumors / Otto Rapalino, Tracy Batchelor, R. Gilberto González -- Extra-axial brain tumors / Otto Rapalino, James G. Smirniotopoulos -- Imaging acute ischemic stroke / R. Gilberto González, Lee H. Schwamm -- Other cerebrovascular occlusive disease / Erica C.S. Camargo, Pamela W. Schaefer, Aneesh B. Singhal -- Hemorrhagic cerebrovascular disease / Javier M. Romero, Jonathan Rosand -- Infection / Gaurav Saigal, Natalya Nagornaya, M. Judith D. Post -- Multiple sclerosis / Massimo Filippi, Paolo Preziosa, Maria A. Rocca -- Other noninfectious inflammatory disorders / Álex Rovira, Cristina Auger, Antoni Rovira -- Imaging of head trauma / Sandra Rincon, Rajiv Gupta, Thomas Ptak -- Cerebellar disorders: clinical/radiologic findings and modern imaging tools / Mario Manto, Christophe Habas -- Imaging of genetic and degenerative disorders primarily causing Parkinsonism / David J. Brooks -- Genetic and degenerative disorders primarily causing other movement disorders / Nicola Pavese, Yen F. Tai -- Genetic and degenerative disorders primarily causing dementia / Joseph C. Masdeu, Belen Pascual -- Neurocutaneous syndromes / Nitasha Klar, Bernard Cohen, Doris D.M. Lin -- Cerebrospinal fluid flow in adults / William G. Bradley, Victor Haughton, Kent-Andre Mardal -- Inherited or acquired metabolic disorders / Florian Eichler, Eva Ratai, Jason J. Carroll, Joseph C. Masdeu -- Imaging of skull base lesions / Hillary R. Kelly, Hugh D. Curtin -- Imaging of orbital disorders / Mary Beth Cunnane, Hugh David Curtin.Neuroimaging, Part One, a text from The Handbook of Clinical Neurology illustrates how neuroimaging is rapidly expanding its reach and applications in clinical neurology. It is an ideal resource for anyone interested in the study of the nervous system, and is useful to both beginners in various related fields and to specialists who want to update or refresh their knowledge base on neuroimaging. This first volume specifically covers a description of imaging techniques used in the adult brain, aiming to bring a comprehensive view of the field of neuroimaging to a varying audience. It brings broad coverage of the topic using many color images to illustrate key points. Contributions from leading global experts are collated, providing the broadest view of neuroimaging as it currently stands. For a number of neurological disorders, imaging is not only critical for diagnosis, but also for monitoring the effect of therapies, and the entire field is moving from curing diseases to preventing them. Most of the information contained in this volume reflects the newness of this approach, pointing to this new horizon in the study of neurological disorders.Description based on online resource; title from pdf title page (ScienceDirect, viewed October 31, 2016).Elsevie