Advanced Magnetic Resonance Imaging Biomarkers of the Injured Spinal Cord: A Comparative Study of Imaging and Histology in Human Traumatic Spinal Cord Injury.

A significant problem in the diagnosis and management of traumatic spinal cord injury (tSCI) is the heterogeneity of secondary injury and the prediction of neurological outcome. Imaging biomarkers specific to myelin loss and inflammation after tSCI would enable detailed assessment of the pathophysiological processes underpinning secondary damage to the cord. Such biomarkers could be used to biologically stratify injury severity and better inform prognosis for neurological recovery. While much work has been done to establish magnetic resonance imaging (MRI) biomarkers for SCI in animal models, the relationship between imaging findings and the underlying pathology has been difficult to discern in human tSCI because of the paucity of human spinal cord tissue. We utilized post-mortem spinal cords from individuals who had a tSCI to examine this relationship by performing ex vivo MRI scans before histological analysis. We investigated the correlation between the histological distribution of myelin loss and inflammatory cells in the injured spinal cord and a number of myelin and inflammation-sensitive MRI measures: myelin water fraction (MWF), inhomogeneous magnetization transfer ratio (ihMTR), and diffusion tensor and diffusion kurtosis imaging-derived fractional anisotropy (FA) and axial, radial, and mean diffusivity (AD, RD, MD). The histological features were analyzed by staining with Luxol Fast Blue (LFB) for myelin lipids and Class II major histocompatibility complex (Class II MHC) and CD68 for microglia and macrophages. Both MWF and ihMTR were strongly correlated with LFB staining for myelin, supporting the use of both as biomarkers for myelin loss after SCI. A decrease in ihMTR was also correlated with the presence of Class II MHC positive immune cells. FA and RD correlated with both Class II MHC and CD68 and may therefore be useful biomarkers for inflammation after tSCI. Our work demonstrates the utility of advanced MRI techniques sensitive to biological tissue damage after tSCI, which is an important step toward using these MRI techniques in the clinic to aid in decision-making.

Characterizing the Relationship Between Arterial Carbon Dioxide Trajectory and Serial Brain Biomarkers with Central Nervous System Injury During Veno-Venous Extracorporeal Membrane Oxygenation: A Prospective Cohort Study.

BACKGROUND: Central nervous system (CNS) injury following initiation of veno-venous extracorporeal membrane oxygenation (VV-ECMO) is common. An acute decrease in partial pressure of arterial carbon dioxide (PaCO2) following VV-ECMO initiation has been suggested as an etiological factor, but the challenges of diagnosing CNS injuries has made discerning a relationship between PaCO2 and CNS injury difficult. METHODS: We conducted a prospective cohort study of adult patients undergoing VV-ECMO for acute respiratory failure. Arterial blood gas measurements were obtained prior to initiation of VV-ECMO, and at every 2-4 h for the first 24 h. Neuroimaging was conducted within the first 7-14 days in patients who were suspected of having neurological injury or unable to be examined because of sedation. We collected blood biospecimens to measure brain biomarkers [neurofilament light (NF-L); glial fibrillary acidic protein (GFAP); and phosphorylated-tau 181] in the first 7 days following initiation of VV-ECMO. We assessed the relationship between both PaCO2 over the first 24 h and brain biomarkers with CNS injury using mixed methods linear regression. Finally, we explored the effects of absolute change of PaCO2 on serum levels of neurological biomarkers by separate mixed methods linear regression for each biomarker using three PaCO2 exposures hypothesized to result in CNS injury. RESULTS: In our cohort, 12 of 59 (20%) patients had overt CNS injury identified on head computed tomography. The PaCO2 decrease with VV-ECMO initiation was steeper in patients who developed a CNS injury (- 0.32%, 95% confidence interval - 0.25 to - 0.39) compared with those without (- 0.18%, 95% confidence interval - 0.14 to - 0.21, P interaction < 0.001). The mean concentration of NF-L increased over time and was higher in those with a CNS injury (464 [739]) compared with those without (127 [257]; P = 0.001). GFAP was higher in those with a CNS injury (4278 [11,653] pg/ml) compared with those without (116 [108] pg/ml; P < 0.001). The mean NF-L, GFAP, and tau over time in patients stratified by the three thresholds of absolute change of PaCO2 showed no differences and had no significant interaction for time. CONCLUSIONS: Although rapid decreases in PaCO2 following initiation of VV-ECMO were slightly greater in patients who had CNS injuries versus those without, data overlap and absence of relationships between PaCO2 and brain biomarkers suggests other pathophysiologic variables are likely at play.

Neuroinflammation and the immune system in hypoxic ischaemic brain injury pathophysiology after cardiac arrest.

Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro-inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia-reperfusion. In particular, interleukin-1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia-reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules.

A Systematic Review of the Genetics and Pathology of Psychosis in Frontotemporal Dementia.

OBJECTIVES: Frontotemporal dementia (FTD) patients frequently present with psychosis, which complicates diagnosis and management. In this study, we aim to examine the relationship between psychosis and the most common genetic mutations predisposing to FTD, and in the different pathological subtypes of FTD. DESIGN: We conducted a systematic review, searching the literature up to December 2022, and reviewed 50 articles that met our inclusion criteria. From the reviewed articles, we extracted and summarized data regarding the frequency of psychosis and patient characteristics in each major genetic and pathological subtype of FTD. RESULTS: Among FTD patients with confirmed genetic mutations or pathological diagnosss, the frequency of psychosis was 24.2%. Among the genetic mutation carriers, C9orf72 mutation carriers had the highest frequency of psychosis (31.4%), whereas GRN (15.0%) and MAPT (9.2%) mutation carriers had lower frequencies of psychosis. MAPT mutation carriers notably developed psychosis at a younger age compared to other genetic groups. The most common psychotic symptoms were delusions among C9orf72 carriers and visual hallucinations among GRN mutation carriers. Among the pathological subtypes, 30% of patients with FUS pathology, 25.3% of patients with TDP-43 pathology, and 16.4% of patients with tau pathology developed psychosis. In the TDP-43 group, subtype B pathology was the most common subtype reported in association with psychosis. CONCLUSION: Our systematic review suggests a high frequency of psychosis in specific subgroups of FTD patients. Further studies are required to understand the structural and biological underpinnings of psychosis in FTD.

Psychotic symptoms in frontotemporal dementia with TDP-43 tend to be associated with type B pathology.

AIMS: Psychotic symptoms are increasingly recognized as a distinguishing clinical feature in patients with dementia due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Within this group, carriers of the C9orf72 repeat expansion are particularly prone to develop delusions and hallucinations. METHODS: The present retrospective study sought to provide novel details about the relationship between FTLD-TDP pathology and the presence of psychotic symptoms during life. RESULTS: We found that FTLD-TDP subtype B was more frequent in patients with psychotic symptoms than in those without. This relationship was present even when corrected for the presence of C9orf72 mutation, suggesting that pathophysiological processes leading to the development of subtype B pathology may increase the risk of psychotic symptoms. Within the group of FTLD-TDP cases with subtype B pathology, psychotic symptoms tended to be associated with a greater burden of TDP-43 pathology in the white matter and a lower burden in lower motor neurons. When present, pathological involvement of motor neurons was more likely to be asymptomatic in patients with psychosis. CONCLUSIONS: This work suggests that psychotic symptoms in patients with FTLD-TDP tend to be associated with subtype B pathology. This relationship is not completely explained by the effects of the C9orf72 mutation and raises the possibility of a direct link between psychotic symptoms and this particular pattern of TDP-43 pathology.

Müller cell degeneration and microglial dysfunction in the Alzheimer's retina.

Amyloid beta (Aß) deposits in the retina of the Alzheimer's disease (AD) eye may provide a useful diagnostic biomarker for AD. This study focused on the relationship of Aß with macroglia and microglia, as these glial cells are hypothesized to play important roles in homeostasis and clearance of Aß in the AD retina. Significantly higher Aß load was found in AD compared to controls, and specifically in the mid-peripheral region. AD retina showed significantly less immunoreactivity against glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) compared to control eyes. Immunoreactivity against ionized calcium binding adapter molecule-1 (IBA-1), a microglial marker, demonstrated a higher level of microgliosis in AD compared to control retina. Within AD retina, more IBA-1 immunoreactivity was present in the mid-peripheral retina, which contained more Aß than the central AD retina. GFAP co-localized rarely with Aß, while IBA-1 co-localized with Aß in more layers of control than AD donor retina. These results suggest that dysfunction of the Müller and microglial cells may be key features of the AD retina.

International Spinal Cord Injury Biobank: A Biorepository and Resource for Translational Research.

Over the past few decades, tremendous advances have been made in our understanding of the biological changes underpinning the devastating impairment of traumatic spinal cord injury (SCI). Much of this scientific research has focused on animal models of SCI, and comparatively little has been done in human SCI, largely because biospecimens from human SCI patients are not readily available. This paucity of scientific enquiry in human SCI represents an important void in the spectrum of translational research, as biological differences between animal models and the human condition need to be considered in the pre-clinical development of therapeutic approaches. The International Spinal Cord Injury Biobank (ISCIB) is a multi-user biorepository with the mission of accelerating therapeutic development in traumatic SCI through improved biological understanding of human injury, and the vision of serving as a global research resource where human SCI biospecimens are shared with researchers around the world. Aligned with internationally recognized best practices, ISCIB's formal governance structure and standard operating procedures have earned it official biobank certification through the Canadian Tissue Repository Network. Herein, we describe the translational research gap that ISCIB is helping to fill; its structure, governance and certification; how data and samples are accrued, processed and stored; and finally, the process through which samples and data are shared with global researchers. The purpose of this paper describing ISCIB is to serve as an introductory guidance document for the wider community of SCI researchers. By helping researchers understand the contents of ISCIB and the process of accessing biospecimens, we seek to further ISCIB's vision as being a resource for human and translational research in SCI, with the ultimate goal of finding disease-modifying therapies for this disabling condition.

Brain Hypoxia Is Associated With Neuroglial Injury in Humans Post-Cardiac Arrest.

[Figure: see text].

Clinico-pathological comparison of patients with autopsy-confirmed Alzheimer's disease, dementia with Lewy bodies, and mixed pathology.

INTRODUCTION: Patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) frequently demonstrate coexistent AD neuropathological change (ADNC) and Lewy body pathology (LBP) at autopsy. We investigated the effects of ADNC and LBP on the clinical presentation of these patients. METHODS: We retrospectively compared clinical and pathological features of patients with different severity of ADNC and LBP. We also compared the burden of medullary LBP between patients with and without autonomic dysfunction. RESULTS: Compared to pure ADNC, patients with AD/LBP have higher prevalence of DLB symptoms. Autonomic dysfunction strongly predicted the presence of LBP in patients with clinically diagnosed AD, but was not associated with increased LBP burden in the medulla. Severity of ADNC, but not LBP, was associated with cerebral atrophy. DISCUSSION: Clinical presentation of patients with AD/LBP differs from patients with pure ADNC or LBP. Autonomic dysfunction is a useful marker of otherwise unsuspected LBP.

Detailed neuropathologic report of COVID-19 complicated by large intracerebral hemorrhage and periventricular lesions with macrophagic infiltrates.

Infection with the SARS-CoV-2 virus affects a wide range of systems. Significant involvement of the central nervous system has been described, including ischemic and hemorrhagic strokes. Thus far, neuropathologic reports of patients who passed away from COVID-19 have generally described non-specific findings, such as variable reactive gliosis and meningeal chronic inflammatory infiltrates, as well as the consequences of the infection's systemic complications on the brain, including ischemic infarcts and hypoxic/ischemic encephalopathy. The neuropathological changes in patients with COVID-19 and large hemorrhagic strokes have not been described in detail. We report the case of an elderly male who had a long course of COVID-19 and ultimately passed away from a large intracerebral hemorrhage. In addition to acute hemorrhage, neuropathologic examination demonstrated non-specific reactive changes and chronic periventricular lesions with macrophagic and perivascular lymphocytic infiltrates without evidence of demyelination or presence of SARS-CoV-2 by PCR test. This manuscript expands the spectrum of reported neuropathological changes in patients with COVID-19.

Amyloid Beta Immunoreactivity in the Retinal Ganglion Cell Layer of the Alzheimer's Eye.

Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for 60-70% of all dementias. AD is often under-diagnosed and recognized only at a later, more advanced stage, and this delay in diagnosis has been suggested as a contributing factor in the numerous unsuccessful AD treatment trials. Although there is no known cure for AD, early diagnosis is important for disease management and care. A hallmark of AD is the deposition of amyloid-ß (Aß)-containing senile neuritic plaques and neurofibrillary tangles composed of hyperphosporylated tau in the brain. However, current in vivo methods to quantify Aß in the brain are invasive, requiring radioactive tracers and positron emission tomography. Toward development of alternative methods to assess AD progression, we focus on the retinal manifestation of AD pathology. The retina is an extension of the central nervous system uniquely accessible to light-based, non-invasive ophthalmic imaging. However, earlier studies in human retina indicate that the literature is divided on the presence of Aß in the AD retina. To help resolve this disparity, this study assessed retinal tissues from neuropathologically confirmed AD cases to determine the regional distribution of Aß in retinal wholemounts and to inform on future retinal image studies targeting Aß. Concurrent post-mortem brain tissues were also collected. Neuropathological cortical assessments including neuritic plaque (NP) scores and cerebral amyloid angiopathy (CAA) were correlated with retinal Aß using immunohistochemistry, confocal microscopy, and quantitative image analysis. Aß load was compared between AD and control (non-AD) eyes. Our results indicate that levels of intracellular and extracellular Aß retinal deposits were significantly higher in AD than controls. Mid-peripheral Aß levels were greater than central retina in both AD and control eyes. In AD retina, higher intracellular Aß was associated with lower NP score, while higher extracellular Aß was associated with higher CAA score. Our data support the feasibility of using the retinal tissue to assess ocular Aß as a surrogate measure of Aß in the brain of individuals with AD. Specifically, mid-peripheral retina possesses more Aß deposition than central retina, and thus may be the optimal location for future in vivo ocular imaging.

Expanding the Phenotype of Frontotemporal Lobar Degeneration With FUS-Positive Pathology (FTLD-FUS).

Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is an uncommon cause of frontotemporal dementia characterized by fused in sarcoma-positive inclusions. It is classified as a subtype of frontotemporal lobar degeneration with FUS pathology. Cases with aFTLD-U pathology typically display an early onset of symptoms and severe psychobehavioral changes in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. This phenotype is regarded as being sufficiently unusual and consistent as to allow antemortem diagnosis with a high degree of accuracy. In this report, we describe 2 cases with aFTLD-U pathology that broaden the associated phenotype to include later age of onset, milder behavioral abnormalities and early memory and language impairment.

Clinicopathologic correlations in a family with a TBK1 mutation presenting as primary progressive aphasia and primary lateral sclerosis.

Mutations in the TANK binding kinase 1 gene (TBK1) are associated with amyotrophic lateral sclerosis and/or frontotemporal dementia; however, the range of clinical phenotypes and neuropathological changes associated with these mutations have not yet been completely elucidated. We present the detailed clinical, neuroimaging, and neuropathological features of two brothers carrying the TBK1 p.Gly272_Thr331del mutation. Both presented with very similar and unusual clinical features including primary progressive aphasia and asymmetric-onset primary lateral sclerosis (PLS). Repeated electrophysiological studies failed to reveal any lower motor neuron involvement. Neuropathological evaluation of both cases revealed frontotemporal lobar degeneration with TDP-43 proteinopathy type B and selective involvement of upper motor neurons with TDP-43 inclusions. The stereotypical clinical presentation and neuropathological findings in these cases widen the phenotypic spectrum of TBK1 mutations and provide insights into the pathogenesis of PLS.

Drusen in the Peripheral Retina of the Alzheimer's Eye.

BACKGROUND: Recent work on Alzheimer's disease (AD) diagnosis focuses on neuroimaging modalities; however, these methods are expensive, invasive, and not available to all patients. Ocular imaging of biomarkers, such as drusen in the peripheral retina, could provide an alternative method to diagnose AD. OBJECTIVE: This study compares macular and peripheral drusen load in control and AD eyes. METHODS: Postmortem eye tissues were obtained from donors with a neuropathological diagnosis of AD. Retina from normal donors were processed and categorized into younger (<55 years) and older (>55 years) groups. After fixation and dissection, 3-6 mm punches of RPE/choroid were taken in macular and peripheral (temporal, superior, and inferior) retinal regions. Oil red O positive drusen were counted and grouped into two size categories: small (<63 µm) and intermediate (63-125 µm). RESULTS: There was a significant increase in the total number of macular and peripheral hard drusen in older, compared to younger, normal eyes (p<0.05). Intermediate hard drusen were more commonly found in the temporal region of AD eyes compared to older normal eyes, even after controlling for age (p<0.05). Among the brain and eye tissues from AD donors, there was a significant relationship between cerebral amyloid angiopathy (CAA) severity and number of temporal intermediate hard drusen (r=0.78, p<0.05). CONCLUSION: Imaging temporal drusen in the eye may have benefit for diagnosing and monitoring progression of AD. Our results on CAA severity and temporal intermediate drusen in the AD eye are novel. Future studies are needed to further understand the interactions among CAA and drusen formation.

Clinical and neuropathological features of ALS/FTD with TIA1 mutations.

Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10-6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.

How to Screen for Hereditary Cancers in General Pathology Practice.

CONTEXT: -As a pathologist, an awareness of the particular diagnoses that can serve as "sentinels" for an underlying genetic syndrome can be incredibly beneficial to patients and their families. This is a complex and ever-changing field of medicine, where remaining up to date with diagnostic and treatment options is challenging. Simply raising the possibility of an underlying syndrome may not, in itself, be diagnostic; however, this may present an opportunity for genetic assessment, and possibly early intervention or primary prevention of disease in the kindred. In the last decade, immunohistochemistry has emerged as a useful tool in hereditary cancer screening. This is best exemplified by the use of mismatch repair immunohistochemistry as a screening tool in colorectal and endometrioid carcinomas. Reflex testing of all tumors for deficiencies in these proteins is now resulting in superior identification and treatment of Lynch-associated cancers, and families harboring these syndromes. Despite the success and potential value of immunohistochemistry as a genetic screening tool, hematoxylin-eosin morphology remains a valuable tool for hereditary cancer screening and is the focus of this article. OBJECTIVE: -To highlight the utility of hematoxylin-eosin morphology as a valuable tool for hereditary cancer screening. DATA SOURCES: -Primary literature review with PubMed. CONCLUSIONS: -Recognition of tumors associated with cancer predisposition may identify individuals and families at high risk for cancer and may also have peridiagnostic utility with regard to implications for targeted therapy.

LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice.

A key step in plasma HDL maturation from discoidal to spherical particles is the esterification of cholesterol to cholesteryl ester, which is catalyzed by LCAT. HDL-like lipoproteins in cerebrospinal fluid (CSF) are also spherical, whereas nascent lipoprotein particles secreted from astrocytes are discoidal, suggesting that LCAT may play a similar role in the CNS. In plasma, apoA-I is the main LCAT activator, while in the CNS, it is believed to be apoE. apoE is directly involved in the pathological progression of Alzheimer's disease, including facilitating ß-amyloid (Aß) clearance from the brain, a function that requires its lipidation by ABCA1. However, whether apoE particle maturation by LCAT is also required for Aß clearance is unknown. Here we characterized the impact of LCAT deficiency on CNS lipoprotein metabolism and amyloid pathology. Deletion of LCAT from APP/PS1 mice resulted in a pronounced decrease of apoA-I in plasma that was paralleled by decreased apoA-I levels in CSF and brain tissue, whereas apoE levels were unaffected. Furthermore, LCAT deficiency did not increase Aß or amyloid in APP/PS1 LCAT(-/-) mice. Finally, LCAT expression and plasma activity were unaffected by age or the onset of Alzheimer's-like pathology in APP/PS1 mice. Taken together, these results suggest that apoE-containing discoidal HDLs do not require LCAT-dependent maturation to mediate efficient Aß clearance.