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

Lower locus coeruleus integrity in older COVID-19 survivors: initial findings from an international 7T MRI consortium

Background: The SARS-CoV-2 coronavirus has been associated with structural brain changes, consistent with its neurological manifestations. Recent studies showed a specific predilection for brainstem glial activation and hypometabolism, possibly indicating involvement of the locus coeruleus. The locus coeruleus (LC) modulates many cognitive functions and behaviors and its norepinephrine projections regulate both immune responses and vascular reactivity. We aimed to examine differences in LC integrity between COVID-19 survivors and controls. Method: Participants are enrolled across 3 US and 1 UK sites using harmonized cognitive and 7T MR-imaging protocols. Here, we analyzed data from 18 participants enrolled at Houston Methodist (12 COVID-19 survivors, 6 controls; Figure 1). COVID-19 survivors were required to have had a positive antigen test and an illness syndrome consistent with COVID-19. Healthy controls were required to have no significant pre-existing medical, neurologic, or psychiatric illness and no illness requiring hospitalization in the last 2 years. LC imaging was performed using a dedicated 7T MT-TFL sequence (0.4 x 0.4 x0.5mm). A site-specific normalized template was constructed using ANTs/FSL. The entire average LC integrity as well as voxel-wise integrity values were compared between COVID-19 survivors and controls using a robust linear regression (age-controlled and threshold free cluster enhancement corrected). LC integrity was correlated with age, sex, ethnicity and cognition using Spearman’s rank correlation. Result: Average LC integrity was not correlated with age, sex, or Hispanic ethnicity (p\u3e0.3). COVID-19 survivors did not differ from Controls when examining the entire LC (p=0.54). Voxel-wise analyses revealed a small cluster (19 voxels) in the middle portion of the left LC where COVID-19 survivors exhibited lower LC integrity than controls (p=0.005; Figure 2). Integrity of this cluster was not related to age or Hispanic ethnicity (p=0.9). LC integrity did not correlate with cognitive performance within the COVID-19 survivors (Trail Making Test B: p=0.43; Craft Story delayed recall p=0.47; MoCA p=0.84). Conclusion: Consistent with previous animal and human studies, our initial findings provide evidence for neuroinvasive potential of SARS-CoV-2 localized in the middle LC. In the future, we aim to expand our sample and link these observations to the neurocognitive sequelae of COVID-19

Preliminary neurocognitive finding from a multi-site study investing long-term neurological impact of COVID-19 using ultra-high field 7 Tesla MRI-based neuroimaging

Background: Globally, over six hundred million cases of SARS-CoV-2 have been confirmed. As the number of individuals in recovery rises, examining long-term neurological effects, including cognitive impairment and cerebral microstructural and microvascular changes, has become paramount., We present preliminary cognitive findings from an ongoing multi-site study investigating the long-term neurological impacts of COVID-19 using 7 Tesla MRI-based neuroimaging. Methods: Across 3 US and 1 UK sites, we identified adult (\u3e=18) COVID-19 survivors (CS) and healthy controls (HC) without significant pre-existing medical, neurological, or psychiatric illness. Using the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS-3) battery and Norms Calculator, 12 cognitive scores were adjusted for age, sex, and education and classified as either unimpaired or mild (\u3c9th percentile), moderate (\u3c2nd percentile), or severely impaired (\u3c1st percentile). The observed frequency of impairment across the two groups is reported along with proportional differences (PD) and confidence intervals (CI). Illness severity and time since infection were evaluated as potential associates of cognitive impairment. Results: Over a period of 11 months, we enrolled 108 participants. At the time of reporting, 80 (46.3% female; mean age: 60.3 ± 8.6; 61 CS, 19 HC) had completed cognitive assessments. Of the participants for whom we ascertained time since symptom onset and illness severity (n=51 and 43, respectively), 31.4% had their index COVID-19 infection within the past year, and 60.5% had a severe to critical infection (Table 1). Table 2 reports observed frequency of impairment for each metric. Aggregating all 12 cognitive metrics, we found 45 (73.8%) of CS had at least one impairment [vs HC: 10 (52.6%)]. A significantly greater proportion of CS had at least one moderate to severe or severe impairment (Figure 1). CS also had significantly higher frequencies of presenting with two or more mild to severe impairments [PD 0.33 (0.13, 0.54)]. Illness severity and time since infection were not significantly associated with cognitive impairment. Conclusion: Our preliminary results are consistent with potentially sustained COVID-associated cognitive impairment in a subset of participants. Enrollment in the multi-site cohort is ongoing, and updated results will be presented along with ultra-high field MRI-based neuroimaging correlates

Microlensing by natural wormholes: theory and simulations

We provide an in depth study of the theoretical peculiarities that arise in effective negative mass lensing, both for the case of a point mass lens and source, and for extended source situations. We describe novel observational signatures arising in the case of a source lensed by a negative mass. We show that a negative mass lens produces total or partial eclipse of the source in the umbra region and also show that the usual Shapiro time delay is replaced with an equivalent time gain. We describe these features both theoretically, as well as through numerical simulations. We provide negative mass microlensing simulations for various intensity profiles and discuss the differences between them. The light curves for microlensing events are presented and contrasted with those due to lensing produced by normal matter. Presence or absence of these features in the observed microlensing events can shed light on the existence of natural wormholes in the Universe.Comment: 16 pages, 24 postscript figures (3 coloured), revtex style, submitted to Phys. Rev.

Hypothalamic Inhibition Of Acetyl-coa Carboxylase Stimulates Hepatic Counter-regulatory Response Independent Of Ampk Activation In Rats.

Hypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose homeostasis, and fatty acid biosynthesis. Intrahypothalamic fatty acid injection is known to suppress liver glucose production, mainly by activation of hypothalamic ATP-sensitive potassium (K(ATP)) channels. Since all models employed seem to involve malonyl-CoA biosynthesis, we hypothesized that acetyl-CoA carboxylase can modulate the counter-regulatory response independent of nutrient availability. In this study employing immunoblot, real-time PCR, ELISA, and biochemical measurements, we showed that reduction of the hypothalamic expression of acetyl-CoA carboxylase by antisense oligonucleotide after intraventricular injection increased food intake and NPY mRNA, and diminished the expression of CART, CRH, and TRH mRNA. Additionally, as in fasted rats, in antisense oligonucleotide-treated rats, serum glucagon and ketone bodies increased, while the levels of serum insulin and hepatic glycogen diminished. The reduction of hypothalamic acetyl-CoA carboxylase also increased PEPCK expression, AMPK phosphorylation, and glucose production in the liver. Interestingly, these effects were observed without modification of hypothalamic AMPK phosphorylation. Hypothalamic ACC inhibition can activate hepatic counter-regulatory response independent of hypothalamic AMPK activation.8e6266

Canine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from \u3cem\u3eRPE65\u3c/em\u3e Mutation

Background RPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans with LCA due to RPE65 mutations (RPE65-LCA). Methods and Findings RPE65-mutant dogs were studied with fMRI. Prior to therapy, retinal and subcortical responses to light were markedly diminished, and there were minimal cortical responses within the primary visual areas of the lateral gyrus (activation amplitude mean ± standard deviation [SD] = 0.07% ± 0.06% and volume = 1.3 ± 0.6 cm3). Following therapy, retinal and subcortical response restoration was accompanied by increased amplitude (0.18% ± 0.06%) and volume (8.2 ± 0.8 cm3) of activation within the lateral gyrus (p \u3c 0.005 for both). Cortical recovery occurred rapidly (within a month of treatment) and was persistent (as long as 2.5 y after treatment). Recovery was present even when treatment was provided as late as 1–4 y of age. Human RPE65-LCA patients (ages 18–23 y) were studied with structural magnetic resonance imaging. Optic nerve diameter (3.2 ± 0.5 mm) was within the normal range (3.2 ± 0.3 mm), and occipital cortical white matter density as judged by voxel-based morphometry was slightly but significantly altered (1.3 SD below control average, p = 0.005). Functional magnetic resonance imaging in human RPE65-LCA patients revealed cortical responses with a markedly diminished activation volume (8.8 ± 1.2 cm3) compared to controls (29.7 ± 8.3 cm3, p \u3c 0.001) when stimulated with lower intensity light. Unexpectedly, cortical response volume (41.2 ± 11.1 cm3) was comparable to normal (48.8 ± 3.1 cm3, p = 0.2) with higher intensity light stimulation. Conclusions Visual cortical responses dramatically improve after retinal gene therapy in the canine model of RPE65-LCA. Human RPE65-LCA patients have preserved visual pathway anatomy and detectable cortical activation despite limited visual experience. Taken together, the results support the potential for human visual benefit from retinal therapies currently being aimed at restoring vision to the congenitally blind with genetic retinal disease

Might some gamma ray bursts be an observable signature of natural wormholes?

The extragalactic microlensing scenario for natural wormholes is examined. It is shown that the main features of wormhole lensing events upon the light of distant Active Galactic Nuclei (AGNs) are similar to some types of already observed Gamma Ray Bursts (GRBs). Using recent satellite data on GRBs, an upper limit to the negative mass density -- ${\cal O} (10^{-36})$ g cm$^{-3}$ -- under the form of wormhole-like objects is presented.Comment: extended version, additions on GRB physics, background sources and cosmological consequences. Two ps figures. Accpeted for publication in Phys. Rev.

Canine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation

The study by Samuel Jacobson and colleagues suggests that retinal gene therapy can improve retinal, visual pathway, and visual cortex responses to light stimulation, even after prolonged periods of blindness and in congenitally blind patients

What does aducanumab treatment of Alzheimer's disease mean for research on vascular cognitive disorders?

Non peer reviewe