Medial and Lateral Entorhinal Cortex Differentially Excite Deep versus Superficial CA1 Pyramidal Neurons

Although hippocampal CA1 pyramidal neurons (PNs) were thought to comprise a uniform population, recent evidence supports two distinct sublayers along the radial axis, with deep neurons more likely to form place cells than superficial neurons. CA1 PNs also differ along the transverse axis with regard to direct inputs from entorhinal cortex (EC), with medial EC (MEC) providing spatial information to PNs toward CA2 (proximal CA1) and lateral EC (LEC) providing non-spatial information to PNs toward subiculum (distal CA1). We demonstrate that the two inputs differentially activate the radial sublayers and that this difference reverses along the transverse axis, with MEC preferentially targeting deep PNs in proximal CA1 and LEC preferentially exciting superficial PNs in distal CA1. This differential excitation reflects differences in dendritic spine numbers. Our results reveal a heterogeneity in EC-CA1 connectivity that may help explain differential roles of CA1 PNs in spatial and non-spatial learning and memory

Differential Axonal Projection of Mitral and Tufted Cells in the Mouse Main Olfactory System

In the past decade, much has been elucidated regarding the functional organization of the axonal connection of olfactory sensory neurons to olfactory bulb (OB) glomeruli. However, the manner in which projection neurons of the OB process odorant input and send this information to higher brain centers remains unclear. Here, we report long-range, large-scale tracing of the axonal projection patterns of OB neurons using two-photon microscopy. Tracer injection into a single glomerulus demonstrated widely distributed mitral/tufted cell axonal projections on the lateroventral surface of the mouse brain, including the anterior/posterior piriform cortex (PC) and olfactory tubercle (OT). We noted two distinct groups of labeled axons: PC-orienting axons and OT-orienting axons. Each group occupied distinct parts of the lateral olfactory tract. PC-orienting axons projected axon collaterals to a wide area of the PC but only a few collaterals to the OT. OT-orienting axons densely projected axon collaterals primarily to the anterolateral OT (alOT). Different colored dye injections into the superficial and deep portions of the OB external plexiform layer revealed that the PC-orienting axon populations originated in presumed mitral cells and the OT-orienting axons in presumed tufted cells. These data suggest that although mitral and tufted cells receive similar odor signals from a shared glomerulus, they process the odor information in different ways and send their output to different higher brain centers via the PC and alOT

Table_1_On gaps of clinical diagnosis of dementia subtypes: A study of Alzheimer’s disease and Lewy body disease.DOCX

IntroductionAlzheimer’s disease (AD) and Lewy body disease (LBD) are the two most common neurodegenerative dementias and can occur in combination (AD+LBD). Due to overlapping biomarkers and symptoms, clinical differentiation of these subtypes could be difficult. However, it is unclear how the magnitude of diagnostic uncertainty varies across dementia spectra and demographic variables. We aimed to compare clinical diagnosis and post-mortem autopsy-confirmed pathological results to assess the clinical subtype diagnosis quality across these factors.MethodsWe studied data of 1,920 participants recorded by the National Alzheimer’s Coordinating Center from 2005 to 2019. Selection criteria included autopsy-based neuropathological assessments for AD and LBD, and the initial visit with Clinical Dementia Rating (CDR) stage of normal, mild cognitive impairment, or mild dementia. Longitudinally, we analyzed the first visit at each subsequent CDR stage. This analysis included positive predictive values, specificity, sensitivity and false negative rates of clinical diagnosis, as well as disparities by sex, race, age, and education. If autopsy-confirmed AD and/or LBD was missed in the clinic, the alternative clinical diagnosis was analyzed.FindingsIn our findings, clinical diagnosis of AD+LBD had poor sensitivities. Over 61% of participants with autopsy-confirmed AD+LBD were diagnosed clinically as AD. Clinical diagnosis of AD had a low sensitivity at the early dementia stage and low specificities at all stages. Among participants diagnosed as AD in the clinic, over 32% had concurrent LBD neuropathology at autopsy. Among participants diagnosed as LBD, 32% to 54% revealed concurrent autopsy-confirmed AD pathology. When three subtypes were missed by clinicians, “No cognitive impairment” and “primary progressive aphasia or behavioral variant frontotemporal dementia” were the leading primary etiologic clinical diagnoses. With increasing dementia stages, the clinical diagnosis accuracy of black participants became significantly worse than other races, and diagnosis quality significantly improved for males but not females.DiscussionThese findings demonstrate that clinical diagnosis of AD, LBD, and AD+LBD are inaccurate and suffer from significant disparities on race and sex. They provide important implications for clinical management, anticipatory guidance, trial enrollment and applicability of potential therapies for AD, and promote research into better biomarker-based assessment of LBD pathology.</p

Improving measurement of blood-brain barrier permeability with reduced scan time using deep-learning-derived capillary input function

Purpose: In Dynamic contrast-enhanced MRI (DCE-MRI), Arterial Input Function (AIF) has been shown to be a significant contributor to uncertainty in the estimation of kinetic parameters. This study is to assess the feasibility of using a deep learning network to estimate local Capillary Input Function (CIF) to estimate blood-brain barrier (BBB) permeability, while reducing the required scan time. Materials and Method: A total of 13 healthy subjects (younger ( 67 y/o): 5) were recruited and underwent 25-min DCE-MRI scans. The 25 min data were retrospectively truncated to 10 min to simulate a reduced scan time of 10 min. A deep learning network was trained to predict the CIF using simulated tissue contrast dynamics with two vascular transport models. The BBB permeability (PS) was measured using 3 methods: (i) Ca-25min, using DCE-MRI data of 25 min with individually sampled AIF (Ca); (ii) Ca-10min, using truncated 10min data with AIF (Ca); and (iii) Cp-10min, using truncated 10 min data with CIF (Cp). The PS estimates from the Ca-25min method were used as reference standard values to assess the accuracy of the Ca-10min and Cp-10min methods in estimating the PS values. Results: When compared to the reference method(Ca-25min), the Ca-10min and Cp-10min methods resulted in an overestimation of PS by 217 ± 241 % and 48.0 ± 30.2 %, respectively. The Bland Altman analysis showed that the mean difference from the reference was 8.85 ± 1.78 (x10−4 min−1) with the Ca-10min, while it was reduced to 1.63 ± 2.25 (x10−4 min−1) with the Cp-10min, resulting in an average reduction of 81%. The limits of agreement also reduced by up to 39.2% with the Cp-10min. We found a 75% increase of BBB permeability in the gray matter and a 35% increase in the white matter, when comparing the older group to the younger group. Conclusions: We demonstrated the feasibility of estimating the capillary-level input functions using a deep learning network. We also showed that this method can be used to estimate subtle age-related changes in BBB permeability with reduced scan time, without compromising accuracy. Moreover, the trained deep learning network can automatically select CIF, reducing the potential uncertainty resulting from manual user-intervention

Cognitive Function among World Trade Center-Exposed Community Members with Mental Health Symptoms

The World Trade Center Environmental Health Center (WTC EHC), is a federally designated clinical center of excellence for surveillance and treatment of WTC disaster exposed community members (WTC Survivors). Cognitive impairment (CI) has been extensively described in WTC responders and a concern for progressive impairment in all WTC disaster exposed groups has been raised. Cognitive status, however, has not been systematically characterized in the WTC Survivor population. We describe cognitive status in a subgroup of the Survivor population referred for mental health evaluation (N = 480) in the WTC EHC as measured by scores on the Montreal Cognitive Assessment (MoCA) instrument, and examine their association with WTC exposures and individual-level covariates including PTSD and depression screening inventory scores. In regression analyses, probable cognitive impairment (MoCA score &lt; 26) was found in 59% of the study subjects and was significantly associated with age, race/ethnicity, education, income, depression and PTSD scores. Being caught in the dust cloud on 11 September 2011 was significantly associated with cognitive impairment even after controlling for the above. These data suggest an association with cognitive dysfunction in WTC Survivors with exposure to the toxic dust/fumes and psychological stress from the 9/11 terrorist attack and warrant further systematic study

Intracranial artery stenosis is associated with cortical thinning in stroke-free individuals of two longitudinal cohorts

We examined the association between asymptomatic intracranial artery stenosis (aICAS) and cortical thickness using brain magnetic resonance morphometry in two cohorts. This cross-sectional study included stroke-free participants from the Northern Manhattan Study (NOMAS) and the National Alzheimer's Coordinating Center (NACC). We represented the predictor aICAS in NOMAS as a continuous global stenosis score reflecting an overall burden of stenosis (possible range 0–44) assessed by magnetic resonance angiography and in NACC as a dichotomous autopsy-determined Circle of Willis (CoW) atherosclerosis (none-mild vs moderate-severe). The primary outcome of interest was total cortical thickness. We analyzed each dataset separately using multivariable linear regression. The analysis included 1209 NOMAS (46% had any stenosis, 5% had ≥70% stenosis of at least one vessel; stenosis score range 0–11) and 392 NACC (36% moderate-severe CoW atherosclerosis) participants. We found an inverse relationship between stenosis score and total cortical thickness (β-estimate [95% confidence interval (CI)]: −2.98 [−5.85, −0.11]) in adjusted models. We replicated these results in NACC (β-estimate [95% CI]: −0.06 [−0.11, −0.003]). Post-hoc, we segregated stenosis scores by location and only posterior circulation stenosis score was associated with total cortical thickness (anterior β-estimate [95% CI]: −0.90 [−5.16, 3.36], posterior β-estimate [95% CI]: −7.25 [−14.30, −0.20]). We found both radiographically and neuropathologically determined aICAS to be associated with global cortical thinning. Interestingly, posterior circulation stenoses appeared to drive this association with global cortical thinning, raising the possibility of pathophysiologic mechanisms for cortical thinning other than impaired hemodynamics. •Asymptomatic intracranial artery stenosis is associated with cortical thinning.•This relationship was independent of vascular risk factors and Alzheimer's disease•Posterior circulation stenoses drove the finding, implying non-hemodynamic cause