Entorhinal vessel density correlates with phosphorylated tau and TDP-43 pathology.

INTRODUCTION: The entorhinal cortex (EC) and perirhinal cortex (PC) are vulnerable to Alzheimer's disease. A triggering factor may be the interaction of vascular dysfunction and tau pathology. METHODS: We imaged post mortem human tissue at 100 µm3 with 7 T magnetic resonance imaging and manually labeled individual blood vessels (mean = 270 slices/case). Vessel density was quantified and compared per EC subfield, between EC and PC, and in relation to tau and TAR DNA-binding protein 43 (TDP-43) semiquantitative scores. RESULTS: PC was more vascularized than EC and vessel densities were higher in posterior EC subfields. Tau and TDP-43 strongly correlated with vasculature density and subregions with severe tau at the preclinical stage had significantly greater vessel density than those with low tau burden. DISCUSSION: These data impact cerebrovascular maps, quantification of subfield vasculature, and correlation of vasculature and pathology at early stages. The ordered association of vessel density, and tau or TDP-43 pathology, may be exploited in a predictive context. HIGHLIGHTS: Vessel density correlates with phosphorylated tau (p-tau) burden in entorhinal and perirhinal cortices. Perirhinal area 35 and posterior entorhinal cortex showed greatest p-tau burden but also the highest vessel density in the preclinical phase of Alzheimer's disease. We combined an ex vivo magnetic resonance imaging model and histopathology to demonstrate the 3D reconstruction of intracortical vessels and its spatial relationship to the pathology.

Association between of vitamin B12 status during pregnancy and probable postpartum depression: the ECLIPSES study.

BACKGROUND: B12 vitamin is essential for the functioning of the nervous system and the production of mood-related neurotransmitters. However, information on its association with postpartum depression (PPD) is limited. OBJECTIVE: To examine the effect of serum vitamin B12 levels during pregnancy on PPD, in healthy pregnant women from the Mediterranean region of Catalonia, Spain. METHOD: This longitudinal study included a subsample of women at 54 days (7.7 weeks) postpartum (n = 336), who participated in the ECLIPSES Study conducted out in Tarragona, Spain. Maternal concentrations of vitamin B12 were determined in the first and third trimester of pregnancy and sociodemographic, nutritional, and psychological data were collected. PPD was assessed using the Edinburgh Postnatal Depression Scale (EPDS). RESULTS: The prevalence of probable PPD was 21%. After adjusting for sociodemographic, lifestyle, biochemical parameters, and postpartum characteristics the regression model showed a negative association between EPDS scores and the highest quartile of serum vitamin B12 (first quartile (reference) vs. fourth quartile), (ß = -1.267, 95% CI = -2.461, -0.073, p = 0.038). CONCLUSION: Maintaining a normal-high level of vitamin B12 during early pregnancy can contributes to preventing PPD.

Prenatal vitamin B12 status and cognitive functioning in children at 4 years of age: The ECLIPSES Study.

Maternal vitamin B12 deficiency has been associated with disturbed cognitive functioning in offspring at different ages during childhood. However, this association has not been explored in pre-school-age children. The objective of this study was to examine the association between maternal vitamin B12 levels at the beginning and end of pregnancy and cognitive functioning in their children at 4 years of age. This longitudinal prospective study included a subsample of pregnant women and their children aged 4 years (n = 249) who participated in the ECLIPSES Study conducted in the province of Tarragona, Spain, from 2013 to 2017. Maternal vitamin B12 concentrations were determined in the first and third trimesters, and sociodemographic, nutritional and psychological data were collected. The children's cognitive functioning was assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) and subtests of the Neuropsychological Assessment of Development (NEPSY-II). The multivariable models showed a significant relationship between vitamin B12 and the working memory index in the first trimester of the pregnancy but not in the third trimester. Children of mothers in the second vitamin B12 level tertile (314-413 pg/mL) (ß = 6.468, 95% confidence interval [CI]: = 2.054, 10.882, p = 0.004) and third vitamin B12 level tertile (≥414 pg/mL) (ß = 4.703, 95% CI: = 0.292, 9.114, p = 0.037) scored higher in the working memory index of the WPPSI-IV than the children of mothers with vitamin B12 levels in the first tertile (<314 pg/mL). Maintaining an adequate level of maternal vitamin B12 during early pregnancy contributes to improved performance in childhood working memory at 4 years of age.

Compact, portable, thermal-noise-limited optical cavity with low acceleration sensitivity.

We develop and demonstrate a compact (less than 6 mL) portable Fabry-Pérot optical reference cavity. A laser locked to the cavity is thermal noise limited at 2 × 10-14 fractional frequency stability. Broadband feedback control with an electro-optic modulator enables near thermal-noise-limited phase noise performance from 1 Hz to 10 kHz offset frequencies. The additional low vibration, temperature, and holding force sensitivity of our design makes it well suited for out-of-the-lab applications such as optically derived low noise microwave generation, compact and mobile optical atomic clocks, and environmental sensing through deployed fiber networks.

Temperature Effect on the Corrosion Inhibition of Carbon Steel by Polymeric Ionic Liquids in Acid Medium.

In the present research work, the temperature effect on the corrosion inhibition process of API 5L X60 steel in 1 M H2SO4 by employing three vinylimidazolium poly(ionic liquid)s (PILs) was studied by means of electrochemical techniques, surface analysis and computational simulation. The results revealed that the maximal inhibition efficiency (75%) was achieved by Poly[VIMC4][Im] at 308 K and 175 ppm. The PILs showed Ecorr displacements with respect to the blank from -14 mV to -31 mV, which revealed the behavior of mixed-type corrosion inhibitors (CIs). The steel micrographs, in the presence and absence of PILs, showed less surface damage in the presence of PILs, thus confirming their inhibiting effect. The computational studies of the molecular orbitals and molecular electrostatic potential of the monomers suggested that the formation of a protecting film could be mainly due to the nitrogen and oxygen heteroatoms present in each structure.

Gas Sensing and Half-Metallic Materials Design Using Metal Embedded into S Vacancies in WS2 Monolayers: Adsorption of NO, CO, and O2 Molecules.

The adsorption of CO, NO, and O2 molecules onto Cu, Ag, and Au atoms placed in the S vacancies of a WS2 monolayer was elucidated within dispersion-corrected density functional theory. The binding energies computed for embedded defects into S vacancies were 2.99 (AuS), 2.44 (AgS), 3.32 eV (CuS), 3.23 (Au2S2), 2.55 (Ag2S2), and 3.48 eV/atom (Cu2S2), respectively. The calculated diffusion energy barriers from an S vacancy to a nearby site for Cu, Ag, and Au were 2.29, 2.18, and 2.16 eV, respectively. Thus, the substitutional atoms remained firmly fixed at temperatures above 700 K. Similarly, the adsorption energies showed that nitric oxide and carbon oxide molecules exhibited stronger chemisorption than O2 molecules on any of the metal atoms (Au, Cu, or Ag) placed in the S vacancies of the WS2 monolayer. Therefore, the adsorption of O2 did not compete with NO or CO adsorption and did not displace them. The density of states showed that a WS2 monolayer modified with a Cu, Au, or Ag atom could be used to design sensing devices, based on electronic or magnetic properties, for atmospheric pollutants. More interestingly, the adsorption of CO changed only the electronic properties of the MoS2-AuS monolayer, which could be used for sensing applications. In contrast, the O2 molecule was chemisorbed more strongly than CO or NO on Au2S2, Cu2S2, or Ag2S2 placed into di-S vacancies. Thus, if the experimental system is exposed to air, the low quantities of O2 molecules present should result in the oxidation of the metallic atoms. Furthermore, the O2 molecules adsorbed on WS2-Au2S2 and WS2-CuS introduced a half-metallic behavior, making the system suitable for applications in spintronics.

Substitutional Coinage Metals as Promising Defects for Adsorption and Detection of Gases on MoS2 Monolayers: A Computational Approach.

Defective molybdenum disulfide (MoS2) monolayers (MLs) modified with coinage metal atoms (Cu, Ag and Au) embedded in sulfur vacancies are studied at a dispersion-corrected density functional level. Atmospheric constituents (H2, O2 and N2) and air pollutants (CO and NO), known as secondary greenhouse gases, are adsorbed on up to two atoms embedded into sulfur vacancies in MoS2 MLs. The adsorption energies suggest that the NO (1.44 eV) and CO (1.24 eV) are chemisorbed more strongly than O2 (1.07 eV) and N2 (0.66 eV) on the ML with a cooper atom substituting for a sulfur atom. Therefore, the adsorption of N2 and O2 does not compete with NO or CO adsorption. Besides, NO adsorbed on embedded Cu creates a new level in the band gap. In addition, it was found that the CO molecule could directly react with the pre-adsorbed O2 molecule on a Cu atom, forming the complex OOCO, via the Eley-Rideal reaction mechanism. The adsorption energies of CO, NO and O2 on Au2S2, Cu2S2 and Ag2S2 embedded into two sulfur vacancies were competitive. Charge transference occurs from the defective MoS2 ML to the adsorbed molecules, oxidizing the later ones (NO, CO and O2) since they act as acceptors. The total and projected density of states reveal that a MoS2 ML modified with copper, gold and silver dimers could be used to design electronic or magnetic devices for sensing applications in the adsorption of NO, CO and O2 molecules. Moreover, NO and O2 molecules adsorbed on MoS2-Au2s2 and MoS2-Cu2s2 introduce a transition from metallic to half-metallic behavior for applications in spintronics. These modified monolayers are expected to exhibit chemiresistive behavior, meaning their electrical resistance changes in response to the presence of NO molecules. This property makes them suitable for detecting and measuring NO concentrations. Also, modified materials with half-metal behavior could be beneficial for spintronic devices, particularly those that require spin-polarized currents.

A Network Analysis of Executive Functions in Children and Adolescents With and Without Attention-Deficit/Hyperactivity Disorder.

This study applied network analysis to executive function test performances to examine differences in network parameters between demographically matched children and adolescents with and without attention-deficit/hyperactivity disorder (ADHD) (n = 141 per group; M = 12.7 ± 2.9 years-old; 72.3% boys, 66.7% White, 65.2% ≥ 12 years maternal education). All participants completed the NIH Toolbox Cognition Battery, including the Flanker, measuring inhibition, Dimensional Change Card Sort, measuring shifting, and List Sorting test, measuring working memory. Children with and without ADHD had comparable mean test performances (d range: .05-0.11) but presented with differences in network parameters. Among participants with ADHD, shifting was less central, had a weaker relationship with inhibition, and did not mediate the relationship between inhibition and working memory. These network characteristics were consistent with the executive function network structure of younger ages in prior research and may reflect an immature executive function network among children and adolescents with ADHD, aligning with the delayed maturation hypothesis.

Neuromuscular Mechanosensitivity in Subjects with Chronic Ankle Sprain: A Cross-Sectional Study.

BACKGROUND: Ankle sprain is one of the most common musculoskeletal injuries in sports, at work, and at home. Subjects who suffer from this injury may develop ankle instability. Functional instability has been associated with a high rate of resprain and impaired neuromuscular control in patients with ankle instability. OBJECTIVE: Measurement of neural and muscular mechanosensitivity after ankle sprain injury and establishment of the relationship between these variables. METHODS: A cross-sectional case-control study was performed with a sample of 58 students from Alcalá de Henares University (21 males and 37 females, mean age ± SD = 21 ± 3.7 years). Subjects were divided into two groups: a case group (N = 29, subjects with unstable ankle) and a control group (N = 29, healthy subjects). The pressure pain threshold (PPT) of the tibialis anterior, peroneus longus, and peroneus brevis muscles and mechanosensitivity of the common peroneus and tibial nerves were evaluated in all subjects through a manual mechanical algometer. RESULTS: Neuromuscular PPTs showed significant differences (P < 0.05) between both groups, such that, compared with the control group, the case group exhibited significantly lower PPT levels. In the case group, a strong positive correlation was observed between neural and muscular homolateral mechanosensitivity in both lower limbs. CONCLUSIONS: Participants with chronic ankle instability showed higher neuromuscular mechanosensitivity in muscles and nerves surrounding the ankle joint than healthy subjects. These findings indicate that low PPT values may be associated with symptoms that characterize this disease.

Doppler Cooling Trapped Ions with a UV Frequency Comb.

We demonstrate Doppler cooling of trapped magnesium ions using a frequency comb at 280 nm obtained from a frequency tripled Ti:sapphire laser. A comb line cools on the 3s_{1/2}-3p_{3/2} transition, while the nearest blue-detuned comb line contributes negligible heating. We observe the cooling-heating transition and long-term cooling of ion chains with several sympathetically cooled ions. Spatial thermometry shows that the ion is cooled to near the Doppler limit. Doppler cooling with frequency combs has the potential to open many additional atomic species to laser cooling by reaching further into the vacuum and extreme ultraviolet via high-harmonic generation and by providing a broad bandwidth from which multiple excitation sidebands can be obtained.

The Six-Transmembrane Enzyme GDE2 Is Required for the Release of Molecularly Distinct Small Extracellular Vesicles from Neurons.

Extracellular vesicles (EVs) are implicated in a multitude of physiological and pathophysiological processes in the nervous system; however, their biogenesis and cargoes are not well defined. Glycerophosphodiester Phosphodiesterase 2 (GDE2 or GDPD5) is a six-transmembrane protein that cleaves the Glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane and has important roles in neurodevelopment and disease-relevant pathways of neuronal survival. We show here that GDE2 regulates the number of small EVs (sEVs) released from the cell surface of neurons via its GPI-anchor cleavage activity and contributes to the loading of protein cargo through enzymatic and non-enzymatic mechanisms. Proteomic profiling reveals that GDE2 releases at least two distinct EV populations, one containing GDE2 itself and the other harboring the putative ectosomal markers CD9 and BSG. sEVs released by GDE2 are enriched in cytoskeletal and actin-remodeling proteins, suggesting a potential mechanism for GDE2-dependent EV release. Further, sEV populations released by GDE2 are enriched in proteins responsible for modulating synaptic activity and proteins that are critical for cellular redox homeostasis. These studies identify GDE2 as a novel regulator of molecularly distinct sEV populations from neurons with potential roles in the synaptic and redox pathways required for neuronal function and survival.

Large-scale RNA-seq mining reveals ciclopirox triggers TDP-43 cryptic exons.

Nuclear clearance and cytoplasmic aggregation of TDP-43 in neurons, initially identified in ALS-FTD, are hallmark pathological features observed across a spectrum of neurodegenerative diseases. We previously found that TDP-43 loss-of-function leads to the transcriptome-wide inclusion of deleterious cryptic exons in brains and biofluids post-mortem as well as during the presymptomatic stage of ALS-FTD, but upstream mechanisms that lead to TDP-43 dysregulation remain unclear. Here, we developed a web-based resource (SnapMine) to determine the levels of TDP-43 cryptic exon inclusion across hundreds of thousands of publicly available RNA sequencing datasets. We established cryptic exon inclusion across a variety of human cells and tissues to provide ground truth references for future studies on TDP-43 dysregulation. We then explored studies that were entirely unrelated to TDP-43 or neurodegeneration and found that ciclopirox olamine (CPX), an FDA-approved antifungal, can trigger the inclusion of TDP-43-associated cryptic exons in a variety of mouse and human primary cells. CPX induction of cryptic exon occurs via heavy metal toxicity and oxidative stress, suggesting that similar vulnerabilities could play a role in neurodegeneration. Our work demonstrates how diverse datasets can be linked through common biological features and underscores that public archives of sequencing data represent a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases.

Neuron collinearity differentiates human hippocampal subregions: a validated deep learning approach.

The hippocampus is heterogeneous in its architecture. It contributes to cognitive processes such as memory and spatial navigation and is susceptible to neurodegenerative disease. Cytoarchitectural features such as neuron size and neuronal collinearity have been used to parcellate the hippocampal subregions. Moreover, pyramidal neuron orientation (orientation of one individual neuron) and collinearity (how neurons align) have been investigated as a measure of disease in schizophrenia. However, a comprehensive quantitative study of pyramidal neuron orientation and collinearity within the hippocampal subregions has not yet been conducted. In this study, we present a high-throughput deep learning approach for the automated extraction of pyramidal neuron orientation in the hippocampal subregions. Based on the pretrained Cellpose algorithm for cellular segmentation, we measured 479 873 pyramidal neurons in 168 hippocampal partitions. We corrected the neuron orientation estimates to account for the curvature of the hippocampus and generated collinearity measures suitable for inter- and intra-individual comparisons. Our deep learning results were validated with manual orientation assessment. This study presents a quantitative metric of pyramidal neuron collinearity within the hippocampus. It reveals significant differences among the individual hippocampal subregions (P  < 0.001), with cornu ammonis 3 being the most collinear, followed by cornu ammonis 2, cornu ammonis 1, the medial/uncal subregions and subiculum. Our data establishes pyramidal neuron collinearity as a quantitative parameter for hippocampal subregion segmentation, including the differentiation of cornu ammonis 2 and cornu ammonis 3. This novel deep learning approach could facilitate large-scale multicentric analyses in subregion parcellation and lays groundwork for the investigation of mental illnesses at the cellular level.

Frequency stability of a 10 GHz optical frequency comb from a semiconductor-based mode-locked laser with an intracavity 10,000 finesse etalon.

An optical frequency comb is constructed using a semiconductor gain medium with a fiber-coupled external cavity and stabilized to an intracavity 10,000 finesse etalon, which is temperature stabilized and held in a vacuum chamber at 10(-6) Torr. Optical frequency stability measurements show that the comb has a reduced sensitivity to environmental fluctuations. An upper limit on the optical frequency variation of 100 kHz over >12 min of continuous operation is measured using a real-time spectrum analyzer. This measurement is limited by the linewidth of the reference source, and further measurements with a frequency counter show a fractional deviation of 2×10(-11) at 50 ms. Furthermore, out-of-band ASE rejection is shown to be >36 dB, a tenfold improvement over that of a laser with a 1000 finesse FPE.

Heterogeneous heterogeneity by default: Testing categorical moderators in mixed-effects meta-analysis.

Categorical moderators are often included in mixed-effects meta-analysis to explain heterogeneity in effect sizes. An assumption in tests of categorical moderator effects is that of a constant between-study variance across all levels of the moderator. Although it rarely receives serious thought, there can be statistical ramifications to upholding this assumption. We propose that researchers should instead default to assuming unequal between-study variances when analysing categorical moderators. To achieve this, we suggest using a mixed-effects location-scale model (MELSM) to allow group-specific estimates for the between-study variance. In two extensive simulation studies, we show that in terms of Type I error and statistical power, little is lost by using the MELSM for moderator tests, but there can be serious costs when an equal variance mixed-effects model (MEM) is used. Most notably, in scenarios with balanced sample sizes or equal between-study variance, the Type I error and power rates are nearly identical between the MEM and the MELSM. On the other hand, with imbalanced sample sizes and unequal variances, the Type I error rate under the MEM can be grossly inflated or overly conservative, whereas the MELSM does comparatively well in controlling the Type I error across the majority of cases. A notable exception where the MELSM did not clearly outperform the MEM was in the case of few studies (e.g., 5). With respect to power, the MELSM had similar or higher power than the MEM in conditions where the latter produced non-inflated Type 1 error rates. Together, our results support the idea that assuming unequal between-study variances is preferred as a default strategy when testing categorical moderators.

Development of a Mobile App to Increase the Uptake of HIV Pre-exposure Prophylaxis Among Latino Sexual Minority Men: Qualitative Needs Assessment.

BACKGROUND: HIV disproportionally impacts Latino sexual minority men (SMM). Uptake of pre-exposure prophylaxis (PrEP), an effective biomedical intervention to prevent HIV, is low in this group compared with White SMM. Mobile health technology represents an innovative strategy to increase PrEP uptake among Latino SMM. OBJECTIVE: We aimed to describe the qualitative process leading to the development of SaludFindr, a comprehensive HIV prevention mobile app aiming to increase PrEP uptake, HIV testing, and condom use by Latino SMM. METHODS: We conducted 13 in-depth interviews with Latino SMM living in the Atlanta area to explore their main barriers and facilitators to PrEP uptake and to analyze their opinions of potential SaludFindr app functionalities. To explore potential app functions, we used HealthMindr, an existing HIV prevention app, as a template and added new proposed features intended to address the specific community needs. RESULTS: We identified general PrEP uptake barriers that, although common among non-Latino groups, had added complexities such as the influence of religion and family on stigma. Low perceived PrEP eligibility, intersectional stigma, lack of insurance, cost concerns, and misconceptions about PrEP side effects were described as general barriers. We also identified Latino-specific barriers that predominantly hinder access to existing services, including a scarcity of PrEP clinics that are prepared to provide culturally concordant services, limited availability of Spanish language information related to PrEP access, distrust of peers as credible sources of information, perceived ineligibility for low-cost services owing to undocumented status, fear of immigration authorities, and competing work obligations that prevent PrEP clinic attendance. Health care providers represented a trusted source of information, and 3 provider characteristics were identified as PrEP facilitators: familiarity with prescribing PrEP; being Latino; and being part of lesbian, gay, bisexual, transgender, queer, intersex, and asexual (LGBTQIA+) group or ally. The proposed app was very well accepted, with a particularly high interest in features that facilitate PrEP access, including a tailored list of clinics that meet the community needs and a private platform to seek PrEP information. Spanish language availability and free or low-cost PrEP care represented the 2 main clinic criteria that would facilitate PrEP uptake. Latino representation in clinic staff and providers; clinic perception as a safe space for undocumented patients; and LGBTQIA+ representation was listed as additional criteria. Only 8 of 47 clinics listed on the Centers for Diseases Control and Prevention PrEP locator website for the Atlanta area fulfilled at least 2 main criteria. CONCLUSIONS: This study provides further evidence of the substantial PrEP uptake barriers that Latino SMM face; exposes the urgent need to increase the number of accessible PrEP-providing clinics for Latino SMM; and proposes an innovative, community-driven, and mobile technology-based tool as a future intervention to overcome some of these barriers.

Making an Impact with E.M.P.A.C.T. Engage, Mentor Prepare, Advocate, Cultivate, and Teach: An Innovative Pilot Mentoring Program Evaluation for Students Underrepresented in Medicine.

Purpose: Medicine has yet to increase the representation of historically excluded persons in medicine to reflect the general population. The lack of support and guidance in the medical training of these individuals is a significant contributor to this disparity. The Engage, Mentor, Prepare, Advocate for, Cultivate, and Teach (EMPACT) Mentoring program was created to address this problem by providing support for learners who are historically underrepresented in medicine (URiM) as they progress through medical school. Methods: The EMPACT Pilot Program was formed and conducted during the 2019-2020 academic year. A total of 19 EMPACT mentorship groups were created, each consisting of two mentors and four medical student mentees. Additionally, four professional development workshops were held along with a final Wrap-up and Awards event. Pre and post pilot program surveys along with surveys after each workshop and focus groups were conducted with a random selection of program participants. Results: When compared to data from before and after the implementation of the EMPACT program, there were statistically significant differences (p < 0.05) in EMPACT mentees reporting they agree or strongly agree they felt ready to handle their clinical rotations (28% to 65%), felt the need to have an advocate (85% to 47%), possessed insight on day-to-day activities of an attending (26% to 56%) and felt a sense of community (79% to 94%). Mentors revealed an increase in their awareness of the concepts of microaggressions and imposter phenomenon. Finally, both groups felt an increase in their support system and sense of community at the school of medicine. Conclusion: Despite COVID-19 limitations, the EMPACT program met its goals. We effectively supported URiM medical students through mentorship, networking, and community.

Maternal Vitamin B12 Status during Pregnancy and Early Infant Neurodevelopment: The ECLIPSES Study.

In this prospective cohort study of 434 mother-infant pairs from the ECLIPSES study, we examine the association between maternal vitamin B12 status at the beginning and end of pregnancy and the neurodevelopmental outcomes of infants 40 days after birth in a pregnant population from a Mediterranean region of northern Spain. Maternal vitamin B12 concentrations were determined in the first and third trimesters, and sociodemographic, nutritional, and psychological data were collected. At 40 days postpartum, the Bayley Scales of Infant Development-III (BSID-III, cognitive, language, and motor skills) were administered to the infants and several obstetrical data were recorded. In the multivariable models, medium maternal first-trimester vitamin B12 levels (312 to 408 pg/mL, tertile 2) were associated with better neonatal performance in the motor, gross motor, language, and cognitive skills with respect to tertile 1 (<312 pg/mL). The probability of obtaining a neonatal motor, gross motor, and receptive language score >75th percentile was significantly higher also in the tertile 2 group. In summary, good maternal vitamin B12 status in the early stage of pregnancy appears to be associated with better infant motor, language, and cognitive performance at 40 days postpartum.

TDP-43 and tau concurrence in the entorhinal subfields in primary age-related tauopathy and preclinical Alzheimer's disease.

Phosphorylated tau (p-tau) pathology correlates strongly with cognitive decline and is a pathological hallmark of Alzheimer's Disease (AD). In recent years, phosphorylated transactive response DNA-binding protein (pTDP-43) has emerged as a common comorbidity, found in up to 70% of all AD cases (Josephs et al., Acta Neuropathol, 131(4), 571-585; Josephs, Whitwell, et al., Acta Neuropathol, 127(6), 811-824). Current staging schemes for pTDP-43 in AD and primary age-related tauopathy (PART) track its progression throughout the brain, but the distribution of pTDP-43 within the entorhinal cortex (EC) at the earliest stages has not been studied. Moreover, the exact nature of p-tau and pTDP-43 co-localization is debated. We investigated the selective vulnerability of the entorhinal subfields to phosphorylated pTDP-43 pathology in preclinical AD and PART postmortem tissue. Within the EC, posterior-lateral subfields showed the highest semi-quantitative pTDP-43 density scores, while the anterior-medial subfields had the lowest. On the rostrocaudal axis, pTDP-43 scores were higher posteriorly than anteriorly (p < 0.010), peaking at the posterior-most level (p < 0.050). Further, we showed the relationship between pTDP-43 and p-tau in these regions at pathology-positive but clinically silent stages. P-tau and pTDP-43 presented a similar pattern of affected subregions (p < 0.0001) but differed in density magnitude (p < 0.0001). P-tau burden was consistently higher than pTDP-43 at every anterior-posterior level and in most EC subfields. These findings highlight pTDP-43 burden heterogeneity within the EC and the posterior-lateral subfields as the most vulnerable regions within stage II of the current pTDP-43 staging schemes for AD and PART. The EC is a point of convergence for p-tau and pTDP-43 and identifying its most vulnerable neuronal populations will prove key for early diagnosis and disease intervention.

Pentad: A reproducible cytoarchitectonic protocol and its application to parcellation of the human hippocampus.

Introduction: The hippocampus is integral for learning and memory and is targeted by multiple diseases. Neuroimaging approaches frequently use hippocampal subfield volumes as a standard measure of neurodegeneration, thus making them an essential biomarker to study. Collectively, histologic parcellation studies contain various disagreements, discrepancies, and omissions. The present study aimed to advance the hippocampal subfield segmentation field by establishing the first histology based parcellation protocol, applied to n = 22 human hippocampal samples. Methods: The protocol focuses on five cellular traits observed in the pyramidal layer of the human hippocampus. We coin this approach the pentad protocol. The traits were: chromophilia, neuron size, packing density, clustering, and collinearity. Subfields included were CA1, CA2, CA3, CA4, prosubiculum, subiculum, presubiculum, parasubiculum, as well as the medial (uncal) subfields Subu, CA1u, CA2u, CA3u, and CA4u. We also establish nine distinct anterior-posterior levels of the hippocampus in the coronal plane to document rostrocaudal differences. Results: Applying the pentad protocol, we parcellated 13 subfields at nine levels in 22 samples. We found that CA1 had the smallest neurons, CA2 showed high neuronal clustering, and CA3 displayed the most collinear neurons of the CA fields. The border between presubiculum and subiculum was staircase shaped, and parasubiculum had larger neurons than presubiculum. We also demonstrate cytoarchitectural evidence that CA4 and prosubiculum exist as individual subfields. Discussion: This protocol is comprehensive, regimented and supplies a high number of samples, hippocampal subfields, and anterior-posterior coronal levels. The pentad protocol utilizes the gold standard approach for the human hippocampus subfield parcellation.