Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties.

Recent research with classic psychedelics suggests significant therapeutic potential, particularly for neuropsychiatric disorders. A mediating influence behind symptom resolution is thought to be the personal insight - at times, bordering on the mystical - one acquires during the acute phase of a psychedelic session. Indeed, current clinical trials have found strong correlations between the acute subjective effects (ASE) under the influence of psychedelics and their enduring therapeutic properties. However, with potential barriers to widespread clinical implementation, including the healthcare resource-intensive nature of psychedelic sessions and the exclusion of certain at-risk patient groups, there is an active search to determine whether ASE elimination can be accompanied by the retention of persisting therapeutic benefits of these class of compounds. Recognizing the aberrant underlying neural circuitry that characterizes a range of neuropsychiatric disorders, and that classic psychedelics promote neuroplastic changes that may correct abnormal circuitry, investigators are rushing to design and discover compounds with psychoplastogenic, but not hallucinogenic (i.e., ASE), therapeutic potential. These efforts have paved the discovery of 'non-psychedelic/subjective psychedelics', or compounds that lack hallucinogenic activity but with therapeutic efficacy in preclinical models. This review aims to distill the current evidence - both clinical and preclinical - surrounding the question: can the ASE of classic psychedelics be dissociated from their sustained therapeutic properties? Several plausible clinical scenarios are then proposed to offer clarity on and potentially answer this question.

Tailoring Network Topology in Mechanically Robust Hydrogels for 3D Printing and Injection.

Tissue engineering and regenerative medicine are confronted with a persistent challenge: the urgent demand for robust, load-bearing, and biocompatible scaffolds that can effectively endure substantial deformation. Given that inadequate mechanical performance is typically rooted in structural deficiencies─specifically, the absence of energy dissipation mechanisms and network uniformity─a crucial step toward solving this problem is generating synthetic approaches that enable exquisite control over network architecture. This work systematically explores structure-property relationships in poly(ethylene glycol)-based hydrogels constructed utilizing thiol-yne chemistry. We systematically vary polymer concentration, constituent molar mass, and cross-linking protocols to understand the impact of architecture on hydrogel mechanical properties. The network architecture was resolved within the molecular model of Rubinstein-Panyukov to obtain the densities of chemical cross-links and entanglements. We employed both nucleophilic and radical pathways, uncovering notable differences in mechanical response, which highlight a remarkable degree of versatility achievable by tuning readily accessible parameters. Our approach yielded hydrogels with good cell viability and remarkably robust tensile and compression profiles. Finally, the hydrogels are shown to be amenable to advanced processing techniques by demonstrating injection- and extrusion-based 3D printing. Tuning the mechanism and network regularity during the cell-compatible formation of hydrogels is an emerging strategy to control the properties and processability of hydrogel biomaterials by making simple and rational design choices.

Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion.

The most prominent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a repeat expansion in the gene C9orf72. Importantly, the transcriptomic consequences of the C9orf72 repeat expansion remain largely unclear. Here, we used short-read RNA sequencing (RNAseq) to profile the cerebellar transcriptome, detecting alterations in patients with a C9orf72 repeat expansion. We focused on the cerebellum, since key C9orf72-related pathologies are abundant in this neuroanatomical region, yet TDP-43 pathology and neuronal loss are minimal. Consistent with previous work, we showed a reduction in the expression of the C9orf72 gene and an elevation in homeobox genes, when comparing patients with the expansion to both patients without the C9orf72 repeat expansion and control subjects. Interestingly, we identified more than 1000 alternative splicing events, including 4 in genes previously associated with ALS and/or FTLD. We also found an increase of cryptic splicing in C9orf72 patients compared to patients without the expansion and controls. Furthermore, we demonstrated that the expression level of select RNA-binding proteins is associated with cryptic splice junction inclusion. Overall, this study explores the presence of widespread transcriptomic changes in the cerebellum, a region not confounded by severe neurodegeneration, in post-mortem tissue from C9orf72 patients.

Light Control in Microbial Systems.

Light is a key environmental component influencing many biological processes, particularly in prokaryotes such as archaea and bacteria. Light control techniques have revolutionized precise manipulation at molecular and cellular levels in recent years. Bacteria, with adaptability and genetic tractability, are promising candidates for light control studies. This review investigates the mechanisms underlying light activation in bacteria and discusses recent advancements focusing on light control methods and techniques for controlling bacteria. We delve into the mechanisms by which bacteria sense and transduce light signals, including engineered photoreceptors and light-sensitive actuators, and various strategies employed to modulate gene expression, protein function, and bacterial motility. Furthermore, we highlight recent developments in light-integrated methods of controlling microbial responses, such as upconversion nanoparticles and optical tweezers, which can enhance the spatial and temporal control of bacteria and open new horizons for biomedical applications.

Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Current and future advances in practice: IgG4-related disease.

IgG4-related disease (IgG4-RD) is an increasingly recognized cause of fibroinflammatory lesions in patients of diverse racial and ethnic backgrounds and is associated with an increased risk of death. The aetiology of IgG4-RD is incompletely understood, but evidence to date suggests that B and T cells are important players in pathogenesis, both of which are key targets of ongoing drug development programmes. The diagnosis of IgG4-RD requires clinicopathological correlation because there is no highly specific or sensitive test. Glucocorticoids are highly effective, but their use is limited by toxicity, highlighting the need for studies investigating the efficacy of glucocorticoid-sparing agents. B cell-targeted therapies, particularly rituximab, have demonstrated benefit, but no randomized clinical trials have evaluated their efficacy. If untreated or under-treated, IgG4-RD can cause irreversible organ damage, hence close monitoring and consideration for long-term immunosuppression is warranted in certain cases.

MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Elementary school-aged children's perceptions of academic dishonesty: Definitions and moral evaluations of cheating behaviors in school.

A total of 76 children (Mage = 9 years 5 months, SD = 2.22 years) participated in a structured interview about their experiences with and knowledge of academic dishonesty. Overall, 27% of the sample reported having cheated in school. Most of these children were 10 to 13 years old, and the most prevalent form of cheating behavior reported was using forbidden materials during a test. Children's age group was a significant positive predictor of their reported cheating history; however, no significant difference was found between children's gender and engagement with cheating. Children's moral evaluations of cheating did not predict their reported cheating history, nor did children's parents' cheating history. Vignette type (cheating vs. non-cheating), age group, and the interaction between vignette type and age group were significant predictors of children's ability to accurately identify behaviors that constitute cheating. Children rated cheating behaviors as significantly less moral than non-cheating behaviors. Overall, the current results provide insight into what forms of cheating behavior children engage in at the elementary school-age level.

Outcomes of the EMDataResource Cryo-EM Ligand Modeling Challenge.

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein/nucleic-acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution. Three published maps were selected as targets: E. coli beta-galactosidase with inhibitor, SARS-CoV-2 RNA-dependent RNA polymerase with covalently bound nucleotide analog, and SARS-CoV-2 ion channel ORF3a with bound lipid. Sixty-one models were submitted from 17 independent research groups, each with supporting workflow details. We found that (1) the quality of submitted ligand models and surrounding atoms varied, as judged by visual inspection and quantification of local map quality, model-to-map fit, geometry, energetics, and contact scores, and (2) a composite rather than a single score was needed to assess macromolecule+ligand model quality. These observations lead us to recommend best practices for assessing cryo-EM structures of liganded macromolecules reported at near-atomic resolution.

Variation the in relationship between urban tree canopy and air temperature reduction under a range of daily weather conditions.

Mitigating heat is a vital ecosystem service of trees, particularly with climate change. Land surface temperature measures captured at a single time of day (in the morning) dominate the urban heat island literature. Less is known about how local tree canopy and impervious surface regulate air temperature throughout the day, and/or across many days with varied weather conditions, including cloud cover. We use bike-mounted air temperature sensors throughout the day in New Haven, Connecticut, USA, from 2019 to 2021 and generalized additive mixed models across 156 rides to estimate the daily variation in cooling benefits associated with tree canopy cover, and warming from impervious surface cover in 90 m buffers surrounding bike observations. Cooling is inferred by subtracting the bicycle-observed temperature from a reference station. The cooling benefits from tree canopy cover were strongest in the midday (11:00-14:00, -1.62 °C), afternoon (14:00-17:00, -1.19 °C), and morning (8:00-11:00, -1.15 °C) on clear days. The cooling effect was comparatively smaller on cloudy mornings -0.92 °C and afternoons -0.51 °C. Warming from impervious surfaces was most pronounced in the evening (17:00-20:00, 1.11 °C) irrespective of clouds, and during cloudy nights (20:00-23:00) and cloudy mornings 1.03 °C 95 % CI [1.03, 1.04]. Among the hottest observed days (top 25th percentile of reference station daily maxima), tree canopy was associated with lower temperatures on clear afternoons -1.78 °C [-1.78, -1.78], cloudy midday -1.17 °C [-1.19, -1.15], clear midday -1.12 °C [-1.12, -1.11]. We add a broader spectrum of weather conditions by explicitly including clouds, and greater temporal resolution by measuring throughout the day to bike-based urban heat research. Future mobile sampling campaigns may broaden the spatial extent with more environmental variation, representing an opportunity for public science and engagement.

Predictive modeling and cryo-EM: A synergistic approach to modeling macromolecular structure.

Over the last 15 years, structural biology has seen unprecedented development and improvement in two areas: electron cryo-microscopy (cryo-EM) and predictive modeling. Once relegated to low resolutions, single-particle cryo-EM is now capable of achieving near-atomic resolutions of a wide variety of macromolecular complexes. Ushered in by AlphaFold, machine learning has powered the current generation of predictive modeling tools, which can accurately and reliably predict models for proteins and some complexes directly from the sequence alone. Although they offer new opportunities individually, there is an inherent synergy between these techniques, allowing for the construction of large, complex macromolecular models. Here, we give a brief overview of these approaches in addition to illustrating works that combine these techniques for model building. These examples provide insight into model building, assessment, and limitations when integrating predictive modeling with cryo-EM density maps. Together, these approaches offer the potential to greatly accelerate the generation of macromolecular structural insights, particularly when coupled with experimental data.

3D Niche-Inspired Scaffolds as a Stem Cell Delivery System for the Regeneration of the Osteochondral Interface.

The regeneration of the osteochondral unit represents a challenge due to the distinct cartilage and bone phases. Current strategies focus on the development of multiphasic scaffolds that recapitulate features of this complex unit and promote the differentiation of implanted bone-marrow derived stem cells (BMSCs). In doing so, challenges remain from the loss of stemness during in vitro expansion of the cells and the low control over stem cell activity at the interface with scaffolds in vitro and in vivo. Here, this work scaffolds inspired by the bone marrow niche that can recapitulate the natural healing process after injury. The construct comprises an internal depot of quiescent BMSCs, mimicking the bone marrow cavity, and an electrospun (ESP) capsule that "activates" the cells to migrate into an outer "differentiation-inducing" 3D printed unit functionalized with TGF-ß and BMP-2 peptides. In vitro, niche-inspired scaffolds retained a depot of nonproliferative cells capable of migrating and proliferating through the ESP capsule. Invasion of the 3D printed cavity results in location-specific cell differentiation, mineralization, secretion of alkaline phosphatase (ALP) and glycosaminoglycans (GAGs), and genetic upregulation of collagen II and collagen I. In vivo, niche-inspired scaffolds are biocompatible, promoted tissue formation in rat subcutaneous models, and regeneration of the osteochondral unit in rabbit models.

An examination of questioning methods and the influence of child maltreatment on paediatric pain assessments: Perspectives of healthcare providers.

AIMS AND OBJECTIVES: Children with a history of maltreatment have underestimated and undertreated pain; however, it is unknown if healthcare providers consider maltreatment when assessing children's pain. The current study aimed to address this issue by investigating healthcare providers' pain assessment practices, and specifically, their consideration of child maltreatment. METHOD: Healthcare providers (N = 100) completed a survey, asking them to reflect upon their pediatric pain assessment practices (e.g., methods and questions used to assess pain) through self-report and case vignette questions. RESULTS: Participants who received continuing education about child maltreatment were more likely to consider maltreatment in several areas of their pediatric pain assessment practice, whereas participants who received continuing education about pediatric pain, were not. Participants were also more likely to report that they would consider maltreatment in vignette responses than in questions regarding their daily practice. CONCLUSION: Findings indicate healthcare providers use multidimensional methods when assessing children's pain, although it is unclear when or how they use open-ended vs. option posing questions. Healthcare providers also tended to consider the effects of child maltreatment on children's ability to communicate their pain more so when the history of maltreatment was known to them.

Genetic association between atopic disease and osteoarthritis.

OBJECTIVES: To evaluate the association between genetically determined risk for atopic disease and osteoarthritis (OA). METHODS: We performed linkage disequilibrium (LD) score regression using 1000 Genomes Project European samples as a reference for patterns of genome-wide LD. Summary statistics for atopic disease traits were obtained from the UK Biobank. We generated a pairwise genetic correlation between OA and traits for atopic disease to estimate the genetic correlation between traits (rg) and heritability for each trait. The association between atopy-related traits and OA was examined using Mendelian randomization (MR) on summary statistics; we reported inverse-variance weighted (IVW), MR-Egger, maximum likelihood estimation, weighted median, and weighted mode. RESULTS: There was a significant positive correlation between the genome-wide genetic architecture of asthma and all OA traits. Using the IVW (random effects), there was a significant association between asthma and knee OA ((odds ratio) OR = 1.04, 95% (confidence interval) CI 1.01-1.08, p = 0.0169). Using IVW (fixed effects), significant associations were identified between knee OA and allergic disease (OR = 1.07, 95% CI 1.01-1.14, p = 0.0342), allergic rhinitis (OR = 1.07, 95% CI 1.00-1.13, p = 0.0368), and asthma (OR = 1.04, 95% CI 1.01-1.07, p = 0.0139), as well as for OA at any site and asthma (OR = 1.02, 95% CI 1.00-1.04, p = 0.0166). CONCLUSIONS: We found a significant correlation between the overall genetic architecture of asthma and OA, as well as an increased risk of developing OA in patients with genetic variants associated with asthma and allergic rhinitis; predominately, this risk was for the development of knee OA. These results support a causal relationship between asthma and/or allergic rhinitis and knee OA.

Training, Deployment Preparation, and Behavioral Health of New York National Guard Personnel Deployed to Assist with COVID-19 Decedent Work.

INTRODUCTION: A small body of research conducted mostly among civilians has shown that adequate training and preparation can prevent or reduce the development of behavioral health problems in first responders. Several civilian studies have shown that social support is protective against behavioral health problems. However, very few studies have examined the impact of these factors on the behavioral health of military first responders. Military first responders, who serve in the aftermath of natural disasters and disease outbreaks such as the coronavirus disease 2019 (COVID-19) pandemic, are often members of the National Guard (NG). The purpose of this study was to examine the impact of mortuary affairs training/handling human remains, role preparation, equipment preparation, and unit social support provided to families on the behavioral health of New York (NY) NG personnel deployed to assist the NY Office of Chief Medical Examiner with handling the remains of COVID-19 decedents. MATERIALS AND METHODS: We invited 410 NYNG personnel who deployed for the Office of Chief Medical Examiner mission to complete an anonymous online questionnaire 3 to 6 months post-mission. Of the 158 participants, we used the data of the 141 participants who provided consent. Standard behavioral health measures (depression, anxiety, post-traumatic stress disorder, alcohol misuse, and insomnia) as well as study-specific items designed to understand the unique dynamics of this deployment were included. Hierarchical logistic regression analysis was used to examine the relationships between mortuary training, role preparation, equipment preparation, and unit support with behavioral health. RESULTS: Close to two-thirds of the sample reported that they had not been trained in mortuary affairs/handling human remains before the mission. We also found that that lower levels of role preparation and unit support provided to the service members' families increased the odds of meeting criteria for one or more behavioral health problems, but that training in mortuary affairs and equipment preparation was unrelated to behavioral health. CONCLUSIONS: Our research points to the importance of emotionally and cognitively preparing service members for the specific dynamics of a deployment and the roles that that they are expected to play. Furthermore, it suggests that supporting the families of NG personnel during domestic missions can benefit the behavioral health of the NG personnel. Additional research is needed to corroborate these findings, particularly the impact of unit support provided to family members on service members' behavioral health.

Introducing Dynamicity: Engineering Stress Relaxation Into Hydrogels Via Thiol-Ene Modified Alginate for Mechanobiological in vitro Modeling of the Cornea.

Developing biomaterials for corneal repair and regeneration is crucial for maintaining clear vision. The cornea, a specialized tissue, relies on corneal keratocytes, that respond to their mechanical environment. Altering stiffness affects keratocyte behavior, but static stiffness alone cannot capture the dynamic properties of in vivo tissue. This study proposes that the cornea exhibits time-dependent mechanical properties, similar to other tissues, and aims to replicate these properties in potential therapeutic matrices. First, the cornea's stress relaxation properties are investigated using nanoindentation, revealing 15% relaxation within 10 seconds. Hydrogel dynamicity is then modulated using a specially formulated alginate-PEG and alginate-norbornene mixture. The tuning of the hydrogel's dynamicity is achieved through a photoinitiated norbornene-norbornene dimerization reaction, resulting in relaxation times ranging from 30 seconds to 10 minutes. Human primary corneal keratocytes are cultured on these hydrogels, demonstrating reduced αSMA (alpha smooth muscle actin) expression and increased filopodia formation on slower relaxing hydrogels, resembling their native phenotype. This in vitro model can enable the optimization of stress relaxation for various cell types, including corneal keratocytes, to control tissue formation. Combining stress relaxation optimization with stiffness assessment provides a more accurate tool for studying cell behavior and reduces mechanical mismatch with native tissues in implanted constructs.

Senile plaque-associated transactive response DNA-binding protein 43 in Alzheimer's disease: A case report spanning 16 years of memory loss.

Transactive response DNA-binding protein 43 (TDP-43) pathological inclusions are found in frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer's disease (AD-TDP). While clinically different, TDP-43 inclusions in FTLD-TDP and AD can have similar morphological characteristics. However, TDP-43 colocalizing with tau and forming "apple-bite" or "flame-shaped" neuronal cytoplasmic inclusions (NCI) are only found in AD-TDP. Here, we describe a case with AD and neuritic plaque-associated TDP-43. The patient was a 96-year-old right-handed Caucasian woman who had developed a slowly progressive amnestic syndrome compatible with typical AD at age 80. Genetic testing revealed APOE ε3/ε4, GRN r5848 CT, and MAPT H1/H2 genotype. Consistent with the old age at onset and long disease duration, limbic-predominant AD was found at autopsy, with high hippocampal yet low cortical neurofibrillary tangle (NFT) counts. Hippocampal and amygdala sclerosis were present. Immunohistochemistry for phospho-TDP-43 showed NCIs, dystrophic neurites, and rare neuronal intranuclear inclusions consistent with FTLD-TDP type A, as well as tau NFT-associated TDP-43 inclusions. These were frequent in the amygdala, entorhinal cortex, hippocampus, occipitotemporal gyrus, and inferior temporal gyrus but sparse in the mid-frontal cortex. Additionally, there were TDP-43-immunoreactive inclusions forming plaque-like structures in the molecular layer of the dentate fascia of the hippocampus. The presence of neuritic plaques in the same region was confirmed using thioflavin-S fluorescent microscopy and immunohistochemistry for phospho-tau. Double labeling immunofluorescence showed colocalization of TDP-43 and tau within neuritic plaques. Other pathologies included mild Lewy body pathology predominantly affecting the amygdala and olfactory bulb, aging-related tau astrogliopathy, and mixed small vessel disease (arteriolosclerosis and amyloid angiopathy) with several cortical microinfarcts. In conclusion, we have identified TDP-43 colocalizing with tau in neuritic plaques in AD, which expands the association of TDP-43 and tau in AD beyond NFTs. The clinical correlate of this plaque-associated TDP-43 appears to be a slowly progressive amnestic syndrome.

The MAPT p.E342K and p.R406W mutations are associated with progressive supranuclear palsy with atypical features.

INTRODUCTION: Progressive supranuclear palsy (PSP) is an atypical parkinsonism caused by the intracerebral aggregation of the microtubule-associated protein tau (MAPT) which is encoded by MAPT gene. Although PSP is a sporadic disease, MAPT mutations have been reported in rare cases. METHODS: Among 190 patients with PSP who were recruited by the Neurodegenerative Research Group at Mayo Clinic during 2009-2023, we identified two patients who fulfilled diagnostic criteria for PSP-Richardson's syndrome (PSP-RS) and harbor novel MAPT mutations. To better investigate the potential effects of these mutations, we compared the clinical, and neuroimaging characteristics of these two patients to 20 randomly selected patients with PSP-RS without a MAPT mutation. RESULTS: MAPT c.1024G > A, p. Glu342Lys, and MAPT c.1217 G > A, p. Arg406Gln mutations were found in 2 men who developed PSP-RS with atypical features at the ages of 60 and 62 years, respectively. Glu342Lys mutation was associated with features resembling alpha-synucleinopathies (autonomic dysfunction, dream enactment behavior), while both mutations were associated with features suggestive of Alzheimer's disease with poorer performance on tests of episodic memory. Comparison of 18F-flortaucipir uptake between the two MAPT mutation cases with 20 patients without a mutation revealed increased signal on flortaucipir-PET in bilateral medial temporal lobe regions (amygdala, entorhinal cortices, hippocampus, parahippocampus) but not in PSP-related regions (globus pallidum, midbrain, superior frontal cortex and dentate nucleus of the cerebellum). CONCLUSION: Glu342Lys and Arg406Gln mutations appear to modify the PSP-RS phenotype by targeting the medial temporal lobe regions resulting in more memory loss and greater flortaucipir uptake.