Incidence and outcomes of hypertensive phase after glaucoma drainage device surgery.

PURPOSE: To describe the incidence, risk factors, clinical characteristics, and long-term outcomes of a hypertensive phase (HP) after glaucoma drainage device (GDD) implantation. DESIGN: Retrospective cohort study SUBJECTS: Eyes that underwent implantation of their first GDD from January 2010 to October 2020 at a tertiary care center. METHODS: HP was defined as intraocular pressure (IOP) >21 mmHg occurring at 2 consecutive visits in the first 90 days after the date of surgery for Ahmed Glaucoma Valve (AGV) or in the first 90 days after tube opening for Baerveldt Glaucoma Implant (BGI). Generalized estimating equations and Fisher's exact tests were used to evaluate risk factors for HP and risk factors for failure of GDD surgery after occurrence of a HP. MAIN OUTCOME MEASURES: Incidence and risk factors for HP. Overall surgical success rates, defined as the absence of failure criteria: IOP >21 mmHg, ≤5 mmHg, or <20% reduction below baseline IOP after 3 months for 2 consecutive visits, with or without adjunctive ocular hypotensive therapy; additional glaucoma surgery; or loss of light perception. RESULTS: Among 419 eyes of 360 patients that underwent GDD implantation, 42 (10.0%) eyes developed HP. Onset of HP was 20.8±10.5 days after Ahmed Glaucoma Valve and 11.7±20.3 days from the date of tube opening after Baerveldt implantation. Mean IOP during HP was 26.5±3.2 mmHg with peak IOP of 30.0±5.9 mmHg. Median follow-up duration was 21.5 months after onset of HP. Younger age and neovascular glaucoma were significant risk factors for HP occurrence in a multivariable model. Resolution of HP occurred in 32 eyes (76.2%) after a mean duration of 48.0±53.0 days. Additional surgery with a second GDD or cyclophotocoagulation was performed for 12 eyes (28.6%). The overall success rate among eyes with a HP was 52.6% at 2 years, which was significantly lower than that observed among control eyes that did not experience HP (76.3%), P<0.01. CONCLUSIONS: The incidence of HP was 10.0%. Younger age and neovascular glaucoma were significant risk factors for HP in the multivariable model. The risk of surgical failure after HP is significantly higher compared to eyes that did not experience HP.

Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias.

Pick's disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.

Effect of Early Aqueous Suppression After Valved Tube Shunt Surgery for Uveitic Glaucoma.

PURPOSE: To compare outcomes of early aqueous suppression (EAS) and standard therapy (ST) after Ahmed Glaucoma Valve (AGV) implantation for uveitic glaucoma. DESIGN: Retrospective comparative cohort study. PARTICIPANTS: All patients with uveitic glaucoma underwent AGV implantation from January 2010 to October 2020 at Northwestern Medicine. METHODS: Excluding the first postoperative day 1 (POD1), only eyes with IOP 10-15 mmHg at their first visit with IOP ≥ 10 mmHg were included in the main analysis. Early aqueous suppression (EAS) was defined as initiation of ocular hypotensive therapy when IOP was first 10-15 mmHg. Standard therapy was initiation of therapy at any later time. Failure was defined as IOP > 21 mmHg, < 5 mmHg, or < 20% reduction in IOP from baseline after 3 months, for 2 consecutive study visits. Hypotony was defined as IOP ≤ 5 mmHg for ≥ 2 visits. Hypertensive phase was defined as IOP > 21 mmHg for 2 consecutive visits in the first 3 months. MAIN OUTCOME MEASURES: Proportion achieving overall success; incidence of hypotony and hypertensive phase. RESULTS: Twenty-eight eyes of 26 patients were in the EAS group and 20 eyes of 19 patients were in the ST group, with a mean follow-up of 17.7 and 28.2 months, respectively. Baseline IOP was similar in the EAS (31.2 ± 10.1 mmHg) and ST (34.6 ± 12.2 mmHg) groups; P = 0.18. Final IOP was lower in the EAS group (12.9 ± 4.6 mmHg) than the ST group (16.4 ± 5.7 mmHg; P = 0.02) on 2.6 ± 0.9 medications in the EAS group and 1.8 ± 1.5 in the ST group (P = 0.07). Overall success was achieved in 87% of EAS eyes and 74% of ST eyes (P = 0.43). There were no statistically significant differences in the occurrence of additional glaucoma surgery (4% for EAS, 20% for ST; P = 0.11), hypotony (7% for EAS, 0% for ST; P = 0.50), or hypertensive phase (4% for EAS, 21% for ST; P = 0.09). CONCLUSIONS: EAS was associated with a lower final IOP after AGV in uveitic glaucoma eyes; however, more medications were in use at the final visit. No statistically significant differences in overall success or the incidence of adverse events were observed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Distinct Patterns of Hippocampal Pathology in Alzheimer's Disease with Transactive Response DNA-binding Protein 43.

OBJECTIVE: Age-related dementia syndromes are often not related to a single pathophysiological process, leading to multiple neuropathologies found at autopsy. An amnestic dementia syndrome can be associated with Alzheimer's disease (AD) with comorbid transactive response DNA-binding protein 43 (TDP-43) pathology (AD/TDP). Here, we investigated neuronal integrity and pathological burden of TDP-43 and tau, along the well-charted trisynaptic hippocampal circuit (dentate gyrus [DG], CA3, and CA1) in participants with amnestic dementia due to AD/TDP, amnestic dementia due to AD alone, or non-amnestic dementia due to TDP-43 proteinopathy associated with frontotemporal lobar degeneration (FTLD-TDP). METHODS: A total of 48 extensively characterized cases (14 AD, 16 AD/TDP, 18 FTLD-TDP) were analyzed using digital HALO software (Indica Labs, Albuquerque, NM, USA) to quantify pathological burden and neuronal loss. RESULTS: In AD/TDP and FTLD-TDP, TDP-43 immunoreactivity was greatest in the DG. Tau immunoreactivity was significantly greater in DG and CA3 in AD/TDP compared with pure AD. All clinical groups showed the highest amounts of neurons in DG, followed by CA3, then CA1. The AD and AD/TDP groups showed lower neuronal counts compared with the FTLD-TDP group across all hippocampal subregions consistent with the salience of the amnestic phenotype. INTERPRETATION: We conclude that AD/TDP can be distinguished from AD and FTLD-TDP based on differential regional distributions of hippocampal tau and TDP-43. Findings suggest that tau aggregation in AD/TDP might be enhanced by TDP-43. ANN NEUROL 2023;94:1036-1047.

Distinct and shared neuropsychiatric phenotypes in FTLD-tauopathies.

Frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-tau) commonly causes dementia syndromes that include primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD). Cognitive decline in PPA and bvFTD is often accompanied by debilitating neuropsychiatric symptoms. In 44 participants with PPA or bvFTD due to autopsy-confirmed FTLD-tau, we characterized neuropsychiatric symptoms at early and late disease stages and determined whether the presence of certain symptoms predicted a specific underlying FTLD-tauopathy. Participants completed annual research visits at the Northwestern University Alzheimer's Disease Research Center. All participants had an initial Global Clinical Dementia Rating (CDR) Scale score ≤ 2, and neuropsychiatric symptoms were evaluated via the Neuropsychiatric Inventory-Questionnaire (NPI-Q). We assessed the frequency of neuropsychiatric symptoms across all participants at their initial and final visits and performed logistic regression to determine whether symptoms predicted a specific FTLD-tau pathologic diagnosis. Across the FTLD-tau cohort, irritability and apathy were most frequently endorsed at initial and final visits, respectively, whereas psychosis was highly uncommon at both timepoints. Irritability at initial visit predicted greater odds of a 4-repeat compared to a 3-repeat tauopathy (OR = 3.95, 95% CI = 1.10-15.83, p < 0.05). Initial sleep disturbance predicted greater odds of progressive supranuclear palsy (PSP) compared to other FTLD-tau subtypes (OR = 10.68, 95% CI = 2.05-72.40, p < 0.01). Appetite disturbance at final evaluation predicted lower odds of PSP (OR = 0.15, 95% CI = 0.02-0.74, p < 0.05). Our findings suggest that characterization of neuropsychiatric symptoms can aid in the prediction of underlying FTLD-tauopathies. Given considerable pathologic heterogeneity underlying dementias, neuropsychiatric symptoms may be useful for differential diagnosis and treatment planning.

Reduced fire severity offers near-term buffer to climate-driven declines in conifer resilience across the western United States.

Increasing fire severity and warmer, drier postfire conditions are making forests in the western United States (West) vulnerable to ecological transformation. Yet, the relative importance of and interactions between these drivers of forest change remain unresolved, particularly over upcoming decades. Here, we assess how the interactive impacts of changing climate and wildfire activity influenced conifer regeneration after 334 wildfires, using a dataset of postfire conifer regeneration from 10,230 field plots. Our findings highlight declining regeneration capacity across the West over the past four decades for the eight dominant conifer species studied. Postfire regeneration is sensitive to high-severity fire, which limits seed availability, and postfire climate, which influences seedling establishment. In the near-term, projected differences in recruitment probability between low- and high-severity fire scenarios were larger than projected climate change impacts for most species, suggesting that reductions in fire severity, and resultant impacts on seed availability, could partially offset expected climate-driven declines in postfire regeneration. Across 40 to 42% of the study area, we project postfire conifer regeneration to be likely following low-severity but not high-severity fire under future climate scenarios (2031 to 2050). However, increasingly warm, dry climate conditions are projected to eventually outweigh the influence of fire severity and seed availability. The percent of the study area considered unlikely to experience conifer regeneration, regardless of fire severity, increased from 5% in 1981 to 2000 to 26 to 31% by mid-century, highlighting a limited time window over which management actions that reduce fire severity may effectively support postfire conifer regeneration.

Fast estimation of mixed-effects location-scale regression models.

As a result of advances in data collection technology and study design, modern longitudinal datasets can be much larger than they historically have been. Such "intensive" longitudinal datasets are rich enough to allow for detailed modeling of the variance of a response as well as the mean, and a flexible class of models called mixed-effects location-scale (MELS) regression models are commonly used to do so. However, fitting MELS models can pose computational challenges related to the numerical evaluation of multi-dimensional integrals; the slow runtime of current methods is inconvenient for data analysis and makes bootstrap inference impractical. In this paper, we introduce a new fitting technique, called FastRegLS, that is considerably faster than existing techniques while still providing consistent estimators for the model parameters.

Differential vulnerability of the dentate gyrus to tauopathies in dementias.

The dentate gyrus (DG), a key hippocampal subregion in memory processing, generally resists phosphorylated tau accumulation in the amnestic dementia of the Alzheimer's type due to Alzheimer's disease (DAT-AD), but less is known about the susceptibility of the DG to other tauopathies. Here, we report stereologic densities of total DG neurons and tau inclusions in thirty-two brains of human participants with autopsy-confirmed tauopathies with distinct isoform profiles-3R Pick's disease (PiD, N = 8), 4R corticobasal degeneration (CBD, N = 8), 4R progressive supranuclear palsy (PSP, N = 8), and 3/4R AD (N = 8). All participants were diagnosed during life with primary progressive aphasia (PPA), an aphasic clinical dementia syndrome characterized by progressive deterioration of language abilities with spared non-language cognitive abilities in early stages, except for five patients with DAT-AD as a comparison group. 51% of total participants were female. All specimens were stained immunohistochemically with AT8 to visualize tau pathology, and PPA cases were stained for Nissl substance to visualize neurons. Unbiased stereological analysis was performed in granule and hilar DG cells, and inclusion-to-neuron ratios were calculated. In the PPA group, PiD had highest mean total (granule + hilar) densities of DG tau pathology (p < 0.001), followed by CBD, AD, then PSP. PPA-AD cases showed more inclusions in hilar cells compared to granule cells, while the opposite was true in PiD and CBD. Inclusion-to-neuron ratios revealed, on average, 33% of all DG neurons in PiD cases contained a tau inclusion, compared to ~ 7% in CBD, 2% in AD, and 0.4% in PSP. There was no significant difference between DAT-AD and PPA-AD pathologic tau burden, suggesting that differences in DG burden are not specific to clinical phenotype. We conclude that the DG is differentially vulnerable to pathologic tau accumulation, raising intriguing questions about the structural integrity and functional significance of hippocampal circuits in neurodegenerative dementias.

Integrity of Neuronal Size in the Entorhinal Cortex Is a Biological Substrate of Exceptional Cognitive Aging.

Average aging is associated with a gradual decline of memory capacity. SuperAgers are humans ≥80 years of age who show exceptional episodic memory at least as good as individuals 20-30 years their junior. This study investigated whether neuronal integrity in the entorhinal cortex (ERC), an area critical for memory and selectively vulnerable to neurofibrillary degeneration, differentiated SuperAgers from cognitively healthy younger individuals, cognitively average peers ("Normal Elderly"), and individuals with amnestic mild cognitive impairment. Postmortem sections of the ERC were stained with cresyl violet to visualize neurons and immunostained with mouse monoclonal antibody PHF-1 to visualize neurofibrillary tangles. The cross-sectional area (i.e., size) of layer II and layer III/V ERC neurons were quantified. Two-thirds of total participants were female. Unbiased stereology was used to quantitate tangles in a subgroup of SuperAgers and Normal Elderly. Linear mixed-effect models were used to determine differences across groups. Quantitative measurements found that the soma size of layer II ERC neurons in postmortem brain specimens were significantly larger in SuperAgers compared with all groups (p < 0.05)-including younger individuals 20-30 years their junior (p < 0.005). SuperAgers had significantly fewer stereologically quantified Alzheimer's disease-related neurofibrillary tangles in layer II ERC than Normal Elderly (p < 0.05). This difference in tangle burden in layer II between SuperAgers and Normal Elderly suggests that tangle-bearing neurons may be prone to shrinkage during aging. The finding that SuperAgers show ERC layer II neurons that are substantially larger even compared with individuals 20-30 years younger is remarkable, suggesting that layer II ERC integrity is a biological substrate of exceptional memory in old age.SIGNIFICANCE STATEMENT Average aging is associated with a gradual decline of memory. Previous research shows that an area critical for memory, the entorhinal cortex (ERC), is susceptible to the early formation of Alzheimer's disease neuropathology, even during average (or typical) trajectories of aging. The Northwestern University SuperAging Research Program studies unique individuals known as SuperAgers, individuals ≥80 years old who show exceptional memory that is at least as good as individuals 20-30 years their junior. In this study, we show that SuperAgers harbor larger, healthier neurons in the ERC compared with their cognitively average same-aged peers, those with amnestic mild cognitive impairment, and - remarkably - even compared with individuals 20-30 years younger. We conclude that larger ERC neurons are a biological signature of the SuperAging trajectory.

Geometric deep learning reveals a structuro-temporal understanding of healthy and pathologic brain aging.

Background: Brain age has historically been investigated primarily at the whole brain level. The ability to deconstruct the brain into its composite parts and explore brain age at the sub-structure level offers unique advantages. These include the exploration of dynamic and interconnected relationships between different brain structures in healthy and pathologic aging. To achieve this, individual brain structures can be rendered as surface representations on which morphologic analysis is carried out. Combining the advantages of deep learning with the strengths of surface analysis, we investigate the aging process at the individual structure level with the hypothesis being that pathologic aging does not uniformly affect the aging process of individual structures. Methods: MRI data, age at scan time and diagnosis of dementia were collected from seven publicly available data repositories. The data from 17,440 unique subjects were collected, representing a total of 26,276 T1-weighted MRI accounting for longitudinal acquisitions. Surfaces were extracted for the cortex and seven subcortical structures. Deep learning networks were trained to estimate a subject's age either using several structures together or a single structure. We conducted a cross-sectional analysis to assess the difference between the predicted and actual ages for all structures between healthy subjects, individuals with mild cognitive impairment (MCI) or Alzheimer's disease dementia (ADD). We then performed a longitudinal analysis to assess the difference in the aging pace for each structure between stable healthy controls and healthy controls converting to either MCI or ADD. Findings: Using an independent cohort of healthy subjects, age was well estimated for all structures. Cross-sectional analysis identified significantly larger predicted age for all structures in patients with either MCI and ADD compared to healthy subjects. Longitudinal analysis revealed varying degrees of involvement of individual subcortical structures for both age difference across groups and aging pace across time. These findings were most notable in the whole brain, cortex, hippocampus and amygdala. Conclusion: Although similar patterns of abnormal aging were found related to MCI and ADD, the involvement of individual subcortical structures varied greatly and was consistently more pronounced in ADD patients compared to MCI patients.

Eye movements as a measure of word comprehension deficits in primary progressive aphasia.

INTRODUCTION: Eye movement studies can uncover subtle aspects of language processing impairment in individuals with primary progressive aphasia (PPA), who may have difficulty understanding words. This study examined eye movement patterns on a word-object matching task in response to varying levels of word-knowledge in PPA. METHODS: Participants with semantic and non-semantic PPA completed an object-matching task, where a word was presented and participants then selected the corresponding pictured object from an array. Afterwards, participants defined words for trials to which they incorrectly pointed. Linear mixed-effects analyses examined fixation differences on targets and related and unrelated foils. RESULTS: On incorrectly-pointed trials, participants demonstrated greater fixation duration on related foils, demonstrating intra-category blurring. For words that could not be defined, there was similar fixation duration on related and unrelated foils, demonstrating inter-category semantic blurring. DISCUSSION: This study demonstrated that fixation patterns reflect varying levels of word knowledge in PPA.

Neuropathological fingerprints of survival, atrophy and language in primary progressive aphasia.

Primary progressive aphasia is a neurodegenerative disease that selectively impairs language without equivalent impairment of speech, memory or comportment. In 118 consecutive autopsies on patients with primary progressive aphasia, primary diagnosis was Alzheimer's disease neuropathological changes (ADNC) in 42%, corticobasal degeneration or progressive supranuclear palsy neuropathology in 24%, Pick's disease neuropathology in 10%, transactive response DNA binding proteinopathy type A [TDP(A)] in 10%, TDP(C) in 11% and infrequent entities in 3%. Survival was longest in TDP(C) (13.2 ± 2.6 years) and shortest in TDP(A) (7.1 ± 2.4 years). A subset of 68 right-handed participants entered longitudinal investigations. They were classified as logopenic, agrammatic/non-fluent or semantic by quantitative algorithms. Each variant had a preferred but not invariant neuropathological correlate. Seventy-seven per cent of logopenics had ADNC, 56% of agrammatics had corticobasal degeneration/progressive supranuclear palsy or Pick's disease and 89% of semantics had TDP(C). Word comprehension impairments had strong predictive power for determining underlying neuropathology positively for TDP(C) and negatively for ADNC. Cortical atrophy was smallest in corticobasal degeneration/progressive supranuclear palsy and largest in TDP(A). Atrophy encompassed posterior frontal but not temporoparietal cortex in corticobasal degeneration/progressive supranuclear palsy, anterior temporal but not frontoparietal cortex in TDP(C), temporofrontal but not parietal cortex in Pick's disease and all three lobes with ADNC or TDP(A). There were individual deviations from these group patterns, accounting for less frequent clinicopathologic associations. The one common denominator was progressive asymmetric atrophy overwhelmingly favouring the left hemisphere language network. Comparisons of ADNC in typical amnestic versus atypical aphasic dementia and of TDP in type A versus type C revealed fundamental biological and clinical differences, suggesting that members of each pair may constitute distinct clinicopathologic entities despite identical downstream proteinopathies. Individual TDP(C) participants with unilateral left temporal atrophy displayed word comprehension impairments without additional object recognition deficits, helping to dissociate semantic primary progressive aphasia from semantic dementia. When common and uncommon associations were considered in the set of 68 participants, one neuropathology was found to cause multiple clinical subtypes, and one subtype of primary progressive aphasia to be caused by multiple neuropathologies, but with different probabilities. Occasionally, expected clinical manifestations of atrophy sites were absent, probably reflecting individual peculiarities of language organization. The hemispheric asymmetry of neurodegeneration and resultant language impairment in primary progressive aphasia reflect complex interactions among the cellular affinities of the degenerative disease, the constitutive biology of language cortex, familial or developmental vulnerabilities of this network and potential idiosyncrasies of functional anatomy in the affected individual.

Path-level interpretation of Gaussian graphical models using the pair-path subscore.

BACKGROUND : Construction of networks from cross-sectional biological data is increasingly common. Many recent methods have been based on Gaussian graphical modeling, and prioritize estimation of conditional pairwise dependencies among nodes in the network. However, challenges remain on how specific paths through the resultant network contribute to overall 'network-level' correlations. For biological applications, understanding these relationships is particularly relevant for parsing structural information contained in complex subnetworks. RESULTS: We propose the pair-path subscore (PPS), a method for interpreting Gaussian graphical models at the level of individual network paths. The scoring is based on the relative importance of such paths in determining the Pearson correlation between their terminal nodes. PPS is validated using human metabolomics data from the Hyperglycemia and adverse pregnancy outcome (HAPO) study, with observations confirming well-documented biological relationships among the metabolites. We also highlight how the PPS can be used in an exploratory fashion to generate new biological hypotheses. Our method is implemented in the R package pps, available at https://github.com/nathan-gill/pps . CONCLUSIONS: The PPS can be used to probe network structure on a finer scale by investigating which paths in a potentially intricate topology contribute most substantially to marginal behavior. Adding PPS to the network analysis toolkit may enable researchers to ask new questions about the relationships among nodes in network data.

Cortical and subcortical pathological burden and neuronal loss in an autopsy series of FTLD-TDP-type C.

The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer's Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin-eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a 'neuron-to-inclusion' score (TDP-type C mean score - neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.

The propagule doesn't fall far from the tree, especially after short-interval, high-severity fire.

Subalpine forests that historically burned every 100-300 yr are expected to burn more frequently as climate warms, perhaps before trees reach reproductive maturity or produce a serotinous seedbank. Tree regeneration after short-interval (<30-yr) high-severity fire will increasingly rely on seed dispersal from unburned trees, but how dispersal varies with age and structure of surrounding forest is poorly understood. We studied wind dispersal of three conifers (Picea engelmannii, Abies lasiocarpa, and Pinus contorta var. latifolia, which can be serotinous and nonserotinous) after a stand-replacing fire that burned young (≤30 yr) and older (>100 yr) P. contorta forest in Grand Teton National Park (Wyoming, USA). We asked how propagule pressure varied with time since last fire, how seed delivery into burned forest varied with age and structure of live forest edges, what variables explained seed delivery into burned forest, and how spatial patterns of delivery across the burned area could vary with alternate patterns of surrounding live forest age. Seeds were collected in traps along 100-m transects (n = 18) extending from live forest edges of varying age (18, 30, and >100 yr) into areas of recent (2-yr) high-severity fire, and along transects in live forests to measure propagule pressure. Propagule pressure was low in 18-yr-old stands (~8 seeds/m2 ) and similarly greater in 30- and 100-yr-old stands (~32 seeds/m2 ). Mean dispersal distance was lowest from 18-yr-old edges and greatest from >100-yr-old edges. Seed delivery into burned forest declined with increasing distance and increased with height of trees at live forest edges, and was consistently higher for P. contorta than for other conifers. Empirical dispersal kernels revealed that seed delivery from 18-yr-old edges was very low (≤2.4 seeds/m2 ) and concentrated within 10 m of the live edge, whereas seed delivery from >100-yr-old edges was >4.9 seeds/m2 out to 80 m. When extrapolated throughout the burned landscape, estimated seed delivery was low (<49,400 seeds/ha) in >70% of areas that burned in short-interval fire (<30 yr). As fire frequency increases, immaturity risk will be compounded in short-interval fires because seed dispersal from surrounding young trees is limited.

Remote allergen exposure elicits eosinophil infiltration into allergen nonexposed mucosal organs and primes for allergic inflammation.

The natural history of allergic diseases suggests bidirectional and progressive relationships between allergic disorders of the skin, lung, and gut indicative of mucosal organ crosstalk. However, impacts of local allergic inflammation on the cellular landscape of remote mucosal organs along the skin:lung:gut axis are not yet known. Eosinophils are tissue-dwelling innate immune leukocytes associated with allergic diseases. Emerging data suggest heterogeneous phenotypes of tissue-dwelling eosinophils contribute to multifaceted roles that favor homeostasis or disease. This study investigated the impact of acute local allergen exposure on the frequency and phenotype of tissue eosinophils within remote mucosal organs. Our findings demonstrate allergen challenge to skin, lung, or gut elicited not only local eosinophilic inflammation, but also increased the number and frequency of eosinophils within remote, allergen nonexposed lung, and intestine. Remote allergen-elicited lung eosinophils exhibited an inflammatory phenotype and their presence associated with enhanced susceptibility to airway inflammation induced upon subsequent inhalation of a different allergen. These data demonstrate, for the first time, a direct effect of acute allergic inflammation on the phenotype and frequency of tissue eosinophils within antigen nonexposed remote mucosal tissues associated with remote organ priming for allergic inflammation.

Invasive rat control is an efficient, yet insufficient, method for recovery of the critically endangered Hawaiian plant hau kuahiwi (Hibiscadelphus giffardianus).

Biological invasions of rodents and other species have been especially problematic on tropical islands. Invasive Rattus rattus consumption of Hibiscadelphus giffardianus (Malvaceae; common Hawaiian name hau kuahiwi) fruit and seeds has been hypothesized to be the most-limiting factor inhibiting the critically endangered tree, but this has not been experimentally tested, and little is known about other factors affecting seed dispersal, germination, and seedling establishment. Thus, we do not know if rat removal is sufficient to increase hau kuahiwi recruitment. This study aims to evaluate the effect of rat population control on the ability of hau kuahiwi to retain fruit and establish seedlings. We compared hau kuahiwi fruiting and seedling recruitment in a stand treated to reduce rat abundance and a neighbouring control stand. Fruit retention increased following treatment but seedling establishment did not. Although rat control improves the ability of hau kuahiwi to retain fruit, other, presently unknown inhibitors to seed dispersal, germination, and/or seedling development remain. Seed and seedling predation by other species, competition from numerous invasive plant species, unsuitable climate, and/or other factors may be primary inhibitors in the absence of rats, but we emphasize that progressive isolation of these factors at individual hau kuahiwi life stages may be necessary to identify the remaining threats to the conservation of this critically endangered plant.