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Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid β-protein (Aβ42) forms and novel intraneuronal Aβ oligomers (AβOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aβ uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aβ42, S100 calcium-binding protein B+ macrogliosis, and atrophy correlated with severity of brain Aβ pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aβ42, far-peripheral AβOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.

Purpose: This tutorial aims to introduce school-based speech-language pathologists (SLPs) to developmental systems theory as a framework for considering interactions across functional domains, such as language, vision, and motor, for students with complex needs. Method: This tutorial summarizes the current literature on developmental systems theory in its application to working with students who have needs in multiple domains of functioning in addition to communication. A hypothetical case of a student, James, with cerebral palsy, cortical visual impairment, and complex communication needs, is presented to illustrate the primary tenets of the theory. Results: Specific reason-based recommendations are presented that SLPs can put to practice with their own caseload in direct response to the three tenets of developmental systems theory. Conclusions: A developmental systems approach will be useful in expanding SLP knowledge of where to begin and how to best serve children with language, motor, vision, and other concomitant needs. The tenets, including sampling, context dependency, and interdependency, and the application of developmental systems theory can be instrumental in providing a way forward for SLPs struggling with the assessment and intervention of students with complex needs.

Synaptic transfer of tau has long been hypothesized from the human pathology pattern and has been demonstrated in vitro and in vivo, but the precise mechanisms remain unclear. Extracellular vesicles such as exosomes have been suggested as a mechanism, but not all tau is exosomal. The present experiments use a novel flow cytometry assay to quantify depolarization of synaptosomes by KCl after loading with FM2-10, which induces a fluorescence reduction associated with synaptic vesicle release; the degree of reduction in cryopreserved human samples equaled that seen in fresh mouse synaptosomes. Depolarization induced the release of vesicles in the size range of exosomes, along with tetraspanin markers of extracellular vesicles. A number of tau peptides were released, including tau oligomers; released tau was primarily unphosphorylated and C-terminal truncated, with Aβ release just above background. When exosomes were immunopurified from release supernatants, a prominent tau band showed a dark smeared appearance of SDS-stable oligomers along with the exosomal marker syntenin-1, and these exosomes induced aggregation in the HEK tau biosensor assay. However, the flow-through did not seed aggregation. Size exclusion chromatography of purified released exosomes shows faint signals from tau in the same fractions that show a CD63 band, an exosomal size signal, and seeding activity. Crude synaptosomes from control, tauopathy, and AD cases demonstrated lower seeding in tauopathy compared to AD that is correlated with the measured Aβ42 level. These results show that AD synapses release exosomal tau that is C-terminal-truncated, oligomeric, and with seeding activity that is enhanced by Aβ. Taken together with previous findings, these results are consistent with a direct prion-like heterotypic seeding of tau by Aβ within synaptic terminals, with subsequent loading of aggregated tau onto exosomes that are released and competent for tau seeding activity.

We describe a patient with cerebral amyloid angiopathy-related inflammation (CAA-ri) presenting as Alzheimer disease (AD) with a mass lesion with symptom onset at age 59. He was found to have a nonenhancing lesion in the right temporal lobe on magnetic resonance imaging without evidence of hemorrhage. He underwent a biopsy which showed amyloid beta in blood vessel walls and a perivascular inflammatory infiltrate consistent with CAA-ri. Neurofibrillary tangles were present and a flortaucipir positron emission tomography showed bilateral signal highest in the lateral temporal and parietal cortices. A lumbar puncture showed tau, p-tau, and amyloid beta levels consistent with AD without evidence of inflammation. He was homozygous for the APOE ε4 allele. He died at age 67. A focus of CAA-ri can be present in the context of AD with a mass lesion and without evidence of hemorrhage, significant ischemic changes, or overt inflammation on cerebrospinal fluid examination.

Pericyte loss and deficient vascular platelet-derived growth factor receptor-β (PDGFRβ) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid β-protein (Aβ) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored. Here, by modifying a method of enzymatically clearing non-vascular retinal tissue and fluorescent immunolabeling of the isolated blood vessel network, we identified substantial pericyte loss together with significant Aβ deposition in retinal microvasculature and pericytes in AD. Evaluation of postmortem retinas from a cohort of 56 human donors revealed an early and progressive decrease in vascular PDGFRβ in mild cognitive impairment (MCI) and AD compared to cognitively normal controls. Retinal PDGFRβ loss significantly associated with increased retinal vascular Aβ40 and Aβ42 burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFRβ and Aβ40 levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, correlations were identified between retinal vascular abnormalities and cerebral Aβ burden, cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFRβ loss accompanying increased vascular amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and therapy.

Apolipoprotein E (apoE) colocalizes with amyloid-β (Aβ) in Alzheimer disease (AD) plaques and in synapses, and evidence suggests that direct interactions between apoE and Aβ are important for apoE's effects in AD. The present work examines the hypothesis that apoE receptors mediate uptake of apoE/Aβ complex into synaptic terminals. Western blot analysis shows multiple SDS-stable assemblies in synaptosomes from human AD cortex; apoE/Aβ complex was markedly increased in AD compared with aged control samples. Complex formation between apoE and Aβ was confirmed by coimmunoprecipitation experiments. The apoE receptors low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1) were quantified in synaptosomes using flow cytometry, revealing up-regulation of LRP1 in early- and late-stage AD. Dual-labeling flow cytometry analysis of LRP1- and LDLR positives indicate most (approximately 65%) of LDLR and LRP1 is associated with postsynaptic density-95 (PSD-95)-positive synaptosomes, indicating that remaining LRP1 and LDLR receptors are exclusively presynaptic. Flow cytometry analysis of Nile red labeling revealed a reduction in cholesterol esters in AD synaptosomes. Dual-labeling experiments showed apoE and Aβ concentration into LDLR and LRP1-positive synaptosomes, along with free and esterified cholesterol. Synaptic Aβ was increased by apoE4 in control and AD samples. These results are consistent with uptake of apoE/Aβ complex and associated lipids into synaptic terminals, with subsequent Aβ clearance in control synapses and accumulation in AD synapses.

The interrelatedness of lexical items, typically defined in termsof semantic or phonological overlap, has been shown toinfluence language learning. Given that language also containssequential structure, we investigate here whether temporaloverlap among words, formalized in graph theoretical terms asdisplaying the property of community structure, might alsohave consequences for learning. We create a graph organizedinto clusters of densely interconnected nodes with relativelysparse external connections. After assigning a novelpseudoword to each node in the graph, we generate acontinuous sequence of visually-presented items by walkingalong its edges. Word-by-word reading times suggest thatlearners are indeed sensitive to temporal overlap.Compellingly, we also demonstrate that prior exposure tosequences organized into temporal communities influencesperformance on a subsequent word recognition task.

Background & Aims: Given that standardized language measures alone are inadequate for identifying functionally defined developmental language disorder (fDLD), this study investigated whether non-linguistic cognitive abilities (procedural learning, motor functions, executive attention, processing speed) can increase the prediction accuracy of fDLD in children in linguistically diverse settings. Methods & Procedures: We examined non-linguistic cognitive abilities in mono- and bilingual school-aged children (ages 8-12) with and without fDLD. Typically developing (TD) children (14 monolinguals, 12 bilinguals) and children with fDLD (28 monolinguals, 12 bilinguals) completed tasks measuring motor functions, procedural learning, executive attention and processing speed. Children were assigned as fDLD based on parental or professional concerns regarding children's daily language functioning. If no concerns were present, children were assigned as TD. Standardized English scores, non-verbal IQ scores and years of maternal education were also obtained. Likelihood ratios were used to examine how well each measure separated the fDLD versus TD groups. A binary logistic regression was used to test whether combined measures enhanced the prediction of identifying fDLD status. Outcomes & Results: A combination of linguistic and non-linguistic measures provided the best distinction between fDLD and TD for both mono- and bilingual groups. For monolingual children, the combined measures include English language scores, functional motor abilities and processing speed, whereas for bilinguals, the combined measures include English language scores and procedural learning. Conclusions & Implications: A combination of non-linguistic and linguistic measures significantly improved the distinction between fDLD and TD for both mono- and bilingual groups. This study supports the possibility of using non-linguistic cognitive measures to identify fDLD in linguistically diverse settings.

Purpose: The aim of the current study was to investigate whether dual language experience modulates processing speed in typically developing (TD) children and in children with developmental language disorder (DLD). We also examined whether processing speed predicted vocabulary and sentence-level abilities in receptive and expressive modalities. Method: We examined processing speed in monolingual and bilingual school-age children (ages 8--12 years) with and without DLD. TD children (35 monolinguals, 24 bilinguals) and children with DLD (17 monolinguals, 10 bilinguals) completed a visual choice reaction time task. The Clinical Evaluation of Language Fundamentals, the Peabody Picture Vocabulary Test, and the Expressive Vocabulary Test were used as language measures. Results: The children with DLD exhibited slower response times relative to TD children. Response time was not modified by bilingual experience, neither in children with typical development nor children with DLD. Also, we found that faster processing speed was related to higher language abilities, but this relationship was not significant when socioeconomic status was controlled for. The magnitude of the association did not differ between the monolingual and bilingual groups across the language measures. Conclusions: Slower processing speed is related to lower language abilities in children. Processing speed is minimally influenced by dual language experience, at least within this age range.

Purpose: The aim of the current study was to investigate whether dual language experience modulates the efficiency of the 3 attentional networks (alerting, orienting, and executive control) in typically developing (TD) children and in children with developmental language disorder (DLD). Method: We examined the attentional networks in monolingual and bilingual school-aged children (ages 8-12 years) with and without DLD. TD children (35 monolinguals, 23 bilinguals) and children with DLD (17 monolinguals, 9 bilinguals) completed the Attention Network Test (Fan et al., 2002; Fan, McCandliss, Fossella, Flombaum, & Posner, 2005). Results: Children with DLD exhibited poorer executive control than TD children, but executive control was not modified by bilingual experience. The bilingual group with DLD and both TD groups exhibited an orienting effect, but the monolingual group with DLD did not. No group differences were found for alerting. Conclusions: Children with DLD have weak executive control skills. These skills are minimally influenced by dual language experience, at least in this age range. A potential bilingual advantage in orienting may be present in the DLD group.

This study is a test of the effectiveness of a classroom role-playing exercise used to increase the understanding of cultural practices with which many Midwestern college students are uncomfortable. I employed a pre-test/post-test comparison group design. Students enrolled in two sections of a general education global issues course (N = 56) were asked about their perceptions about, and explanations for, the existence of female genital cutting in Egypt (the country they were studying). One section discussed the issue during a PowerPoint presentation, and the other section participated in an exercise in which they role-played family members deciding whether a daughter or sister would undergo the procedure. A comparison of post-test responses demonstrated increased understanding in both sections, but students in the experimental group better understood the collective implications of the practice on the entire family.

Using an oral sentence production task, we investigated how preschoolers (N = 28) produce agreement with complex noun phrases and compared their performance to college students (N = 32) to determine whether preschoolers produce agreement patterns that are qualitatively similar to adults'. We also conducted corpus analyses to investigate relevant input to preschoolers and found very few sentences in which the verb expressed unambiguous agreement with the head noun of a complex noun phrase. In the oral production task, preschoolers made more errors when the head and local nouns had different number specifications than when the nouns were both singular or plural. Response bias calculations indicated that preschoolers often produced one type of agreement (singular or plural) when the subject head and local nouns differed in number. College students were more accurate overall, and a comparison between preschoolers and college students revealed qualitative differences in agreement patterns between the two groups.

Climate change is increasing the frequency and intensity of extreme precipitation events, raising the risk of urban flood disasters. This study uses a crowd‐sourced municipal call database to characterize the spatial distribution of flood risk in Detroit, MI. Call data including dates and addresses were obtained from the City of Detroit Department of Public Works for 2021. Calls were mapped and aggregated to census tract counts and merged with neighborhood‐level data. Associations of predictors with flood calls were tested using spatial regression models. Flooding calls were located throughout the city but were concentrated in specific areas. Multivariate models of census tract level call counts indicated that increased poverty and Black, immigrant, and older residents were positively associated with flood calls, while increased elevation was associated with protective effects. Longer distances from waste water interceptors were associated with higher risk for calls. Crowd‐sourced flood hotline call data can be used for effective spatial flood risk assessment. Though flooding occurs throughout the city of Detroit, infrastructural, neighborhood, and household factors influence flooding extent. Limitations included the self‐reported nature of calls. Future modeling efforts might include input from local stakeholders to improve spatial risk assessment. [ABSTRACT FROM AUTHOR]

Amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Aβ and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Aβ and p-tau in large populations of individual synaptic terminals. Soluble Aβ oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Aβ was elevated in patients with early- and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Aβ oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Aβ-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Aβ drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed.

© 2015 The Author(s) Context: More than a century of forest and fire management of Inland Pacific landscapes has transformed their successional and disturbance dynamics. Regional connectivity of many terrestrial and aquatic habitats is fragmented, flows of some ecological and physical processes have been altered in space and time, and the frequency, size and intensity of many disturbances that configure these habitats have been altered. Current efforts to address these impacts yield a small footprint in comparison to wildfires and insect outbreaks. Moreover, many current projects emphasize thinning and fuels reduction within individual forest stands, while overlooking large-scale habitat connectivity and disturbance flow issues. Methods: We provide a framework for landscape restoration, offering seven principles. We discuss their implication for management, and illustrate their application with examples. Results: Historical forests were spatially heterogeneous at multiple scales. Heterogeneity was the result of variability and interactions among native ecological patterns and processes, including successional and disturbance processes regulated by climatic and topographic drivers. Native flora and fauna were adapted to these conditions, which conferred a measure of resilience to variability in climate and recurrent contagious disturbances. Conclusions: To restore key characteristics of this resilience to current landscapes, planning and management are needed at ecoregion, local landscape, successional patch, and tree neighborhood scales. Restoration that works effectively across ownerships and allocations will require active thinking about landscapes as socio-ecological systems that provide services to people within the finite capacities of ecosystems. We focus attention on landscape-level prescriptions as foundational to restoration planning and execution.