LET-381/FoxF and its target UNC-30/Pitx2 specify and maintain the molecular identity of C. elegans mesodermal glia that regulate motor behavior.

While most glial cell types in the central nervous system (CNS) arise from neuroectodermal progenitors, some, like microglia, are mesodermally derived. To understand mesodermal glia development and function, we investigated C. elegans GLR glia, which envelop the brain neuropil and separate it from the circulatory system cavity. Transcriptome analysis shows that GLR glia combine astrocytic and endothelial characteristics, which are relegated to separate cell types in vertebrates. Combined fate acquisition is orchestrated by LET-381/FoxF, a fate-specification/maintenance transcription factor also expressed in glia and endothelia of other animals. Among LET-381/FoxF targets, the UNC-30/Pitx2 transcription factor controls GLR glia morphology and represses alternative mesodermal fates. LET-381 and UNC-30 co-expression in naive cells is sufficient for GLR glia gene expression. GLR glia inactivation by ablation or let-381 mutation disrupts locomotory behavior and promotes salt-induced paralysis, suggesting brain-neuropil activity dysregulation. Our studies uncover mechanisms of mesodermal glia development and show that like neuronal differentiation, glia differentiation requires autoregulatory terminal selector genes that define and maintain the glial fate.

Dysphagia in primary progressive aphasia: Clinical predictors and neuroanatomical basis.

BACKGROUND AND PURPOSE: Dysphagia is an important feature of neurodegenerative diseases and potentially life-threatening in primary progressive aphasia (PPA) but remains poorly characterized in these syndromes. We hypothesized that dysphagia would be more prevalent in nonfluent/agrammatic variant (nfv)PPA than other PPA syndromes, predicted by accompanying motor features, and associated with atrophy affecting regions implicated in swallowing control. METHODS: In a retrospective case-control study at our tertiary referral centre, we recruited 56 patients with PPA (21 nfvPPA, 22 semantic variant [sv]PPA, 13 logopenic variant [lv]PPA). Using a pro forma based on caregiver surveys and clinical records, we documented dysphagia (present/absent) and associated, potentially predictive clinical, cognitive, and behavioural features. These were used to train a machine learning model. Patients' brain magnetic resonance imaging scans were assessed using voxel-based morphometry and region-of-interest analyses comparing differential atrophy profiles associated with dysphagia presence/absence. RESULTS: Dysphagia was significantly more prevalent in nfvPPA (43% vs. 5% svPPA and no lvPPA). The machine learning model revealed a hierarchy of features predicting dysphagia in the nfvPPA group, with excellent classification accuracy (90.5%, 95% confidence interval = 77.9-100); the strongest predictor was orofacial apraxia, followed by older age, parkinsonism, more severe behavioural disturbance, and more severe cognitive impairment. Significant grey matter atrophy correlates of dysphagia in nfvPPA were identified in left middle frontal, right superior frontal, and right supramarginal gyri and right caudate. CONCLUSIONS: Dysphagia is a common feature of nfvPPA, linked to underlying corticosubcortical network dysfunction. Clinicians should anticipate this symptom particularly in the context of other motor features and more severe disease.

Symptom-based staging for logopenic variant primary progressive aphasia.

BACKGROUND AND PURPOSE: Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction across AD phenotypes. A clinical staging system is lacking for the evolution of AD-associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom-based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum. METHODS: An international lvPPA caregiver cohort was surveyed on symptom development under an 'exploratory' survey (34 UK caregivers). Feedback from this survey informed the development of a 'consolidation' survey (27 UK, 10 Australian caregivers) in which caregivers were presented with six provisional clinical stages and feedback was analysed using a mixed-methods approach. RESULTS: Six clinical stages were endorsed. Early symptoms included word-finding difficulty, with loss of message comprehension and speech intelligibility signalling later-stage progression. Additionally, problems with hearing in noise, memory and route-finding were prominent early non-verbal symptoms. 'Milestone' symptoms were identified that anticipate daily-life functional transitions and care needs. CONCLUSIONS: This work introduces a new symptom-based staging scheme for lvPPA, and highlights milestone symptoms that could inform future clinical scales for anticipating and managing communication dysfunction across the AD spectrum.

Comprehension of acoustically degraded speech in Alzheimer's disease and primary progressive aphasia.

Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer's disease and 30 patients representing the three canonical syndromes of primary progressive aphasia (non-fluent/agrammatic variant primary progressive aphasia; semantic variant primary progressive aphasia; logopenic variant primary progressive aphasia), compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients' brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer's disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all P < 0.05). In a receiver operating characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer's disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in predefined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (P < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals. Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications.

Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.

INTRODUCTION: Here we set out to create a symptom-led staging system for the canonical semantic and non-fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias. METHODS: An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed-methods sequential explanatory design. RESULTS: Both PPA syndromes were characterized by initial communication dysfunction and non-verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid ("PPA-Squared"). DISCUSSION: This work introduces a symptom-led staging scheme and functional scale for semantic and non-fluent/agrammatic variants of PPA. Our findings have implications for diagnostic and care pathway guidelines, trial design, and personalized prognosis and treatment for PPA. HIGHLIGHTS: We introduce new symptom-led perspectives on primary progressive aphasia (PPA). The focus is on non-fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non-verbal features of PPA and clinical trajectories is featured. We introduce a symptom-led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.

"Each week feels like a mountain": The impact of COVID-19 on mental health providers' wellbeing and clinical work.

The SARS-CoV-2 (COVID-19) pandemic has placed a tremendous strain on healthcare providers. Although there is a burgeoning body of literature on how COVID-19 has impacted frontline healthcare workers (i.e., providers treating COVID-19 patients), little attention has been dedicated to second-line workers (i.e., providers treating the mental health of people impacted by COVID-19). In this paper, we present findings from a thematic analysis of open text responses (n = 136) examining how COVID-19 shaped both the wellbeing of second-line workers, specifically mental health providers, as well as their clinical work in the early months of the COVID-19 pandemic in the United States. Results indicated that mental health providers were experiencing significant COVID-19-related burnout and poor physical and mental health outcomes. Participants described diminished negative effects on the quality of their clinical care from the burnout and trauma associated with COVID-19. Many also demonstrated resilience, identifying the duality of both negative (e.g., exhaustion) and positive (e.g., pride in helping others) meaning derived from their second-line work experiences. We conclude with recommendations for preventing and addressing burnout among mental health professionals in the era of COVID-19 and subsequent health emergencies.

Primary Progressive Aphasia: Toward a Pathophysiological Synthesis.

PURPOSE OF REVIEW: The term primary progressive aphasia (PPA) refers to a diverse group of dementias that present with prominent and early problems with speech and language. They present considerable challenges to clinicians and researchers. RECENT FINDINGS: Here, we review critical issues around diagnosis of the three major PPA variants (semantic variant PPA, nonfluent/agrammatic variant PPA, logopenic variant PPA), as well as considering 'fragmentary' syndromes. We next consider issues around assessing disease stage, before discussing physiological phenotyping of proteinopathies across the PPA spectrum. We also review evidence for core central auditory impairments in PPA, outline critical challenges associated with treatment, discuss pathophysiological features of each major PPA variant, and conclude with thoughts on key challenges that remain to be addressed. New findings elucidating the pathophysiology of PPA represent a major step forward in our understanding of these diseases, with implications for diagnosis, care, management, and therapies.

Interpreter-mediated neuropsychological assessment: Clinical considerations and recommendations from the European Consortium on Cross-Cultural Neuropsychology (ECCroN).

OBJECTIVE: With increasing international migration, societies have become increasingly diverse worldwide. Although neuropsychological assessment is influenced by several diversity characteristics, language barriers have repeatedly been identified as one of the main challenges to cross-cultural neuropsychological assessment in migrant populations. Importantly, neuropsychologists are often required to conduct interpreter-mediated neuropsychological assessments without any graduate training or continuing education on the topic. To address this gap, the objective of this paper is to provide guidelines for interpreter-mediated neuropsychological assessment. METHOD: A European Consortium on Cross-Cultural Neuropsychology (ECCroN) task force conducted a conceptual literature review and provided recommendations for good practice and working principles to inform the preparation and administration of interpreter-mediated assessments. RESULTS: ECCroN takes the position that it is the responsibility of neuropsychologists, as well as the institutions or organizations that employ them, to ensure effective communication between themselves and their patients. This may be accomplished by preparing for an interpreter-mediated assessment by engaging an appropriate interpreter, which in most circumstances will be a professional in-person interpreter speaking the same language(s) or dialect(s) as the patient, and considering practical, language, and cross-cultural issues. During the assessment, reasonable steps should be taken to proactively manage the proceedings and adopt a communication style that facilitates effective patient-directed communication, and when interpreting test data and determining formulations and diagnoses, the limitations of interpreter-mediated assessment should be carefully considered. CONCLUSION: Adhering to the provided recommendations and working principles may help neuropsychologists provide competent interpreter-mediated neuropsychological assessments to linguistically diverse patients.

Primary progressive aphasia: six questions in search of an answer.

Here, we review recent progress in the diagnosis and management of primary progressive aphasia-the language-led dementias. We pose six key unanswered questions that challenge current assumptions and highlight the unresolved difficulties that surround these diseases. How many syndromes of primary progressive aphasia are there-and is syndromic diagnosis even useful? Are these truly 'language-led' dementias? How can we diagnose (and track) primary progressive aphasia better? Can brain pathology be predicted in these diseases? What is their core pathophysiology? In addition, how can primary progressive aphasia best be treated? We propose that pathophysiological mechanisms linking proteinopathies to phenotypes may help resolve the clinical complexity of primary progressive aphasia, and may suggest novel diagnostic tools and markers and guide the deployment of effective therapies.

Musical experience influences socio-emotional functioning in behavioural variant frontotemporal dementia.

Objectives: On phenotypic and neuroanatomical grounds, music exposure might potentially affect the clinical expression of behavioural variant frontotemporal dementia (bvFTD). However, this has not been clarified. Methods: 14 consecutive patients with bvFTD fulfilling consensus diagnostic criteria were recruited via a specialist cognitive clinic. Earlier life musical experience, current musical listening habits and general socio-emotional behaviours were scored using a bespoke semi-quantitative musical survey and standardised functional scales, completed with the assistance of patients' primary caregivers. Associations of musical scores with behavioural scales were assessed using a linear regression model adjusted for age, sex, educational attainment and level of executive and general cognitive impairment. Results: Greater earlier life musical experience was associated with significantly lower Cambridge Behavioural Inventory (Revised) scores (ß ± SE = -17.2 ± 5.2; p = 0.01) and higher Modified Interpersonal Reactivity Index (MIRI) perspective-taking scores (ß ± SE = 2.8 ± 1.1; p = 0.03), after adjusting for general cognitive ability. Number of hours each week currently spent listening to music was associated with higher MIRI empathic concern (ß ± SE = 0.7 ± 0.21; p = 0.015) and MIRI total scores (ß ± SE = 1.1 ± 0.34; p = 0.014). Discussion: Musical experience in earlier life and potentially ongoing regular music listening may ameliorate socio-emotional functioning in bvFTD. Future work in larger cohorts is required to substantiate the robustness of this association, establish its mechanism and evaluate its clinical potential.

LET-381/FoxF and UNC-30/Pitx2 control the development of C. elegans mesodermal glia that regulate motor behavior.

While most CNS glia arise from neuroectodermal progenitors, some, like microglia, are mesodermally derived. To understand mesodermal glia development and function, we investigated C. elegans GLR glia, which ensheath the brain neuropil and separate it from the circulatory-system cavity. Transcriptome analysis suggests GLR glia merge astrocytic and endothelial characteristics relegated to separate cell types in vertebrates. Combined fate acquisition is orchestrated by LET-381/FoxF, a fate-specification/maintenance transcription factor expressed in glia and endothelia of other animals. Among LET-381/FoxF targets, UNC-30/Pitx2 transcription factor controls GLR glia morphology and represses alternative mesodermal fates. LET-381 and UNC-30 co-expression in naïve cells is sufficient for GLR glia gene expression. GLR glia inactivation by ablation or let-381 mutation disrupts locomotory behavior and induces salt hypersensitivity, suggesting brain-neuropil activity dysregulation. Our studies uncover mechanisms of mesodermal glia development and show that like neurons, glia differentiation requires autoregulatory terminal selector genes that define and maintain the glial fate.

Symptom-led staging for primary progressive aphasia.

The primary progressive aphasias (PPA) present complex and diverse challenges of diagnosis, management and prognosis. A clinically-informed, syndromic staging system for PPA would take a substantial step toward meeting these challenges. This study addressed this need using detailed, multi-domain mixed-methods symptom surveys of people with lived experience in a large international PPA cohort. We administered structured online surveys to caregivers of patients with a canonical PPA syndromic variant (nonfluent/agrammatic (nvPPA), semantic (svPPA) or logopenic (lvPPA)). In an 'exploratory' survey, a putative list and ordering of verbal communication and nonverbal functioning (nonverbal thinking, conduct and wellbeing, physical) symptoms was administered to 118 caregiver members of the UK national PPA Support Group. Based on feedback, we expanded the symptom list and created six provisional clinical stages for each PPA subtype. In a 'consolidation' survey, these stages were presented to 110 caregiver members of UK and Australian PPA Support Groups, and refined based on quantitative and qualitative feedback. Symptoms were retained if rated as 'present' by a majority (at least 50%) of respondents representing that PPA syndrome, and assigned to a consolidated stage based on majority consensus; the confidence of assignment was estimated for each symptom as the proportion of respondents in agreement with the final staging for that symptom. Qualitative responses were analysed using framework analysis. For each PPA syndrome, six stages ranging from 1 ('Very mild') to 6 ('Profound') were identified; earliest stages were distinguished by syndromic hallmark symptoms of communication dysfunction, with increasing trans-syndromic convergence and dependency for basic activities of daily living at later stages. Spelling errors, hearing changes and nonverbal behavioural features were reported at early stages in all syndromes. As the illness evolved, swallowing and mobility problems were reported earlier in nfvPPA than other syndromes, while difficulty recognising familiar people and household items characterised svPPA and visuospatial symptoms were more prominent in lvPPA. Overall confidence of symptom staging was higher for svPPA than other syndromes. Across syndromes, functional milestones were identified as key deficits that predict the sequence of major daily life impacts and associated management needs. Qualitatively, we identified five major themes encompassing 15 subthemes capturing respondents' experiences of PPA and suggestions for staging implementation. This work introduces a prototypical, symptom-led staging scheme for canonical PPA syndromes: the PPA Progression Planning Aid (PPA 2 ). Our findings have implications for diagnostic and care pathway guidelines, trial design and personalised prognosis and treatment for people living with these diseases.

Phonemic restoration in Alzheimer's disease and semantic dementia: a preliminary investigation.

Phonemic restoration-perceiving speech sounds that are actually missing-is a fundamental perceptual process that 'repairs' interrupted spoken messages during noisy everyday listening. As a dynamic, integrative process, phonemic restoration is potentially affected by neurodegenerative pathologies, but this has not been clarified. Here, we studied this phenomenon in 5 patients with typical Alzheimer's disease and 4 patients with semantic dementia, relative to 22 age-matched healthy controls. Participants heard isolated sounds, spoken real words and pseudowords in which noise bursts either overlaid a consonant or replaced it; a tendency to hear replaced (missing) speech sounds as present signified phonemic restoration. All groups perceived isolated noises normally and showed phonemic restoration of real words, most marked in Alzheimer's patients. For pseudowords, healthy controls showed no phonemic restoration, while Alzheimer's patients showed marked suppression of phonemic restoration and patients with semantic dementia contrastingly showed phonemic restoration comparable to real words. Our findings provide the first evidence that phonemic restoration is preserved or even enhanced in neurodegenerative diseases, with distinct syndromic profiles that may reflect the relative integrity of bottom-up phonological representation and top-down lexical disambiguation mechanisms in different diseases. This work has theoretical implications for predictive coding models of language and neurodegenerative disease and for understanding cognitive 'repair' processes in dementia. Future research should expand on these preliminary observations with larger cohorts.

Remote versus face-to-face neuropsychological testing for dementia research: a comparative study in people with Alzheimer's disease, frontotemporal dementia and healthy older individuals.

OBJECTIVES: We explored whether adapting neuropsychological tests for online administration during the COVID-19 pandemic was feasible for dementia research. DESIGN: We used a longitudinal design for healthy controls, who completed face-to-face assessments 3-4 years before remote assessments. For patients, we used a cross-sectional design, contrasting a prospective remote cohort with a retrospective face-to-face cohort matched for age/education/severity. SETTING: Remote assessments were conducted using video-conferencing/online testing platforms, with participants using a personal computer/tablet at home. Face-to-face assessments were conducted in testing rooms at our research centre. PARTICIPANTS: The remote cohort comprised 25 patients (n=8 Alzheimer's disease (AD); n=3 behavioural variant frontotemporal dementia (bvFTD); n=4 semantic dementia (SD); n=5 progressive non-fluent aphasia (PNFA); n=5 logopenic aphasia (LPA)). The face-to-face patient cohort comprised 64 patients (n=25 AD; n=12 bvFTD; n=9 SD; n=12 PNFA; n=6 LPA). Ten controls who previously participated in face-to-face research also took part remotely. OUTCOME MEASURES: The outcome measures comprised the strength of evidence under a Bayesian framework for differences in performances between testing environments on general neuropsychological and neurolinguistic measures. RESULTS: There was substantial evidence suggesting no difference across environments in both the healthy control and combined patient cohorts (including measures of working memory, single-word comprehension, arithmetic and naming; Bayes Factors (BF)01 >3), in the healthy control group alone (including measures of letter/category fluency, semantic knowledge and bisyllabic word repetition; all BF01 >3), and in the combined patient cohort alone (including measures of working memory, episodic memory, short-term verbal memory, visual perception, non-word reading, sentence comprehension and bisyllabic/trisyllabic word repetition; all BF01 >3). In the control cohort alone, there was substantial evidence in support of a difference across environments for tests of visual perception (BF01=0.0404) and monosyllabic word repetition (BF01=0.0487). CONCLUSIONS: Our findings suggest that remote delivery of neuropsychological tests for dementia research is feasible.

Processing of Degraded Speech in Brain Disorders.

The speech we hear every day is typically "degraded" by competing sounds and the idiosyncratic vocal characteristics of individual speakers. While the comprehension of "degraded" speech is normally automatic, it depends on dynamic and adaptive processing across distributed neural networks. This presents the brain with an immense computational challenge, making degraded speech processing vulnerable to a range of brain disorders. Therefore, it is likely to be a sensitive marker of neural circuit dysfunction and an index of retained neural plasticity. Considering experimental methods for studying degraded speech and factors that affect its processing in healthy individuals, we review the evidence for altered degraded speech processing in major neurodegenerative diseases, traumatic brain injury and stroke. We develop a predictive coding framework for understanding deficits of degraded speech processing in these disorders, focussing on the "language-led dementias"-the primary progressive aphasias. We conclude by considering prospects for using degraded speech as a probe of language network pathophysiology, a diagnostic tool and a target for therapeutic intervention.

Impaired phonemic discrimination in logopenic variant primary progressive aphasia.

Logopenic variant primary progressive aphasia (lvPPA) is the least well defined of the major primary progressive aphasia (PPA) syndromes. We assessed phoneme discrimination in patients with PPA (semantic, nonfluent/agrammatic, and logopenic variants) and typical Alzheimer's disease, relative to healthy age-matched participants. The lvPPA group performed significantly worse than all other groups apart from tAD, after adjusting for auditory verbal working memory. In the combined PPA cohort, voxel-based morphometry correlated phonemic discrimination score with grey matter in left angular gyrus. Our findings suggest that impaired phonemic discrimination may help differentiate lvPPA from other PPA subtypes, with important diagnostic and management implications.

Flaxseed does not antagonize the effect of ultra-low-dose estrogen therapy on bone mineral density and biomechanical bone strength in ovariectomized rats.

A previous study showed that flaxseed (FS) combined with low-dose (LD) estrogen therapy, resembling LD transdermal estrogen therapy in postmenopaual women, inhibited loss of bone mineral density (BMD), bone mineral content (BMC), and strength in lumbar vertebrae in ovariectomized rats. Whether FS combined with an even lower dose of estrogen is effective at preserving bone or whether FS interferes with the effect of this lower dose of estrogen is unknown. Thus, this study determined whether an ultra-low-dose (ULD) estrogen therapy, half the dose previously studied, in combination with FS preserved bone mass and strength in the lumbar vertebrae in ovariectomized rats. Rats were treated for 12 wk with (1) basal diet (BD) (ovariectomized control), (2) BD + ULD estrogen implant, or (3) BD containing 10% FS + ULD estrogen implant. A sham-operated control group was fed BD. Unlike ULD, FS + ULD attenuated loss of BMD and strength at the lumbar vertebrae and BMD in femurs and tibias. FS + ULD resulted in higher percentages of n-3 fatty acids including alpha-linolenic acid and eicosapentaenoic acid and lower percentages of n-6 fatty acids including linoleic acid compared to all other groups. Differences in fatty acid composition at the lumbar vertebrae and tibia were significantly related to BMD, BMC, and strength. No treatment-induced effects on uterus weight were observed, but histological analyses are needed to confirm safety. In conclusion, FS did not antagonize the activity of ULD, and their combination attenuated the loss of BMD and strength at the lumbar vertebrae, which was associated with differences in bone fatty acid composition.

Implementing a health literacy module fostering patient-centered written communication in a cardiovascular prevention elective course.

BACKGROUND: A universal approach to health literacy employs clear communication and emphasizes patient action in support of understanding cardiovascular risks and making healthy lifestyle changes. The aim of this project was to evaluate the impact of a health literacy module on enhancing students' written patient education material using standardized readability assessment tools. EDUCATIONAL ACTIVITY: A professional elective course employed team-based learning and a community health fair activity. The course was enhanced with four hours of health literacy content. Pharmacy student learners were assigned a cardiovascular condition and designed an informational pamphlet. Two faculty members evaluated the student pamphlets in the pre-health literacy module (n = 15) and post-module (n = 23) groups using the Flesch grade level, Flesch reading ease score, and 15 health literacy criteria identified from previous literature. CRITICAL ANALYSIS OF THE EDUCATIONAL ACTIVITY: There was a modest integration of health literacy concepts based on the Flesch grade level and the mean total health literacy criteria achieved. Student learners improved in areas of readability, message content, numeracy/statistics, and patient actionability concepts. Simplifying technical jargon remains to be a barrier. The results will be used to improve our health literacy pamphlet rubric and classroom instruction. The health literacy module was valuable in fostering understanding and application of health literacy concepts, and preparing student learners for providing patient-centered communication.

Autophagy protein NRBF2 has reduced expression in Alzheimer's brains and modulates memory and amyloid-beta homeostasis in mice.

BACKGROUND: Dysfunctional autophagy is implicated in Alzheimer's Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the disparity of the changes confounds the role of autophagy in AD. METHODS: To further understand the autophagy alteration in AD brains, we analyzed transcriptomic (RNAseq) datasets of several brain regions (BA10, BA22, BA36 and BA44 in 223 patients compared to 59 healthy controls) and measured the expression of 130 ATGs. We used autophagy-deficient mouse models to assess the impact of the identified ATGs depletion on memory, autophagic activity and amyloid-ß (Aß) production. RESULTS: We observed significant downregulation of multiple components of two autophagy kinase complexes BECN1-PIK3C3 and ULK1/2-FIP200 specifically in the parahippocampal gyrus (BA36). Most importantly, we demonstrated that deletion of NRBF2, a component of the BECN1-PIK3C3 complex, which also associates with ULK1/2-FIP200 complex, impairs memory in mice, alters long-term potentiation (LTP), reduces autophagy in mouse hippocampus, and promotes Aß accumulation. Furthermore, AAV-mediated NRBF2 overexpression in the hippocampus not only rescues the impaired autophagy and memory deficits in NRBF2-depleted mice, but also reduces ß-amyloid levels and improves memory in an AD mouse model. CONCLUSIONS: Our data not only implicates NRBF2 deficiency as a risk factor for cognitive impairment associated with AD, but also support the idea of NRBF2 as a potential therapeutic target for AD.

Ovariectomy-induced hyperphagia does not modulate bone mineral density or bone strength in rats.

The ovariectomized (OVX) rat is a widely used animal model for the development of prevention and treatment strategies for postmenopausal osteoporosis. However, ovariectomy-induced hyperphagia results in weight gain and adiposity. To prevent potential protective effects of increased body weight on bone from confounding outcomes of preclinical studies, pair-feeding is used in some but not all studies to control food intake, but its importance is not well elucidated. We investigated if the type of feeding, pair-feeding vs. consumption of diet ad libitum, modulates bone mineral and bone strength in OVX rats. Three-month-old female Sprague-Dawley rats (n = 12/group) were randomized to 1) sham-operated control (SHAM); 2) OVX pair-fed (OVX-PF); and 3) OVX ad libitum (OVX-AL). For 14 wk, OVX-PF rats were pair-fed with the SHAM group and daily food intakes and weekly body weights were obtained. At necropsy, regional body composition was measured by dual energy X-ray absorptiometry. Bone mineral density (BMD) and biomechanical bone strength of femurs and lumbar vertebrae (LV) were also measured. OVX-AL rats had higher overall food intake (P < 0.01), final body weight (P < 0.01), weight gain (P < 0.01), and fat mass (P < 0.05) than either SHAM and OVX-PF rats. Conversely, SHAM rats had higher femur (P < 0.001) and LV1-3 BMD (P < 0.001) as well as LV4 peak load (P < 0.01) than both the OVX groups, whereas bone outcomes did not differ between the OVX-PF and OVX-AL groups. In summary, ovariectomy-induced hyperphagia and weight gain do not modulate BMD or biomechanical strength at 14 wk postovariectomy, suggesting that pair-feeding is not essential.