Alterations to metabolic hormones in amyotrophic lateral sclerosis and frontotemporal dementia postmortem human tissue.

Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.

Gyrase and Topoisomerase IV: Recycling Old Targets for New Antibacterials to Combat Fluoroquinolone Resistance.

Beyond their requisite functions in many critical DNA processes, the bacterial type II topoisomerases, gyrase and topoisomerase IV, are the targets of fluoroquinolone antibacterials. These drugs act by stabilizing gyrase/topoisomerase IV-generated DNA strand breaks and by robbing the cell of the catalytic activities of these essential enzymes. Since their clinical approval in the mid-1980s, fluoroquinolones have been used to treat a broad spectrum of infectious diseases and are listed among the five "highest priority" critically important antimicrobial classes by the World Health Organization. Unfortunately, the widespread use of fluoroquinolones has been accompanied by a rise in target-mediated resistance caused by specific mutations in gyrase and topoisomerase IV, which has curtailed the medical efficacy of this drug class. As a result, efforts are underway to identify novel antibacterials that target the bacterial type II topoisomerases. Several new classes of gyrase/topoisomerase IV-targeted antibacterials have emerged, including novel bacterial topoisomerase inhibitors, Mycobacterium tuberculosis gyrase inhibitors, triazaacenaphthylenes, spiropyrimidinetriones, and thiophenes. Phase III clinical trials that utilized two members of these classes, gepotidacin (triazaacenaphthylene) and zoliflodacin (spiropyrimidinetrione), have been completed with positive outcomes, underscoring the potential of these compounds to become the first new classes of antibacterials introduced into the clinic in decades. Because gyrase and topoisomerase IV are validated targets for established and emerging antibacterials, this review will describe the catalytic mechanism and cellular activities of the bacterial type II topoisomerases, their interactions with fluoroquinolones, the mechanism of target-mediated fluoroquinolone resistance, and the actions of novel antibacterials against wild-type and fluoroquinolone-resistant gyrase and topoisomerase IV.

Experimental laboratory models as tools for understanding modifiable dementia risk.

Experimental laboratory research has an important role to play in dementia prevention. Mechanisms underlying modifiable risk factors for dementia are promising targets for dementia prevention but are difficult to investigate in human populations due to technological constraints and confounds. Therefore, controlled laboratory experiments in models such as transgenic rodents, invertebrates and in vitro cultured cells are increasingly used to investigate dementia risk factors and test strategies which target them to prevent dementia. This review provides an overview of experimental research into 15 established and putative modifiable dementia risk factors: less early-life education, hearing loss, depression, social isolation, life stress, hypertension, obesity, diabetes, physical inactivity, heavy alcohol use, smoking, air pollution, anesthetic exposure, traumatic brain injury, and disordered sleep. It explores how experimental models have been, and can be, used to address questions about modifiable dementia risk and prevention that cannot readily be addressed in human studies. HIGHLIGHTS: Modifiable dementia risk factors are promising targets for dementia prevention. Interrogation of mechanisms underlying dementia risk is difficult in human populations. Studies using diverse experimental models are revealing modifiable dementia risk mechanisms. We review experimental research into 15 modifiable dementia risk factors. Laboratory science can contribute uniquely to dementia prevention.

Target-Mediated Fluoroquinolone Resistance in Neisseria gonorrhoeae: Actions of Ciprofloxacin against Gyrase and Topoisomerase IV.

Fluoroquinolones make up a critically important class of antibacterials administered worldwide to treat human infections. However, their clinical utility has been curtailed by target-mediated resistance, which is caused by mutations in the fluoroquinolone targets, gyrase and topoisomerase IV. An important pathogen that has been affected by this resistance is Neisseria gonorrhoeae, the causative agent of gonorrhea. Over 82 million new cases of this sexually transmitted infection were reported globally in 2020. Despite the impact of fluoroquinolone resistance on gonorrhea treatment, little is known about the interactions of this drug class with its targets in this bacterium. Therefore, we investigated the effects of the fluoroquinolone ciprofloxacin on the catalytic and DNA cleavage activities of wild-type gyrase and topoisomerase IV and the corresponding enzymes that harbor mutations associated with cellular and clinical resistance to fluoroquinolones. Results indicate that ciprofloxacin interacts with both gyrase (its primary target) and topoisomerase IV (its secondary target) through a water-metal ion bridge that has been described in other species. Moreover, mutations in amino acid residues that anchor this bridge diminish the susceptibility of the enzymes for the drug, leading to fluoroquinolone resistance. Results further suggest that ciprofloxacin primarily induces its cytotoxic effects by enhancing gyrase-mediated DNA cleavage as opposed to inhibiting the DNA supercoiling activity of the enzyme. In conclusion, this work links the effects of ciprofloxacin on wild-type and resistant gyrase to results reported for cellular and clinical studies and provides a mechanistic explanation for the targeting and resistance of fluoroquinolones in N. gonorrhoeae.

Development of a smartphone screening test for preclinical Alzheimer's disease and validation across the dementia continuum.

BACKGROUND: Dementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer's disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10-20-year period of progressive brain pathology without noticeable cognitive symptoms, for targeted risk reduction. Current tests of AD pathology are either too invasive, specialised or expensive for population-level assessments. Cognitive tests are normal in preclinical AD. Emerging evidence demonstrates that movement analysis is sensitive to AD across the disease continuum, including preclinical AD. Our new smartphone test, TapTalk, combines analysis of hand and speech-like movements to detect AD risk. This study aims to [1] determine which combinations of hand-speech movement data most accurately predict preclinical AD [2], determine usability, reliability, and validity of TapTalk in cognitively asymptomatic older adults and [3], prospectively validate TapTalk in older adults who have cognitive symptoms against cognitive tests and clinical diagnoses of Mild Cognitive Impairment and AD dementia. METHODS: Aim 1 will be addressed in a cross-sectional study of at least 500 cognitively asymptomatic older adults who will complete computerised tests comprising measures of hand motor control (finger tapping) and oro-motor control (syllabic diadochokinesis). So far, 1382 adults, mean (SD) age 66.20 (7.65) years, range 50-92 (72.07% female) have been recruited. Motor measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 to develop an algorithm that classifies preclinical AD risk. Aim 2 comprises three sub-studies in cognitively asymptomatic adults: (i) a cross-sectional study of 30-40 adults to determine the validity of data collection from different types of smartphones, (ii) a prospective cohort study of 50-100 adults ≥ 50 years old to determine usability and test-retest reliability, and (iii) a prospective cohort study of ~1,000 adults ≥ 50 years old to validate against cognitive measures. Aim 3 will be addressed in a cross-sectional study of ~200 participants with cognitive symptoms to validate TapTalk against Montreal Cognitive Assessment and interdisciplinary consensus diagnosis. DISCUSSION: This study will establish the precision of TapTalk to identify preclinical AD and estimate risk of cognitive decline. If accurate, this innovative smartphone app will enable low-cost, accessible screening of individuals for AD risk. This will have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06114914, 29 October 2023. Retrospectively registered.

When It's Not Worn on the Face: Trait Anxiety and Attention to Neutral Faces Semantically Linked to Threat.

While our direct observations of the features or behaviours of the stimuli around us tell us much about them (e.g., should they be feared?), the origin of much of our knowledge is often untethered from directly observable properties (e.g., through what we have learned or have been told about them, or "semantic knowledge"). Here, we ask whether otherwise neutral visual stimuli that participants learn to associate with emotional qualities in the lab cause the stimuli to be attended in a similar way as stimuli whose emotional qualities can be discerned through their visual properties. In Experiment 1, participants learned to associate negative or neutral characteristics with neutral faces, which then served as valid or invalid spatial cues to targets in an attentional disengagement paradigm. The performance of participants higher in trait anxiety was consistent with attentional avoidance of faces with learned negative associations, while participants lower in trait anxiety showed a general response slowing in trials with these stimuli, compared to those with neutral associations. In contrast, in Experiment 2, using (visually) expressive (angry) faces, the performance of participants higher in trait anxiety was consistent with difficulty disengaging from visually threatening faces, while the performance of those with lower trait anxiety appeared unaffected by the valence of the stimuli. These findings suggest that (1) emotionality acquired indirectly via learned semantic knowledge impacts how attention is allocated to face stimuli, and this impact is influenced by trait anxiety, and (2) there are differences in the effects of stimulus emotionality depending on whether it is acquired indirectly or directly via the perceptual features of the stimulus. These differences are discussed in the context of the variability of attention bias effects reported in the literature and the time course of impacts of emotionality on stimulus processing.

Modifiable dementia risk factors and AT(N) biomarkers: findings from the EPAD cohort.

Introduction: Modifiable risk factors account for a substantial proportion of Alzheimer's disease (AD) cases and we currently have a discrete AT(N) biomarker profile for AD biomarkers: amyloid (A), p-tau (T), and neurodegeneration (N). Here, we investigated how modifiable risk factors relate to the three hallmark AT(N) biomarkers of AD. Methods: Participants from the European Prevention of Alzheimer's Dementia (EPAD) study underwent clinical assessments, brain magnetic resonance imaging, and cerebrospinal fluid collection and analysis. Generalized additive models (GAMs) with penalized regression splines were modeled in the AD Workbench on the NTKApp. Results: A total of 1,434 participants were included (56% women, 39% APOE ε4+) with an average age of 65.5 (± 7.2) years. We found that modifiable risk factors of less education (t = 3.9, p < 0.001), less exercise (t = 2.1, p = 0.034), traumatic brain injury (t = -2.1, p = 0.036), and higher body mass index (t = -4.5, p < 0.001) were all significantly associated with higher AD biomarker burden. Discussion: This cross-sectional study provides further support for modifiable risk factors displaying neuroprotective associations with the characteristic AT(N) biomarkers of AD.

Isolation and Identification of the High-Affinity DNA Aptamer Target to the Brain-Derived Neurotrophic Factor (BDNF).

Aptamers are functional oligonucleotide ligands used for the molecular recognition of various targets. The natural characteristics of aptamers make them an excellent alternative to antibodies in diagnostics, therapeutics, and biosensing. DNA aptamers are mainly single-stranded oligonucleotides (ssDNA) that possess a definite binding to targets. However, the application of aptamers to the fields of brain health and neurodegenerative diseases has been limited to date. Herein, a DNA aptamer against the brain-derived neurotrophic factor (BDNF) protein was obtained by in vitro selection. BDNF is a potential biomarker of brain health and neurodegenerative diseases and has functions in the synaptic plasticity and survival of neurons. We identified eight aptamers that have binding affinity for BDNF from a 50-nucleotide library. Among these aptamers, NV_B12 showed the highest sensitivity and selectivity for detecting BDNF. In an aptamer-linked immobilized sorbent assay (ALISA), the NV_B12 aptamer strongly bound to BDNF protein, in a dose-dependent manner. The dissociation constant (Kd) for NV_B12 was 0.5 nM (95% CI: 0.4-0.6 nM). These findings suggest that BDNF-specific aptamers could be used as an alternative to antibodies in diagnostic and detection assays for BDNF.

Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease: A Randomized Clinical Trial.

Importance: Accumulation of hyperphosphorylated, tangled microtubule-associated protein tau (MAPT) is a pathological hallmark of Alzheimer disease (AD) associated with disease progression and cognitive decline. Objective: To evaluate the effect of tau synthesis reduction on tau biomarkers in patients with mild AD. Design, Setting, and Participants: This randomized clinical trial was a double-blind, placebo-controlled 36-week multiple-ascending dose (MAD) phase 1b trial (October 2017 to September 2020), followed by a 64- or 71-week open-label long-term extension (LTE) (October 2019 to May 2022). After being assessed for eligibility at 12 sites in Canada and Europe, participants with mild AD and confirmed amyloid pathology were randomized 3:1 (BIIB080:placebo) in 4 dose cohorts. Intervention: Intrathecal administration of BIIB080, a MAPT-targeting antisense oligonucleotide, or placebo. Active dose arms included 10 mg every 4 weeks, 30 mg every 4 weeks, 60 mg every 4 weeks, and 115 mg every 12 weeks during the MAD period and 60 mg every 12 weeks or 115 mg every 12 weeks during the LTE. Main Outcome and Measures: The original primary end point was safety. Additionally, BIIB080, total tau (t-tau), and phosphorylated tau 181 (p-tau181) cerebrospinal fluid (CSF) concentrations were evaluated. Tau positron emission tomography (PET) was collected in a substudy, and standard uptake value ratios (SUVRs) were calculated in a priori-defined composite regions of interest. Results: Of 102 participants assessed for eligibility, 46 participants with mild AD were enrolled; 23 (50%) were female, and mean (SD) age was 65.8 (5.70) years. BIIB080 was generally well tolerated and was associated with a dose-dependent reduction in CSF t-tau and p-tau181 in the MAD period (56% reduction; 95% CI, 50% to 62%; and 51% reduction; 95% CI, 38% to 63%, of CSF t-tau in the 2 higher-dose cohorts) that continued and/or was maintained through quarterly dosing in the LTE. Tau PET demonstrated reduced accumulation vs placebo at week 25 (n = 13). At week 100, tau PET showed a reduction from baseline across all regions assessed (n = 12), with the largest reductions from baseline observed in the temporal composite (-0.71 SUVR; 95% CI, -1.40 to -0.02). A moderate correlation was observed between model-predicted cumulative CSF drug exposure and tau PET change. Conclusions and Relevance: In this randomized clinical trial, BIIB080 reduced tau biomarkers, including CSF t-tau, CSF p-tau181, and tau PET, which is associated with cognitive decline, in participants with mild AD. Effects of BIIB080 on biomarkers and clinical outcomes are being further evaluated in a phase 2 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT03186989.

Does serum neurofilament light help predict accelerated cognitive ageing in unimpaired older adults?

Introduction: Neurofilament light (NfL) is a blood biomarker of neurodegeneration. While serum NfL levels have been demonstrated to increase with normal ageing, the relationship between serum NfL levels and normal age-related changes in cognitive functions is less well understood. Methods: The current study investigated whether cross-sectional serum NfL levels measured by single molecule array technology (Simoa®) mediated the effect of age on cognition, measured by a battery of neuropsychological tests administered biannually for 8 years, in a cohort of 174 unimpaired older adults (≥50 years) from the Tasmanian Healthy Brain Project. Mediation analysis was conducted using latent variables representing cognitive test performance on three cognitive domains - episodic memory, executive function, and language (vocabulary, comprehension, naming). Cognitive test scores for the three domains were estimated for each participant, coincident with blood collection in 2018 using linear Bayesian hierarchical models. Results: Higher serum NfL levels were significantly positively associated with age (p < 0.001 for all domains). Cognitive test scores were significantly negatively associated with age across the domains of executive function (p < 0.001), episodic memory (p < 0.001) and language (p < 0.05). However, serum NfL levels did not significantly mediate the relationship between age and cognitive test scores across any of the domains. Discussion: This study adds to the literature on the relationship between serum NfL levels and cognition in unimpaired older adults and suggests that serum NfL is not a pre-clinical biomarker of ensuing cognitive decline in unimpaired older adults.

Modifiable risk factors for dementia, cognition, and plasma phosphorylated tau 181 in a large-scale cohort of Australian older adults.

Alzheimer's disease (AD), the most common form of dementia, is preceded by years of silent pathological change. Our objective was to examine the associations between modifiable dementia risk factors, cognition, and plasma phosphorylated p-tau 181, a hallmark biomarker of AD in a large-scale community cohort. Participants (n = 738, mean age 65.41 years) from the Island Study Linking Ageing and Neurodegenerative Disease responded to online assessments collecting demographics, adherence to dementia risk factors and cognitive function, and provided a blood sample for analysis. We found less education was significantly associated with lower cognitive scores. Modifiable dementia risk factors were not associated with plasma p-tau 181. Further, we did not observe any significant relationships between plasma p-tau 181 and cognition. Nonmodifiable factors such as age, education, sex, and apolipoprotein E epsilon 4 displayed significant associations with cognition and plasma p-tau 181. In a cognitively healthy community cohort of Tasmanian Australians, we did not observe any associations between modifiable risk factors for dementia and plasma p-tau 181. Nonmodifiable risk factors were associated with both cognition and plasma p-tau. This contributes to a growing body of evidence investigating confounding factors in the interpretation of blood-based biomarkers for dementia.

Actions of a Novel Bacterial Topoisomerase Inhibitor against Neisseria gonorrhoeae Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks.

Novel bacterial topoisomerase inhibitors (NBTIs) are an emerging class of antibacterials that target gyrase and topoisomerase IV. A hallmark of NBTIs is their ability to induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, a previous study reported that some dioxane-linked amide NBTIs induced double-stranded DNA breaks mediated by Staphylococcus aureus gyrase. To further explore the ability of this NBTI subclass to increase double-stranded DNA breaks, we examined the effects of OSUAB-185 on DNA cleavage mediated by Neisseria gonorrhoeae gyrase and topoisomerase IV. OSUAB-185 induced single-stranded and suppressed double-stranded DNA breaks mediated by N. gonorrhoeae gyrase. However, the compound stabilized both single- and double-stranded DNA breaks mediated by topoisomerase IV. The induction of double-stranded breaks does not appear to correlate with the binding of a second OSUAB-185 molecule and extends to fluoroquinolone-resistant N. gonorrhoeae topoisomerase IV, as well as type II enzymes from other bacteria and humans. The double-stranded DNA cleavage activity of OSUAB-185 and other dioxane-linked NBTIs represents a paradigm shift in a hallmark characteristic of NBTIs and suggests that some members of this subclass may have alternative binding motifs in the cleavage complex.

A new one-stop interdisciplinary cognitive clinic model tackles rural health inequality and halves the time to diagnosis: Benchmarked against a national dementia registry.

OBJECTIVES: Unequal access to cognitive assessments is a major barrier to timely diagnosis, especially for those living in rural or remote areas. 'One-stop' cognitive clinic models are a proposed solution, but few such clinics exist. We evaluate the implementation of a new one-stop State-wide clinic model in Tasmania, Australia, where 27% of people live in rural/remote areas. METHODS: A novel single-visit protocol has been developed, comprising interdisciplinary medical and cognitive assessments, research participation, consensus diagnosis and management plan. A cross-sectional evaluation was undertaken using the RE-AIM (reach, effectiveness, adoption, implementation, maintenance) framework and results benchmarked against the national Australian Dementia Network Registry. RESULTS: Over the first 52 consecutive weekly clinics: Reach: 130 adults were assessed (mean age [SD] 70.12 years [10.31]; 59.2% female) with 40 (36.8%) from rural/remote areas. EFFECTIVENESS: 98.5% (128/130) received a same-day diagnosis: 30.1% (n = 40) Subjective Cognitive Decline, 35.4% (46) Mild Cognitive Impairment, 33.1% (43) dementia and one case inconclusive. Adoption: 22.9% (156) of General Practitioners referred patients. IMPLEMENTATION: Nearly all 'ideal' diagnostic clinical practices were met and >90% of surveyed patients reported 'good/very good' clinic experience. The wait from referral to diagnosis was 2 months shorter than other national Registry clinics (78 vs. 133 days). CONCLUSIONS: This 'one-stop' model provides an interdisciplinary consensus cognitive diagnosis quickly and is well accepted; this may reduce health inequities especially for people living in rural/remote areas. This cognitive clinic model may be of relevance to other centres worldwide and also provides a rich data source for research studies.

Preserving choice in breast cancer treatment: A different perspective on contralateral prophylactic mastectomy.

Contralateral prophylactic mastectomy is the removal of both breasts when only one is affected by cancer. Rates of this controversial cancer treatment have been increasing since the late 1990s, even among women who do not have the kind of family history or known genetic mutation that would put them at high-risk for another breast cancer. Citing contralateral prophylactic mastectomy's lack of oncologic benefit and increased risk of surgical complications, the American Society of Breast Surgeons discourages contralateral prophylactic mastectomy for average-risk women with unilateral cancer, as does most of the medical literature on this topic. Within this literature, desire for contralateral prophylactic mastectomy is often painted as the product of an emotional overreaction to a cancer diagnosis and misunderstanding of breast cancer risk. Drawing on the personal experience of a breast cancer survivor, as well as relevant medical literature on breast cancer screening and surgery, this article offers a different perspective on the ongoing popularity of contralateral prophylactic mastectomy, one that focuses on practical experiences and logical deliberations about those experiences. Specifically, it calls attention to two features of the contralateral prophylactic mastectomy decision-making situation that have been inadequately covered in the medical literature: (1) the way that breast cancer screening after a breast cancer diagnosis can become a kind of radiological overtreatment, even for "average-risk" women; and (2) how desire for bodily symmetry after breast cancer, which can best be achieved through bilateral reconstruction or no reconstruction, drives interest in contralateral prophylactic mastectomy. The goal of this article is not to suggest that all women who want contralateral prophylactic mastectomy should have the surgery. In some cases, it is not advisable. But many "average-risk" women with unilateral cancer have good reasons for wanting contralateral prophylactic mastectomy, and we believe their right to choose it should be protected.

Microglia directly associate with pericytes in the central nervous system.

Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia associations with capillaries suggest they may play a role in the regulation of CBF or the blood-brain-barrier (BBB). We explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the control of CBF and maintenance of the BBB, discovering a spatially distinct subset of microglia that closely associate with pericytes. We termed these pericyte-associated microglia (PEM). PEM are present throughout the brain and spinal cord in NG2DsRed × CX3 CR1+/GFP mice, and in the human frontal cortex. Using in vivo two-photon microscopy, we found microglia residing adjacent to pericytes at all levels of the capillary tree and found they can maintain their position for at least 28 days. PEM can associate with pericytes lacking astroglial endfeet coverage and capillary vessel width is increased beneath pericytes with or without an associated PEM, but capillary width decreases if a pericyte loses a PEM. Deletion of the microglia fractalkine receptor (CX3 CR1) did not disrupt the association between pericytes and PEM. Finally, we found the proportion of microglia that are PEM declines in the superior frontal gyrus in AD. In summary, we identify microglia that specifically associate with pericytes and find these are reduced in number in AD, which may be a novel mechanism contributing to vascular dysfunction in neurodegenerative diseases.

A systematic review of the prevalence of depression, anxiety, and apathy in frontotemporal dementia, atypical and young-onset Alzheimer's disease, and inherited dementia.

OBJECTIVES: Depression, anxiety, and apathy are the most commonly reported neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD). Understanding their prevalence in rarer dementias such as frontotemporal dementia (FTD), primary progressive aphasia (PPA), posterior cortical atrophy (PCA), young-onset AD (YOAD), and inherited dementias has implications for both clinical practice and research. In this study, we aimed to examine the current state of knowledge of the prevalence of these three NPS in less prevalent dementias. DESIGN: We conducted a systematic review based on searches of EMBASE, PsycINFO, and PubMed up to September 2019. RESULTS: 47 articles meeting inclusion criteria were identified. Depression, anxiety, and apathy were commonly reported across the phenotypes studied but their prevalence showed large variation between studies. Apathy showed the highest reported frequency in FTD (50-100% across studies), behavioral variant frontotemporal dementia (bvFTD) (73-100%), and YOAD (44-100%). Anxiety was frequently reported in FTD (0-100%) and bvFTD (19-63%). Depression showed the highest prevalence in FTD (7-69%) and YOAD (11-55%). Among the three variants of PPA, sv-PPA is the one most investigated (seven articles). Three or fewer articles were identified examining NPS in the remaining PPA variants, PCA, familial AD, and familial FTD. Inconsistency in the tools used to measure symptoms and small sample sizes were common methodological limitations. CONCLUSIONS: Future studies should consider the inclusion of larger sample sizes (e.g. through multicenter collaborations) and the use of harmonized protocols that include the combination of caregiver and patient-derived measures and symptom-specific questionnaires. More research is needed on the phenotype-specific barriers and facilitators for people living with dementia to successfully engage in self-reports of NPS.

Assessing pain catastrophizing and functional disability in pediatric epidermolysis bullosa patients.

BACKGROUND/OBJECTIVES: The primary objective was to assess pain catastrophizing and functional disability in pediatric patients with epidermolysis bullosa (EB) and their parents/guardians. Secondary objectives included examining relationships between pain catastrophizing, functional disability, and correlations with other factors (e.g., age, disease severity, and percent of body surface area (BSA) involved). METHODS: Patients with EB ages 8-16 and their parents/guardians who were English or Spanish speaking completed a one-time online survey. Parent measures included: demographics questionnaire, Pain Catastrophizing Scale-Parent (PCS), and Parent Functional Disability Inventory (FDI). Child measures included: PCS child and child FDI. Higher scores on both scales indicate higher levels of catastrophizing and functional disability. RESULTS: Of 31 children, the mean age was 11.47 years and the majority (70.97%) had dystrophic EB. Mean scores were: 35.84 = PCS parent; 34.58 = PCS child; 30.87 = parent FDI; 29.77 = child FDI. Total scores for PCS parent, parent FDI, and child FDI increased significantly with disease severity and percentage of involved BSA (p < .01 for all). Total scores for PCS child increased significantly with percent of EB skin involvement (p = .04) but not disease severity. Older children reported more functional disability than their parents and younger children (p = .02). CONCLUSIONS: Our results demonstrate significant positive correlations between negative thoughts related to pain and the experience of functional difficulties in patients with EB and their caregivers. Psychological, psychiatric, and/or behavioral interventions to help managing chronic pain may be effective for patients with EB.

Sex-Specific Protective Effects of Cognitive Reserve on Age-Related Cognitive Decline: A 5-Year Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Females have a higher age-adjusted incidence of Alzheimer disease than males but the reasons for this remain unclear. One proposed contributing factor is that, historically, females had less access to education and, therefore, may accumulate less cognitive reserve. However, educational attainment is confounded by IQ, which in itself is a component of cognitive reserve and does not differ between sexes. Steeper age-related cognitive declines are associated with increased risk of dementia. We, therefore, evaluated the moderating effects of 2 proxies for cognitive reserve, education and IQ, on the steepness of age-related declining cognitive trajectories in unimpaired older males and females. METHODS: The Tasmanian Healthy Brain Project, a long-term cohort study, recruited healthy Australians aged 50-80 years without cognitive impairment. Baseline cognitive reserve was measured using educational history and IQ, measured by the Wechsler Test of Adult Reading, Full Scale Predicted IQ (WTAR-FSIQ). Cognitive trajectories for language, executive function, and episodic and working memory over 5 years were extracted from neuropsychological assessments. The adjusted effects of education, estimated IQ, and APOE allelic variant on cognitive trajectories were compared between males and females. RESULTS: Five hundred sixty-two individuals (mean [SD] age 60 [6.7] years; 68% male; 33% APOE ε4+) were followed up over 5 years with 1,924 assessments and 24,946 cognitive test scores (annualized attrition rate 6.6% per year). Estimated IQ correlated with years of education (p < 0.001). Estimated IQ interacted with sex to moderate age-related cognitive trajectories (p = 0.03; adjusted for education); lower IQ males experienced steeper declining trajectories than higher IQ males, but lower IQ females had similar steepness of declining trajectories to higher IQ females. Education was not associated with rate of cognitive decline (p = 0.67; adjusted for WTAR-FSIQ). There were no significant differences in age-related cognitive trajectories between APOE genotypes in either sex. DISCUSSION: IQ, a measure of cognitive reserve, predicted the steepness of declining cognitive trajectories in males only. Education did not explain as much variation in cognitive trajectories as IQ. Our findings do not support the hypothesis that historical sex disparities in access to education contribute to the higher female incidence of Alzheimer disease.

A Visual Interpretation Algorithm for Assessing Brain Tauopathy with 18F-MK-6240 PET.

In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials of Alzheimer disease (AD). 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (18F-MK-6240) is a radiotracer with high selectivity and subnanomolar affinity for neurofibrillary tangles that shows favorable nonspecific brain penetration and excellent kinetic properties. The purpose of the present investigation was to develop a visual assessment method that provides both an overall assessment of brain tauopathy and regional characterization of abnormal tau deposition. Methods: 18F-MK-6240 scans from 102 participants (including cognitively normal volunteers and patients with AD or other neurodegenerative disorders) were reviewed by an expert nuclear medicine physician masked to each participant's diagnosis to identify common patterns of brain uptake. This initial visual read method was field-tested in a separate, nonoverlapping cohort of 102 participants, with 2 additional naïve readers trained on the method. Visual read outcomes were compared with semiquantitative assessments using volume-of-interest SUV ratio. Results: For the visual read, the readers assessed 8 gray-matter regions per hemisphere as negative (no abnormal uptake) or positive (1%-25% of the region involved, 25%-75% involvement, or >75% involvement) and then characterized the tau binding pattern as positive or negative for evidence of tau and, if positive, whether brain uptake was in an AD pattern. The readers demonstrated agreement 94% of the time for overall positivity or negativity. Concordance on the determination of regional binary outcomes (negative or positive) showed agreement of 74.3% and a Fleiss κ of 0.912. Using clinical diagnosis as the ground truth, the readers demonstrated a sensitivity of 73%-79% and specificity of 91%-93%, with a combined reader-concordance sensitivity of 80% and specificity of 93%. The average SUV ratio in cortical regions showed a robust correlation with visually derived ratings of regional involvement (r = 0.73, P < 0.0001). Conclusion: We developed a visual read algorithm for 18F-MK-6240 PET offering determination of both scan positivity and the regional degree of cortical involvement. These cross-sectional results show strong interreader concordance on both binary and regional assessments of tau deposition, as well as good sensitivity and excellent specificity supporting use as a tool for clinical trials.

Critical power and work-prime account for variability in endurance training adaptations not captured by V̇o2max.

Responses to exercise at a given percentage of one's maximum rate of oxygen consumption (V̇o2max), or percentage of the power associated with V̇o2max during a graded exercise test (i.e., PGXT), vary. The purpose of this study was to determine if differences in critical power (PCRIT, maximum metabolic steady state) and work-prime (W', the amount of work tolerated above steady state) are related to training-induced changes in endurance. PCRIT, W', V̇o2max, and other variables were determined before and after 22 adults completed 8 wk of either moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) performed at fixed percentages of PGXT. On average, PCRIT increased to a greater extent following HIIT (MICT: 15.7 ± 3.1% vs. HIIT: 27.5 ± 4.3%; P = 0.03), but the magnitude of change varied widely within each group (MICT: 4%-36%, HIIT: 4%-61%). The intensity of the prescribed exercise relative to pretraining PCRIT, not PGXT, accounted for most of the variance in changes to PCRIT in response to a given protocol (R2 = 0.61-0.64; P < 0.01). Although PCRIT and V̇o2max were related before training (R2 = 0.92, P < 0.01), the training-induced change in PCRIT was not significantly related to the change in V̇o2max (R2 = 0.06, P = 0.26). Before training, time-to-failure at PGXT was related to W' (R2 = 0.52; P < 0.01), but not V̇o2max (R2 = 0.13; P = 0.10). Training-induced changes in time-to-failure at the initial PGXT were better captured by the combined changes in W' and PCRIT (R2 = 0.77, P < 0.01), than by the change in V̇o2max (R2 = 0.24; P = 0.02). Differences in PCRIT and W' account for some of the variability in responses to endurance exercise.NEW & NOTEWORTHY As the highest percentage of V̇O2max at which steady state conditions can be achieved, a person's critical power (PCRIT) strongly influences the metabolic strain of a given exercise. In this study we demonstrate that training-induced changes in endurance are more strongly related to the intensity of an exercise training program, relative to PCRIT than relative to V̇o2max. Thus, exercise may be more homogenously and effectively prescribed in relation to PCRIT than traditional factors like V̇o2max.