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Breast cancer is a common cancer in Australia, affecting one in seven women. Identifying women at moderate or high risk is crucial for personalized surveillance and risk-reductive interventions. Risk factors include genetic mutations, family history, and personal history. Tools like iPrevent and CanRisk can help determine individual risk. Risk-reductive strategies include lifestyle changes, medication, and surgery. Ashkenazi Jewish women have a higher risk of carrying BRCA1 or BRCA2 gene mutations. The article explores breast cancer reconstruction surgery options and risk-reductive interventions. Patients should understand that these procedures do not eliminate future breast cancer risk. Medications like selective estrogen receptor modulators and aromatase inhibitors can also be used. Tailored surveillance and risk-reductive strategies are important for patients at moderate or high risk. [Extracted from the article]

The article discusses that breast cancer is the most common cancer affecting women in Australia, with a lifetime risk of one in seven. It highlights the importance of identifying individuals at moderate or high risk for tailored surveillance and risk-reductive interventions, including discussions on genetic mutations, family history, and modifiable risk factors.

The Transformation of Black Music: The Rhythms, the Songs, and the Ships of the African Diaspora, by Samuel A. Floyd Jr., with Melanie L. Zeck and Guthrie P. Ramsey Jr. [...]

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies., Author(s): Christopher Abbosh [1]; Nicolai J. Birkbak [1, 2]; Gareth A. Wilson [1, 2]; Mariam Jamal-Hanjani [1]; Tudor Constantin [3]; Raheleh Salari [3]; John Le Quesne [4]; David A. Moore [...]

An introduction is presented in which the author discusses articles within the issue on topics including freedom of expression offered by popular dance to African American women, tap dance as a form of art for African American women tap dancers, and the life of choreographer-anthropologist-social activist Pearl Primus.

Pelizaeus-Merzbacher disease is a rare X-linked leukodystrophy accompanied by central nervous system hypomyelination with a spectrum of clinical phenotypes. This is the first survey of caregivers of individuals with Pelizaeus-Merzbacher disease to investigate the presenting symptoms, path to diagnosis, identity and impact of most bothersome symptoms, and needs that future treatment should address. One hundred participants completed the survey. Results from this survey demonstrate that the majority of Pelizaeus-Merzbacher disease symptoms manifest before 2 years of age and commonly include deficits in gross and fine motor skills, speech, and communication. Caregivers rated difficulty crawling, standing, or walking as the most bothersome symptoms due to Pelizaeus-Merzbacher disease, with constipation and difficulty with sleep, manual dexterity, and speech and communication rated nearly as high. The most important treatment goals for caregivers were improved mobility and communication. The survey findings present a caregiver perspective of the impact of symptoms in Pelizaeus-Merzbacher disease and provide helpful guidance to affected families, physicians, and drug developers on the often-long path to diagnosis and the unmet medical needs of this patient population. [ABSTRACT FROM AUTHOR]

Impaired semantic knowledge is a characteristic feature of some forms of frontotemporal dementia (FTD), particularly the sporadic disorder semantic dementia. Less is known about semantic cognition in the genetic forms of FTD caused by mutations in the genes MAPT, C9orf72, and GRN. We developed a modified version of the Camel and Cactus Test (mCCT) to investigate the presence of semantic difficulties in a large genetic FTD cohort from the Genetic FTD Initiative (GENFI) study. Six-hundred-forty-four participants were tested with the mCCT including 67 MAPT mutation carriers (15 symptomatic, and 52 in the presymptomatic period), 165 GRN mutation carriers (33 symptomatic, 132 presymptomatic), and 164 C9orf72 mutation carriers (56 symptomatic, 108 presymptomatic) and 248 mutation-negative members of FTD families who acted as a control group. The presymptomatic mutation carriers were further split into those early and late in the presymptomatic period (more than vs. within 10 years of expected symptom onset). Groups were compared using a linear regression model, adjusting for age and education, with bootstrapping. Performance on the mCCT had a weak negative correlation with age (rho = −0.20) and a weak positive correlation with education (rho = 0.13), with an overall abnormal score (below the 5th percentile of the control population) being below 27 out of a total of 32. All three of the symptomatic mutation groups scored significantly lower than controls: MAPT mean 22.3 (standard deviation 8.0), GRN 24.4 (7.2), C9orf72 23.6 (6.5) and controls 30.2 (1.6). However, in the presymptomatic groups, only the late MAPT and late C9orf72 mutation groups scored lower than controls (28.8 (2.2) and 28.9 (2.5) respectively). Performance on the mCCT correlated strongly with temporal lobe volume in the symptomatic MAPT mutation group (rho > 0.80). In the C9orf72 group, mCCT score correlated with both bilateral temporal lobe volume (rho > 0.31) and bilateral frontal lobe volume (rho > 0.29), whilst in the GRN group mCCT score correlated only with left frontal lobe volume (rho = 0.48). This study provides evidence for presymptomatic impaired semantic knowledge in genetic FTD. The different neuroanatomical associations of the mCCT score may represent distinct cognitive processes causing deficits in different groups: loss of core semantic knowledge associated with temporal lobe atrophy (particularly in the MAPT group), and impaired executive control of semantic information associated with frontal lobe atrophy. Further studies will be helpful to address the longitudinal change in mCCT performance and the exact time at which presymptomatic impairment occurs. [ABSTRACT FROM AUTHOR]

Background: Development of endpoints for clinical trials in frontotemporal dementia (FTD) is increasingly urgent. In other neurodegenerative diseases composite scores are often used as outcome measures but are, as of yet, lacking in FTD. The aim of this study was to create gene‐specific cognitive composite scores for MAPT, GRN and C9orf72 mutation carriers and provide recommendations on recruitment and trial duration. Method: 69 C9orf72, 41 GRN, 28 MAPT mutation carriers with a CDR® plus NACC‐FTLD global score ≥0.5 and 275 controls completed a neuropsychological battery covering five cognitive domains. Logistic regression was used to identify the combination of tests that discriminated best between mutation carrier groups and controls. Weighted averages of the test scores in the models were calculated based on the regression coefficients (GENFI‐cog). Sample size estimates were calculated for individual tests and composite. The treatment effect was estimated as the mean difference between CDR® plus NACC‐FTLD 0.5 and 1 groups. Time‐to‐event analysis was used to determine the fraction of patients within GENFI that converted from CDR® plus NACC‐FTLD 0.5 to ≥1. Result: The most sensitive model in C9orf72 mutation carriers included a combination of executive, social cognitive and visuoconstructive tests (Table 1). A combination of executive, social cognitive, semantic and memory tests was most sensitive in GRN mutation carriers, and a combination of social cognitive, attention, semantic and memory tests in MAPT mutation carriers, resulted in the most sensitive model. The estimated sample size to detect a treatment effect was lower for the composite than for most individual tests (Table 2). A Kaplan‐Meier curve (Figure 1) showed that after three years 50% of individuals convert from CDR® plus NACC‐FTLD global score 0.5 to 1 or more. Conclusion: We created gene‐specific cognitive composite scores for C9orf72, GRN and MAPT mutation carriers (GENFI‐cog) which resulted in substantially lower estimated sample sizes to detect a treatment effect than most individual cognitive tests. Only 50% of patients with a CDR® plus NACC‐FTLD of 0.5 convert to ≥1 in a three‐year period. GENFI‐cog has potential as a cognitive endpoint for upcoming trials and the results from this study provide important information concerning trial duration and sample sizes. [ABSTRACT FROM AUTHOR]

Background: Previous investigations suggest carrier status for Karlow‐variant single‐nucleotide polymorphism (SNP) of butyrylcholinesterase (BCHE‐K) is associated with an earlier age‐at‐onset of AD in APOE4 carriers. Method: In 45 mild AD patients, 50‐74 years, recruited into a clinical trial (NCT03186989), baseline characteristics were evaluated by BCHE‐K and APOE4 allelic status. Hypothesis tested that age‐at‐diagnosis of AD in APOE4 carriers was lowered in BCHE‐K carriers. Exploratory investigations conducted of associations of neuroimaging (ventricular and hippocampal volumes) and CSF biomarkers of amyloid (Aβ42), tau (p‐tau181), and neurodegenerative (NfL, Ng, PSD‐95) pathologies and glial activation (YKL‐40, GFAP, MCP‐1) across gender and genotype subgroups. Result: In APOE4 carriers (N = 33), mean age‐at‐diagnosis of AD in BCHE‐K carriers (N = 11) was 6.4 years earlier than in BCHE‐K non‐carriers (N = 22, p < 0.001). In APOE4 non‐carriers (N = 12) there was no similar influence of BCHE‐K, but men (N = 8) had an age‐at‐diagnosis about 11 years earlier than women (N = 4). In APOE4 carriers, accumulation of amyloid and tau pathologies was slightly greater and ∼6 years earlier in BCHE‐K carriers versus non‐carriers. APOE4 allele frequency‐dependent increase in amyloid pathology observed with highest amyloid burden in APOE4 homozygotes that contrasted with lowest tau burden. Multiple regression analyses demonstrated that factors associated with amyloid accumulation included APOE4 carrier status (p < 0.05), larger total brain ventricle volume (p < 0.05), less synaptic injury (PSD‐95, p = 0.01; Ng, p < 0.001), and less tau (t‐tau and p‐tau181, p < 0.01). Factors associated with tau pathology included higher neuroaxonal damage (NfL, p = 0.002), higher synaptic injury (Ng, p <0.001; PSD‐95, p < 0.001), and higher glial activation (YKL‐40, p = 0.01). Phenotypic spectrum observed from predominant amyloid and limbic‐amnestic, exemplified by APOE4 homozygotes with BCHE‐K, to predominant tau, limbic‐sparing and multi‐domain cognitive impairment, exemplified in older women non‐carriers of APOE4 and BCHE‐K. Conclusion: In mild AD APOE4 carriers aged < 75 years, the mean age‐at‐diagnosis of AD was reduced by about 6 years in BCHE‐K carriers relative to non‐carriers. Relationships between biomarkers of amyloid and tau pathologies, neurodegeneration and glial activation, and putative cortical cholinergic denervation, suggested an age‐, gender‐ and genotype‐dependent phenotypic spectrum. [ABSTRACT FROM AUTHOR]

Background: Mutations in the MAPT gene are known to cause frontotemporal dementia (FTD), but there is heterogeneity in FTD phenotype across individuals. Here we used an unsupervised learning algorithm – Subtype and Stage Inference (SuStaIn) – to relate phenotypic heterogeneity to specific mutations in the MAPT gene. Method: SuStaIn evaluates the optimal grouping of individuals into disease subtypes, where each subtype consists of a sequence (set of stages) in which biomarkers transition between different z‐scores. We applied SuStaIn to cross‐sectional regional brain volumes extracted from T1‐weighted MRI data from MAPT carriers in the GENFI study to find the best stratification of the data into subtypes, and the temporal progression of each subtype. We used data from 82 MAPT carriers (57 presymptomatic and 25 symptomatic) to identify subtypes and data from a control group of 300 non‐carriers to derive z‐scores. We subtyped and staged individuals at up to five annual follow‐up visits to assess the consistency of the subtypes longitudinally. We compared the specific mutations and clinical and neuropsychological test scores of individuals assigned to each subtype. Result: SuStaIn identified two groups of MAPT carriers with distinct atrophy patterns (Figure 1), which we termed a 'temporal' subtype and a 'frontotemporal' subtype. The subtype assignments were consistent at follow‐up visits (Table 1): there were no individuals that changed from the temporal to the frontotemporal subtype or vice‐versa. Subtype assignment was strongly associated with IVS10+16, R406W and P301L mutations (Table 2): there was a one‐to‐one mapping between IVS10+16 and R406W mutations and the temporal subtype, and a near one‐to‐one mapping between P301L mutations and the frontotemporal subtype. The temporal subtype was associated with memory problems, whereas the frontotemporal subtype was associated with worse performance on tests of attention and visuospatial skills (Table 3). Conclusion: Our results demonstrate the utility of SuStaIn for identifying disease subgroups and associating imaging patterns with genetics and cognition. We show that different MAPT mutations give rise to distinct atrophy patterns and clinical syndromes, providing insights into the underlying disease biology, and potential utility for patient stratification. [ABSTRACT FROM AUTHOR]

Objective: Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI).Methods: Abnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception.Results: Altered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum.Conclusion: Changes in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network. [ABSTRACT FROM AUTHOR]

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Introduction: Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD.Methods: We included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN, C9orf72 or MAPT, and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses.Results: Symptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301-872)) than presymptomatic carriers (1003 pg/mL (624-1358), p<0.001) and non-carriers (990 pg/mL (597-1373), p<0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage.Discussion: We conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD. [ABSTRACT FROM AUTHOR]

Our awareness of time, specifically of longer intervals spanning hours, days, months, and years, is critical for ensuring our sense of self-continuity. Disrupted time awareness over such intervals is a clinical feature in a number of frontotemporal dementia syndromes and Alzheimer's disease, but has not been studied and compared systematically in these diseases. We used a semi-structured caregiver survey to capture time-related behavioral alterations in 71 patients representing all major sporadic and genetic syndromes of frontotemporal dementia, in comparison to 28 patients with typical Alzheimer's disease and nine with logopenic aphasia, and 32 healthy older individuals. Survey items pertained to apparent difficulties ordering past personal events or estimating time intervals between events, temporal rigidity and clockwatching, and propensity to relive past events. We used a logistic regression model including diagnosis, age, gender, and disease severity as regressors to compare the proportions of individuals exhibiting each temporal awareness symptom between diagnostic groups. Gray matter associations of altered time awareness were assessed using voxel-based morphometry. All patient groups were significantly more prone to exhibit temporal awareness symptoms than healthy older individuals. Clinical syndromic signatures were identified. While patients with typical and logopenic Alzheimer's disease most frequently exhibited disturbed event ordering or interval estimation, patients with semantic dementia were most prone to temporal rigidity and clockwatching and those with behavioral variant frontotemporal dementia commonly exhibited all these temporal symptoms as well as a propensity to relive past events. On voxel-based morphometry, the tendency to relive past events was associated with relative preservation of a distributed left-sided temporo-parietal gray matter network including hippocampus. These findings reveal a rich and complex picture of disturbed temporal awareness in major dementia syndromes, with stratification of frontotemporal dementia syndromes from Alzheimer's disease. This is the first study to assess symptoms of altered temporal awareness across frontotemporal dementia syndromes and provides a motivation for future work directed to the development of validated clinical questionnaires, analysis of underlying neurobiological mechanisms and design of interventions. [ABSTRACT FROM AUTHOR]

Background: There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker.Methods: Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman's correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures.Results: Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, -61.3 to 54.6), MAPT mutations (12.7, -33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe.Conclusions: Raised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society. [ABSTRACT FROM AUTHOR]

Background: Chronic glial dysfunction may contribute to the pathogenesis of frontotemporal dementia (FTD). Cerebrospinal fluid (CSF) levels of glia-derived proteins YKL-40 and chitotriosidase are increased in Alzheimer's disease (AD) but have not been explored in detail across the spectrum of FTD. Methods: We investigated whether CSF YKL-40 and chitotriosidase levels differed between FTD patients and controls, across different clinical and genetic subtypes of FTD, and between individuals with a clinical FTD syndrome due to AD versus non-AD (frontotemporal lobar degeneration, FTLD) pathology (based on CSF neurodegenerative biomarkers). Eighteen healthy controls and 64 people with FTD (behavioural variant FTD, n = 20; primary progressive aphasia [PPA], n = 44: nfvPPA, n = 16, svPPA, n = 11, lvPPA, n = 14, PPA-NOS, n = 3) were included. 10/64 had familial FTD, with mutations in GRN(n = 3), MAPT(n = 4), or C9orf72 (n = 3). 15/64 had neurodegenerative biomarkers consistent with AD pathology. Levels were measured by immunoassay and compared using multiple linear regressions. We also examined relationships of YKL-40 and chitotriosidase with CSF total tau (T-tau), phosphorylated tau 181 (P-tau) and β-amyloid 1–42 (Aβ42), with each other, and with age and disease du-ration. Results: CSF YKL-40 and chitotriosidase levels were higher in FTD, particularly lvPPA (both) and nfvPPA (YKL-40), compared with controls. GRN mutation carriers had higher levels of both proteins than controls and C9orf72 expansion carriers, and YKL-40 was higher in MAPT mutation carriers than controls. Individuals with underlying AD pathology had higher YKL-40 and chitotriosidase levels than both controls and those with likely FTLD pathology. CSF YKL-40 and chitotriosidase levels were variably associated with levels of T-tau, P-tau and Aβ42, and with each other, depending on clinical syndrome and underlying pathology. CSF YKL-40 but not chitotriosidase was associated with age, but not disease duration. Conclusion: CSF YKL-40 and chitotriosidase levels are increased in individuals with clinical FTD syndromes, particularly due to AD pathology. In a preliminary analysis of genetic groups, levels of both proteins are found to be highly elevated in FTD due to GRN mutations, while YKL-40 is increased in individuals with MAPT mutations. As glia-derived protein levels generally correlate with T-tau and P-tau levels, they may reflect the glial response to neurodegeneration in FTLD. [ABSTRACT FROM AUTHOR]

Impaired processing of emotional signals is a core feature of frontotemporal dementia syndromes, but the underlying neural mechanisms have proved challenging to characterize and measure. Progress in this field may depend on detecting functional changes in the working brain, and disentangling components of emotion processing that include sensory decoding, emotion categorization and emotional contagion. We addressed this using functional MRI of naturalistic, dynamic facial emotion processing with concurrent indices of autonomic arousal, in a cohort of patients representing all major frontotemporal dementia syndromes relative to healthy age-matched individuals. Seventeen patients with behavioural variant frontotemporal dementia [four female; mean (standard deviation) age 64.8 (6.8) years], 12 with semantic variant primary progressive aphasia [four female; 66.9 (7.0) years], nine with non-fluent variant primary progressive aphasia [five female; 67.4 (8.1) years] and 22 healthy controls [12 female; 68.6 (6.8) years] passively viewed videos of universal facial expressions during functional MRI acquisition, with simultaneous heart rate and pupillometric recordings; emotion identification accuracy was assessed in a post-scan behavioural task. Relative to healthy controls, patient groups showed significant impairments (analysis of variance models, all P < 0.05) of facial emotion identification (all syndromes) and cardiac (all syndromes) and pupillary (non-fluent variant only) reactivity. Group-level functional neuroanatomical changes were assessed using statistical parametric mapping, thresholded at P < 0.05 after correction for multiple comparisons over the whole brain or within pre-specified regions of interest. In response to viewing facial expressions, all participant groups showed comparable activation of primary visual cortex while patient groups showed differential hypo-activation of fusiform and posterior temporo-occipital junctional cortices. Bi-hemispheric, syndrome-specific activations predicting facial emotion identification performance were identified (behavioural variant, anterior insula and caudate; semantic variant, anterior temporal cortex; non-fluent variant, frontal operculum). The semantic and non-fluent variant groups additionally showed complex profiles of central parasympathetic and sympathetic autonomic involvement that overlapped signatures of emotional visual and categorization processing and extended (in the non-fluent group) to brainstem effector pathways. These findings open a window on the functional cerebral mechanisms underpinning complex socio-emotional phenotypes of frontotemporal dementia, with implications for novel physiological biomarker development. [ABSTRACT FROM AUTHOR]

Background: ISIS 814907 (BIIB080) is an antisense oligonucleotide (ASO) that hybridizes to a complementary nucleotide sequence of mRNA of the human microtubule‐associated protein tau (MAPT) gene, preventing production of tau protein. Accumulation of hyperphosphorylated tau is associated with cognitive decline and brain atrophy in Alzheimer's Disease (AD). The placebo controlled period of the Phase 1b multiple ascending dose (MAD) study of ISIS 814907 in patients with mild AD is complete and the open‐label long term extension (LTE) is ongoing in the UK, Canada, Germany, Sweden, Netherlands and Finland (EudraCT: 2016‐002713‐22; NCT03186989). Methods: The study is divided into 2 parts. Part 1 is the MAD study, comprising a 3‐month Treatment Evaluation (TE) Period and a 6‐month Post‐Treatment (PT) Period. Part 2 is the open‐label LTE, comprising a 12‐month TE Period and a 4‐ or 6‐month PT Period. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal (IT) bolus administrations of ISIS 814907 or placebo. Male or female patients aged 50‐74 years with mild AD and confirmed amyloid positivity (via CSF) at Screening were considered eligible. The primary objective was to assess safety and tolerability of multiple IT bolus administrations of ISIS 814907. The secondary objective was to evaluate CSF pharmacokinetics (PK). Exploratory objectives include assessment of plasma PK, target engagement and disease biomarkers, genotype and clinical endpoints relevant to AD. Results: All subjects (N=46) completed the MAD TE Period and 43 subjects completed the PT Period. All AEs were mild/moderate in severity. No serious AEs occurred in subjects receiving ISIS 814907. Dose‐dependent mean reduction from baseline in CSF total tau and phospho‐tau was observed in the TE period and continued in the PT period. CSF total tau and phospho‐tau reductions were comparable. Conclusions: IT bolus administration of multiple ascending doses of ISIS 814907 over 3 months was well‐tolerated in patients with mild AD. The robust lowering of CSF total tau and phospho‐tau warrants further investigation for the treatment of AD. [ABSTRACT FROM AUTHOR]

Introduction Serum profiling using proteomic techniques has great potential to detect biomarkers that might improve diagnosis and predict outcome for breast cancer patients (BC). This study used surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS) to identify differentially expressed proteins in sera from BC and healthy volunteers (HV), with the goal of developing a new prognostic biomarker panel. Methods Training set serum samples from 99 BC and 51 HV subjects were applied to four adsorptive chip surfaces (anion-exchange, cation-exchange, hydrophobic, and metal affinity) and analyzed by time-of-flight MS. For validation, 100 independent BC serum samples and 70 HV samples were analyzed similarly. Cluster analysis of protein spectra was performed to identify protein patterns related to BC and HV groups. Univariate and multivariate statistical analyses were used to develop a protein panel to distinguish breast cancer sera from healthy sera, and its prognostic potential was evaluated. Results From 51 protein peaks that were significantly up- or down-regulated in BC patients by univariate analysis, binary logistic regression yielded five protein peaks that together classified BC and HV with a receiver operating characteristic (ROC) area-under-the-curve value of 0.961. Validation on an independent patient cohort confirmed the 5-protein parameter (ROC value 0.939). The 5-protein parameter showed positive association with large tumor size (P = 0.018) and lymph node involvement (P = 0.016). By matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) MS, immunoprecipitation and western blotting the proteins were identified as a fragment of apolipoprotein H (ApoH), ApoCI, complement C3a, transthyretin, and ApoAI. Kaplan-Meier analysis on 181 subjects after median follow-up of >5 years demonstrated that the panel significantly predicted disease-free survival (P = 0.005), its efficacy apparently greater in women with estrogen receptor (ER)-negative tumors (n = 50, P = 0.003) compared to ER-positive (n = 131, P = 0.161), although the influence of ER status needs to be confirmed after longer follow-up. Conclusion Protein mass profiling by MS has revealed five serum proteins which, in combination, can distinguish between serum from women with breast cancer and healthy control subjects with high sensitivity and specificity. The 5-protein panel significantly predicts recurrence-free survival in women with ER-negative tumors and may have value in the management of these patients. [ABSTRACT FROM AUTHOR]

While the performance of its celebrated actors is often in the limelight, an equally important, but often unremarked, element of the Noh world is the many amateur performers who engage in the practice as a leisure activity. This article explores the shifts in identity that women say occur through Noh practice. I examine the ‘states of being’ that arise through these performances, and explore how women say Noh practice contributes to their life course development. Drawing on ethnographic research, I examine how the process of learning Noh intertwines with the everyday lives of women amateurs, and how the rigours and pleasures of learning Noh take on a particular significance as women grow older. [ABSTRACT FROM PUBLISHER]