Explore the vast range of titles available.

The amyloid cascade hypothesis is a useful framework for therapeutic development in Alzheimer's disease (AD). Amyloid b1-42 (Aβ) has been the main target of experimental therapies, based on evidence of the neurotoxic effects of Aβ, and of the potential adverse effects of brain Aβ burden detected in humans in vivo by positron emission tomography (PET). Progress on passive anti-amyloid immunotherapy research includes identification of antibodies that facilitate microglial activation, catalytical disaggregation, and increased flow of Aβ from cerebrospinal fluid (CSF) to plasma, thus decreasing the neurotoxic effects of Aβ. Recently completed phase 2 and 3 trials of 3rd generation anti-amyloid immunotherapies are supportive of their clinical efficacy in reducing brain Aβ burden and preventing cognitive decline. Data from recent trials implicate these agents as the first effective disease-modifying therapies against AD and has led to the US Food and Drug Administration (FDA) recent approval of aducanumab and lecanemab, under an accelerated approval pathway. The clinical effects of these agents are modest, however, and associated with amyloid-related imaging abnormalities (ARIA). Testing the effects of anti-Aβ immunotherapies in pre-symptomatic populations and identification of more potent and safer agents is the scope of ongoing and future research. Innovations in clinical trial design will be the key for the efficient and equitable development of novel anti-Aβ immunotherapies. The progress in the field of AD therapeutics will bring new clinical, logistical, and ethical challenges, which pose to revolutionize the practice of neurology, dementia care, and preventive cognitive healthcare.

Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes. In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18–99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test. Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95–1·00] for p-tau217, AUC=0·97 [0·94–0·99] for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92–1·00] for p-tau217, AUC=0·91 [0·82–1·00] for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91–0·96] for p-tau217, AUC=0·91 [0·88–0·94] for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88–0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86–0·93]; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230). Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology. US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.

ApoE4 exacerbates tau pathogenesis, neuroinflammation and tau-mediated neurodegeneration independently of brain amyloid-β pathology, and exerts a ‘toxic’ gain of function whereas its absence is protective. Alzheimer's risk factor aggravates tau pathology APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology compared to other ApoE isoforms. However, whether APOE independently influences tau pathology is not clear. David Holtzman and colleagues now show that ApoE4 exacerbates tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independent of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function, whereas the absence of ApoE is protective. APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms 1 . However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro , E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4 -carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.

Selecting optimal host plants is critical for herbivorous insects, such as fall armyworm (Spodoptera frugiperda), an important maize pest in the Americas and Africa. Fall armyworm larvae are presumed to have limited mobility, hence female moths are presumed to be largely responsible for selecting hosts. We addressed host selection by fall armyworm moths and neonate and older (3rd-instar) larvae, as mediated by resistance and herbivory in maize plants. Thus, we compared discrimination among three maize cultivars with varying degrees of resistance to fall armyworm, and between plants subjected or not to two types of herbivory. The cultivars were: (i) susceptible, and deficient in jasmonic acid (JA) production and green leaf volatiles (GLV) emissions (inbred line B73-lox10); (ii) modestly resistant (B73), and; (iii) highly resistant (Mp708). The herbivory types were: (i) ongoing (= fall armyworm larvae present), and; (ii) future (= fall armyworm eggs present). In choice tests, moths laid more eggs on the highly resistant cultivar, and least on the susceptible cultivar, though on those cultivars larvae performed poorest and best, respectively. In the context of herbivory, moths laid more eggs: (i) on plants subject to versus free of future herbivory, regardless of whether plants were deficient or not in JA and GLV production; (ii) on plants subject versus free of ongoing herbivory, and; (iii) on plants not deficient in compared to deficient in JA and GLV production. Neonate larvae dispersed aerially from host plants (i.e. ballooned), and most larvae colonized the modestly resistant cultivar, and fewest the highly resistant cultivar, suggesting quasi-directional, directed aerial descent. Finally, dispersing older larvae did not discriminate among the three maize cultivars, nor between maize plants and (plastic) model maize plants, suggesting random, visually-oriented dispersal. Our results were used to assemble a model of host selection by fall armyworm moths and larvae, including recommendations for future research.

Four-repeat tauopathies are a neurodegenerative disease characterized by brain parenchymal accumulation of a specific isoform of the protein tau, which gives rise to a wide breadth of clinical syndromes encompassing diverse symptomatology, with the most common syndromes being progressive supranuclear palsy-Richardson's and corticobasal syndrome. Despite the lack of effective disease-modifying therapies, targeted treatment of symptoms can improve quality of life for patients with 4-repeat tauopathies. However, managing these symptoms can be a daunting task, even for those familiar with the diseases, as they span motor, sensory, cognitive, affective, autonomic, and behavioral domains. This review describes current approaches to symptomatic management of common clinical symptoms in 4-repeat tauopathies with a focus on practical patient management, including pharmacologic and nonpharmacologic strategies, and concludes with a discussion of the history and future of disease-modifying therapeutics and clinical trials in this population.

INTRODUCTION Lewy body disease (LBD) is a common primary or co‐pathology in neurodegenerative syndromes. An alpha‐synuclein seed amplification assay (αSyn‐SAA) is clinically available, but clinical performance, especially lower sensitivity in amygdala‐predominant cases, is not well understood. METHODS Antemortem CSF from neuropathology‐confirmed LBD cases was tested with αSyn‐SAA (N = 56). Diagnostic performance and clinicopathological correlations were examined. RESULTS Similar to prior reports, sensitivity was 100% for diffuse and transitional LBD (9/9), and overall specificity was 96.3% (26/27). Sensitivity was lower in amygdala‐predominant (6/14, 42.8%) and brainstem‐predominant LBD (1/6, 16.7%), but early spread outside these regions (without meeting criteria for higher stage) was more common in αSyn‐SAA‐positive cases (6/7, 85.7%) than negative (2/13, 15.4%). DISCUSSION In this behavioral neurology cohort, αSyn‐SAA had excellent diagnostic performance for cortical LBD. In amygdala‐ and brainstem‐predominant cases, sensitivity was lower, but positivity was associated with anatomical spread, suggesting αSyn‐SAA detects early LBD progression in these cohorts. Highlights A cerebrospinal fluid alpha‐synuclein assay detects cortical LBD with high sensitivity/specificity. Positivity in prodromal stages of LBD was associated with early cortical spread. The assay provides precision diagnosis of LBD that could support clinical trials. The assay can also identify LBD co‐pathology, which may impact treatment responses.

Background The trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown. Method We investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation. Results Increased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo. Conclusions We report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are both 4 microtubule binding repeat tauopathy related disorders. Clinical trials need new biomarkers to assess the effectiveness of tau-directed therapies. This study investigated the regional distribution of longitudinal diffusion tensor imaging changes, measured by fractional anisotropy, radial and axial diffusivity over 6 months median interval, in 23 normal control subjects, 35 patients with PSP, and 25 patients with CBS. A mixed-effects framework was used to test longitudinal changes within and between groups. Correlations between changes in diffusion variables and clinical progression were also tested. The study found that over a 6 month period and compared to controls, the most prominent changes in PSP were up to 3±1% higher rates of FA reduction predominantly in superior cerebellar peduncles, and up to 18±6% higher rates of diffusivity increases in caudate nuclei. The most prominent changes in CBS compared to controls were up to 4±1% higher rates of anisotropy reduction and 18±6% higher rates of diffusivity increase in basal ganglia and widespread white matter regions. Compared to PSP, CBS was mainly associated with up to 3±1% greater rates of anisotropy reduction around the central sulci, and 11±3% greater rates of diffusivity increase in superior fronto-occipital fascicules. Rates of diffusivity increases in the superior cerebellar peduncle correlated with rates of ocular motor decline in PSP patients. This study demonstrated that longitudinal diffusion tensor imaging measurement is a promising surrogate marker of disease progression in PSP and CBS over a relatively short period.

The Mediterranean fruit fly (Ceratitis capitata) is a globally invasive pest that affects a wide range of fruit and vegetable crops. Identifying cost-effective attractants is essential for sustainable integrated pest management (IPM). This study explored whether molecular docking, combined with electrophysiological recordings, can help prioritize structurally diverse compounds with potential relevance to medfly olfaction. We assessed the predicted interactions of more than 100 attractant-related and semiochemical compounds, including multiple stereoisomers, with 14 odorant-binding proteins (OBPs) and four odorant receptors (ORs). Trimedlure served as a benchmark ligand. Docking suggested that several sesquiterpenes may interact favorably with subsets of OBPs and ORs, although these predictions require biochemical validation. A small set of compounds with high predicted affinity, readily available in the laboratory, was further examined using electroantennography (EAG), which confirmed that selected sesquiterpenes elicited peripheral antennal activation in irradiated males. Overall, our results demonstrate the utility of computational screening as an exploratory tool for prioritizing candidate ligands and generating hypotheses about chemosensory processing in C. capitata. Integrating molecular modeling with biochemical and behavioral validation is a promising approach to developing next-generation IPM attractants.

Background Plasma phosphorylated tau (p-tau) has emerged as a promising biomarker for Alzheimer’s disease (AD). Studies have reported strong associations between p-tau and tau-PET that are mainly driven by differences between amyloid-positive and amyloid-negative patients. However, the relationship between p-tau and tau-PET is less characterized within cognitively impaired patients with a biomarker-supported diagnosis of AD. We conducted a head-to-head comparison between plasma p-tau217 and tau-PET in patients at the clinical stage of AD and further assessed their relationships with demographic, clinical, and biomarker variables. Methods We retrospectively included 87 amyloid-positive patients diagnosed with MCI or dementia due to AD who underwent structural MRI, amyloid-PET ( 11 C-PIB), tau-PET ( 18 F-flortaucipir, FTP), and blood draw assessments within 1 year (age = 66 ± 10, 48% female). Amyloid-PET was quantified in Centiloids (CL) while cortical tau-PET binding was measured using standardized uptake value ratios (SUVRs) referenced against inferior cerebellar cortex. Plasma p-tau217 concentrations were measured using an electrochemiluminescence-based assay on the Meso Scale Discovery platform. MRI-derived cortical volume was quantified with FreeSurfer. Mini-Mental State Examination (MMSE) scores were available at baseline ( n  = 85) and follow-up visits ( n  = 28; 1.5 ± 0.7 years). Results Plasma p-tau217 and cortical FTP-SUVR were correlated ( r  = 0.61, p  < .001), especially in temporo-parietal and dorsolateral frontal cortices. Both higher p-tau217 and FTP-SUVR values were associated with younger age, female sex, and lower cortical volume, but not with APOE-ε4 carriership. PIB-PET Centiloids were weakly correlated with FTP-SUVR ( r  = 0.26, p  = 0.02), but not with p-tau217 ( r  = 0.10, p  = 0.36). Regional PET-plasma associations varied with amyloid burden, with p-tau217 being more strongly associated with tau-PET in temporal cortex among patients with moderate amyloid-PET burden, and with tau-PET in primary cortices among patients with high amyloid-PET burden. Higher p-tau217 and FTP-SUVR values were independently associated with lower MMSE scores cross-sectionally, while only baseline FTP-SUVR predicted longitudinal MMSE decline when both biomarkers were included in the same model. Conclusion Plasma p-tau217 and tau-PET are strongly correlated in amyloid-PET-positive patients with MCI or dementia due to AD, and they exhibited comparable patterns of associations with demographic variables and with markers of downstream neurodegeneration.