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Background: Obstructive sleep apnea (OSA) is associated with cognitive disorders, but little is known about prevalence of co-occurring OSA and mild cognitive impairment (MCI) as well as about co-occurring OSA and Alzheimer's disease (AD). Pathophysiological models integrating OSA, cognitive deficits and neurodegeneration remain speculative. Findings in this area could contribute to the knowledge about pathophysiological processes in cognitive disorders and neurodegenerative processes, be helpful for the diagnosis of cognitive disorders and provide approaches for the treatment of cognitive disorders. Objective: Examining the prevalence of OSA and patterns of cognitive deficits as well as AD biomarker profiles associated with OSA in a cohort of 104 MCI patients. Methods: Assessments used include: respiratory polygraphy, The Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD NB), Tau, phosphoTau181, amyloid-β-1–42/1–40, 18F-fluorodeoxyglucose positron emission tomography (F18-FDG-PET). Results: Prevalence of OSA of any severity: 58,7% (Apnea Hypopnea Index (AHI)≥5/h), OSA in a moderate-to-severe extent (AHI≥15/h): 25%. Only 13.1% of MCI patients with OSA reported daytime sleepiness. MCI-OSA patients showed no specific neuropsychological pattern. Presence of OSA was not associated with specific AD biomarker profiles in the whole study group besides a positive association between AD positivity in an AD biomarker sub cohort. Conclusions: OSA is highly prevalent in patients with MCI. It might often remain undiagnosed as only a small number of MCI-OSA patients report daytime sleepiness. OSA could contribute to MCI symptoms and even to AD pathology. Further research is needed to validate these findings and to investigate possible pathophysiological relationships between OSA and MCI as well as between OSA and AD. [ABSTRACT FROM AUTHOR]

Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins and their receptors, the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, has attracted intense research interest and their role in multiple diseases including Alzheimer's disease has been described. Attempts to administer neurotrophins to patients have been reported, but the clinical trials have so far have been hampered by side effects or a lack of clear efficacy. Thus, much of the focus during recent years has been on identifying small molecules acting as agonists or positive allosteric modulators (PAMs) of Trk receptors. Two examples of successful discovery and development of PAMs are the TrkA-PAM E2511 and the pan-Trk PAM ACD856. E2511 has been reported to have disease-modifying effects in preclinical models, whereas ACD856 demonstrates both a symptomatic and a disease-modifying effect in preclinical models. Both molecules have reached the stage of clinical development and were reported to be safe and well tolerated in clinical phase 1 studies, albeit with different pharmacokinetic profiles. These two emerging small molecules are interesting examples of possible novel symptomatic and disease-modifying treatments that could complement the existing anti-amyloid monoclonal antibodies for the treatment of Alzheimer's disease. This review aims to present the concept of positive allosteric modulators of the Trk receptors as a novel future treatment option for Alzheimer's disease and other neurodegenerative and cognitive disorders, and the current preclinical and clinical data supporting this new concept. Preclinical data indicate dual mechanisms, not only as cognitive enhancers, but also a tentative neurorestorative function. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this article is to provide a narrative review synthesizing the literature on differences between women and men in relationships among certain stressors associated with immune system activation and their relationship to cognitive dysfunction and dementia. Method: We review the cycle of stress leading to neuroinflammation via cortisol and neurochemical alterations, cell-mediated immune system activation, and pro-inflammatory cytokines, and how this is implicated in the development of dementia. We follow this by discussing sex differences in stress physiology and immune function. We then review the work on early life adversity (ELA) and adverse childhood experiences (ACEs), post-traumatic stress disorder, acute medical stressors, and their associations with cognitive dysfunction and dementia. Throughout, we emphasize women's presentations and issues unique to women (e.g. trauma disorder prevalence). Conclusions: There is a need for more mechanistic and longitudinal studies that consider trauma accumulation, both physical and emotional, as well as a greater focus on traumas more likely to occur in women (e.g. sexual abuse), and their relationship to early cognitive decline and dementia. [ABSTRACT FROM AUTHOR]

Niemann-Pick disease type C (NPC) is an autosomal recessive, progressive disorder resulting from variants in NPC1 or NPC2 that leads to the accumulation of cholesterol and other lipids in late endosomes and lysosomes. The clinical manifestations of the disease vary by age of onset, and severity is often characterized by neurological involvement. To date, no disease-modifying therapy has been approved by the United States Food and Drug Administration (FDA) and treatment is typically supportive. The lack of robust biomarkers contributes to challenges associated with disease monitoring and quantifying treatment response. In recent years, advancements in detection methods have facilitated the identification of biomarkers in plasma and cerebral spinal fluid from patients with NPC, namely calbindin D, neurofilament light chain, 24(S)hydroxycholesterol, cholestane-triol, trihydroxycholanic acid glycinate, amyloid-β, total and phosphorylated tau, and N-palmitoyl-O-phosphocholine-serine. These biomarkers have been used to support several clinical trials as pharmacodynamic endpoints. Despite the significant advancements in laboratory techniques, translation of those advancements has lagged, and it remains unclear which biomarkers correlate with disease severity and progression, or which biomarkers could inform treatment response. In this review, we assess the landscape of biomarkers currently proposed to guide disease monitoring or indicate treatment response in patients with NPC. [ABSTRACT FROM AUTHOR]

Using a molecular modeling approach for Tau-binding sites, we modified our previously reported imaging agent, [125I]INFT, for the potential improvement of binding properties to Tau in an Alzheimer's disease (AD) brain. Two new derivatives, namely [125I]ISAS and [125I]NIPZ, were designed, where binding energies at site 1 of Tau were −7.4 and −6.0 kcal/mole, respectively, compared to [125I]INFT (−7.6 kcal/mole). The radiosynthesis of [125I]ISAS and [125I]NIPZ was carried out by using iodine-125 and purified chromatographically to achieve >90% purity. In vitro binding affinities (IC50) for Tau were as follows: INFT = 7.3 × 10−8 M; ISAS = 4.7 × 10−8 M; NIPZ > 10−6 M. The binding of [125I]ISAS to gray matter (GM) correlated with the presence of Tau in the AD brain, confirmed by anti-Tau immunohistochemistry. [125I]NIPZ did not bind to Tau, with similar levels of binding observed in GM and white matter (WM). Four radiotracers were compared and the rank order of binding to Tau was found to be [125I]IPPI > [125I]INFT > [125I]ISAS >>> [125I]NIPZ with GM/WM ratios of [125I]IPPI = 7.74 > [125I]INFT = 4.86 > [125I]ISAS = 3.62 >> [125I]NIPZ = 1.24. The predictive value of Chimera–AutoDock for structurally related compounds binding to the Tau binding sites (measured as binding energy) was good. A binding energy of less than −7 kcal/mole is necessary and less than −8 kcal/mole will be more suitable for developing imaging agents. [ABSTRACT FROM AUTHOR]

The diagnostic value of imaging Aβ plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aβ plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aβ and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aβ. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aβ plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aβ plaque PET imaging agent that exhibited high binding to Aβ plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile. [ABSTRACT FROM AUTHOR]

Accurate quantification of amyloid positron emission tomography (PET) is essential for early detection of and intervention in Alzheimer's disease (AD) but there is still a lack of studies comparing the performance of various automated methods. This study compared the PET-only method and PET-and-MRI-based method with a pre-trained deep learning segmentation model. A large sample of 1180 participants in the Catholic Aging Brain Imaging (CABI) database was analyzed to calculate the regional standardized uptake value ratio (SUVR) using both methods. The logistic regression models were employed to assess the discriminability of amyloid-positive and negative groups through 10-fold cross-validation and area under the receiver operating characteristics (AUROC) metrics. The two methods showed a high correlation in calculating SUVRs but the PET-MRI method, incorporating MRI data for anatomical accuracy, demonstrated superior performance in predicting amyloid-positivity. The parietal, frontal, and cingulate importantly contributed to the prediction. The PET-MRI method with a pre-trained deep learning model approach provides an efficient and precise method for earlier diagnosis and intervention in the AD continuum. [ABSTRACT FROM AUTHOR]

As a potential preclinical stage of Alzheimer's dementia, subjective cognitive decline (SCD) reveals a higher risk of future cognitive decline and conversion to dementia. However, it has not been clear whether SCD status increases the clinical progression of older adults in the context of amyloid deposition, cerebrovascular disease (CeVD), and psychiatric symptoms. We identified 99 normal controls (NC), 15 SCD individuals who developed mild cognitive impairment in the next 2 years (P‐SCD), and 54 SCD individuals who did not (S‐SCD) from ADNI database with both baseline and 2‐year follow‐up data. Total white matter hyperintensity (WMH), WMH in deep (DWMH) and periventricular (PWMH) regions, and voxel‐wise grey matter volumes were compared among groups. Furthermore, using structural equation modelling method, we constructed path models to explore SCD‐related brain changes longitudinally and to determine whether baseline SCD status, age, and depressive symptoms affect participants' clinical outcomes. Both SCD groups showed higher baseline amyloid PET SUVR, baseline PWMH volumes, and larger increase of PWMH volumes over time than NC. In contrast, only P‐SCD had higher baseline DWMH volumes and larger increase of DWMH volumes over time than NC. No longitudinal differences in grey matter volume and amyloid was observed among NC, S‐SCD, and P‐SCD. Our path models demonstrated that SCD status contributed to future WMH progression. Further, baseline SCD status increases the risk of future cognitive decline, mediated by PWMH; baseline depressive symptoms directly contribute to clinical outcomes. In conclusion, both S‐SCD and P‐SCD exhibited more severe CeVD than NC. The CeVD burden increase was more pronounced in P‐SCD. In contrast with the direct association of depressive symptoms with dementia severity progression, the effects of SCD status on future cognitive decline may manifest via CeVD pathologies. Our work highlights the importance of multi‐modal longitudinal designs in understanding the SCD trajectory heterogeneity, paving the way for stratification and early intervention in the preclinical stage. Practitioner Points: Both S‐SCD and P‐SCD exhibited more severe CeVD at baseline and a larger increase of CeVD burden compared to NC, while the burden was more pronounced in P‐SCD.Baseline SCD status increases the risk of future PWMH and DWMH volume accumulation, mediated by baseline PWMH and DWMH volumes, respectively.Baseline SCD status increases the risk of future cognitive decline, mediated by baseline PWMH, while baseline depression status directly contributes to clinical outcome. [ABSTRACT FROM AUTHOR]

Introduction: Non-exercise estimates of cardiorespiratory fitness hold great utility for epidemiological research and clinical practice. Older adults may yield the greatest benefit from fitness estimates due to limited capacity to undergo strenuous maximal exercise testing, however, few of the previously developed non-exercise equations are suitable for use in older adults. Thus, the current study developed a non-exercise equation for estimating cardiorespiratory fitness in older adults derived from the widely used International Physical Activity Questionnaire (IPAQ). Methods: This study was a secondary analysis of baseline data from a randomized controlled trial. Participants were community-dwelling, cognitively unimpaired older adults aged 60-80 years (n = 92). They completed the IPAQ and underwent maximal exercise testing on a cycle ergometer. Stepwise linear regression was used to determine the equation in a randomly selected, sexbalanced, derivation subset of participants (n = 60), and subsequently validated using a second subset of participants (n = 32). Results: The final equation included age, sex, body mass index and leisure time activity from the IPAQ and explained 61% and 55% of the variance in the derivation and validation groups, respectively (standard error of estimates = 3.9, 4.0). Seventy-seven and 81% of the sample fell within ±1SD (5.96 and 6.28 ml·kg-1·min-1) of measured VO2peak for the derivation and validation subgroups. The current equation showed better performance compared to equations from Wier et al. (2006), Jackson et al. (1990), and Schembre & Riebe (2011), although it is acknowledged previous equations were developed for different populations. Conclusions: Using non-exercise, easily accessible measures can yield acceptable estimates of cardiorespiratory fitness in older adults, which should be further validated in other samples and examined in relation to public health outcomes. [ABSTRACT FROM AUTHOR]

The increasing burden of Alzheimer's disease (AD) emphasizes the need for effective diagnostic and therapeutic strategies. Despite available treatments targeting amyloid beta (Aβ) plaques, disease-modifying therapies remain elusive. Early detection of mild cognitive impairment (MCI) patients at risk for AD conversion is crucial, especially with anti-Aβ therapy. While plasma biomarkers hold promise in differentiating AD from MCI, evidence on predicting cognitive decline is lacking. This study's objectives were to evaluate whether plasma protein biomarkers could predict both cognitive decline in non-demented individuals and the conversion to AD in patients with MCI. This study was conducted as part of the Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD), a prospective, community-based cohort. Participants were based on plasma biomarker availability and clinical diagnosis at baseline. The study included MCI (n = 50), MCI-to-AD (n = 21), and cognitively unimpaired (CU, n = 40) participants. Baseline plasma concentrations of six proteins—total tau (tTau), phosphorylated tau at residue 181 (pTau181), amyloid beta 42 (Aβ42), amyloid beta 40 (Aβ40), neurofilament light chain (NFL), and glial fibrillary acidic protein (GFAP)—along with three derivative ratios (pTau181/tTau, Aβ42/Aβ40, pTau181/Aβ42) were analyzed to predict cognitive decline over a six-year follow-up period. Baseline protein biomarkers were stratified into tertiles (low, intermediate, and high) and analyzed using a linear mixed model (LMM) to predict longitudinal cognitive changes. In addition, Kaplan–Meier analysis was performed to discern whether protein biomarkers could predict AD conversion in the MCI subgroup. This prospective cohort study revealed that plasma NFL may predict longitudinal declines in Mini-Mental State Examination (MMSE) scores. In participants categorized as amyloid positive, the NFL biomarker demonstrated predictive performance for both MMSE and total scores of the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-TS) longitudinally. Additionally, as a baseline predictor, GFAP exhibited a significant association with cross-sectional cognitive impairment in the CERAD-TS measure, particularly in amyloid positive participants. Kaplan–Meier curve analysis indicated predictive performance of NFL, GFAP, tTau, and Aβ42/Aβ40 on MCI-to-AD conversion. This study suggests that plasma GFAP in non-demented participants may reflect baseline cross-sectional CERAD-TS scores, a measure of global cognitive function. Conversely, plasma NFL may predict longitudinal decline in MMSE and CERAD-TS scores in participants categorized as amyloid positive. Kaplan–Meier curve analysis suggests that NFL, GFAP, tTau, and Aβ42/Aβ40 are potentially robust predictors of future AD conversion. [ABSTRACT FROM AUTHOR]

Brain abscesses in ruminants often arise from primary infection foci, leading to an unfavorable prognosis for affected animals. This highlights the need for comprehensive studies on brain abscesses across different ruminant species. We retrospectively investigated medical records of epidemiological, clinical, neuroimaging, anatomopathological, and bacteriological findings in six ruminants (three goats, two cows, and one sheep) diagnosed with brain abscesses. All animals studied were female. Apathy (50%), compulsive walking (33%), decreased facial sensitivity (33%), head pressing (33%), seizures (33%), semicomatous mental status (33%), strabismus (33%), unilateral blindness (33%), and circling (33%) represented the most common neurologic signs. Leukocytosis and neutrophilia were the main findings in the hematological evaluation. Cerebrospinal fluid (CSF) analysis revealed predominant hyperproteinorrachia and pleocytosis. In three cases, computed tomography or magnetic resonance imaging were used, enabling the identification of typical abscess lesions, which were subsequently confirmed during postmortem examination. Microbiological culture of the abscess samples and/or CSF revealed bacterial coinfections in most cases. Advanced imaging examinations, combined with CSF analysis, can aid in diagnosis, although confirmation typically relies on postmortem evaluation and isolation of the causative agent. This study contributes to clinicopathological aspects, neuroimages, and bacteriological diagnosis of brain abscesses in domestic ruminants. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD), sharing similar pathophysiological traits like impaired insulin signaling. Objective: To test the association between plasma insulin and cerebrospinal fluid (CSF) AD pathology. Methods: A total of 304 participants were included in the Alzheimer's Disease Neuroimaging Initiative, assessing plasma insulin and CSF AD pathology. We explored the cross-sectional and longitudinal associations between plasma insulin and AD pathology and compared their associations across different AD clinical and pathological stages. Results: In the non-demented group, amyloid-β (Aβ)+ participants (e.g., as reflected by CSF Aβ42) exhibited significantly lower plasma insulin levels compared to non-demented Aβ–participants (p < 0.001). This reduction in plasma insulin was more evident in the A+T+ group (as shown by CSF Aβ42 and pTau181 levels) when compared to the A–T– group within the non-dementia group (p = 0.002). Additionally, higher plasma insulin levels were consistently associated with more normal CSF Aβ42 levels (p < 0.001) across all participants. This association was particularly significant in the Aβ–group (p = 0.002) and among non-demented individuals (p < 0.001). Notably, baseline plasma insulin was significantly correlated with longitudinal changes in CSF Aβ42 (p = 0.006), whereas baseline CSF Aβ42 did not show a similar correlation with changes in plasma insulin over time. Conclusions: These findings suggest an association between plasma insulin and early Aβ pathology in the early stages of AD, indicating that plasma insulin may be a potential predictor of changes in early Aβ pathology. [ABSTRACT FROM AUTHOR]

Background: Plasma and cerebrospinal fluid (CSF) levels of p-tau181 have been associated with Alzheimer's disease (AD). The retina and vitreous have shown measurable quantities of phosphorylated tau 181 (p-tau181). The aqueous humor, which can be collected during cataract surgery, may have measurable concentrations of p-tau181. Objective: To determine whether p-tau181 is detectable in the aqueous humor and if so, whether it is associated with other measures that might be consistent with AD such as higher plasma p-tau181 concentration and lower Montreal Cognitive Assessment (MoCA-BLIND version 7.1) score. Methods: Aqueous humor samples, blood samples, and MoCA-BLIND scores were collected from patients who did not carry a clinical diagnosis of cognitive impairment at the time of cataract surgery. Aqueous p-tau181 concentrations and plasma p-tau181 concentrations were then measured using ultra-sensitive single-molecule assay ELISA technology. A rank-transformed mixed-effects multivariate regression model was used to determine associations between aqueous concentrations, plasma concentrations, and MoCA-BLIND scores. Results: 16 eyes of 16 participants were enrolled with an average age of 71.6. Average MoCA-BLIND score was 20.6/22, average aqueous p-tau181 concentration was 6.4 pg/mL, and average plasma p-tau181 concentration was 3.1 pg/mL. Higher plasma p-tau181 was significantly associated with higher aqueous p-tau181 (p = 0.02). Aqueous p-tau181 and plasma p-tau181 were negatively associated with MoCA-BLIND scores (p = 0.005 and p = 0.001 respectively) in these patients. Conclusions: Aqueous p-tau181 is positively correlated with plasma p-tau181 and is negatively correlated with MoCA-BLIND scores. Further study in individuals with mild cognitive impairment or AD characterized by cerebrospinal fluid and volumetric MRI metrics may yield further insights. [ABSTRACT FROM AUTHOR]

Open science movement gains attention since it might enable a second scientific revolution that fundamentally changes research methods and standards across science. However, the discussion topics towards opens science both from the academia and the environments outside the scholarly communication process have not been formally identified. This paper contributes to that end by analyzing 145,716 open-science-related tweets and 3,200 research papers in Scopus from 2011 to 2022. The results show there is increasing interest about open science both on Twitter and from academia. There are similar foci for both the public on Twitter and the academia from Scopus, including cloud computing and COVID-19 pandemic. When the public on Twitter focus on open science events and citizen science, the scholarly research is more concerned about the detailed aspects and novel innovation in research. The findings might interest the policy-maker for offering evidence to facilitate open science policies and practices. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia worldwide and significantly impacts the essential functions of daily life and social activities. Research on AD has found that its pathogenesis is related to the extracellular accumulation of amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles in the cortical and limbic areas of the human brain, as well as cerebrovascular factors. The detection of Aβ or tau can be performed using various probes and methodologies. However, these modalities are expensive to implement and often require invasive procedures, limiting accessibility on a large scale. While magnetic resonance imaging (MRI) and computed tomography (CT) are generally used for morphological and structural brain imaging, they show wide variability in their accuracy for the clinical diagnosis of AD. Several novel imaging modalities have emerged as alternatives that can accurately and vividly display the changes in blood flow and metabolism in each brain area and enable physicians and researchers to gain insights into the generation and progression of the cerebro-microvascular pathologies of AD. In this review, we summarize the current knowledge on microvascular perfusion imaging modalities and their application in AD, including MRI (dynamic susceptibility contrast-MRI, arterial spin labeling-MRI), CT (cerebral CT perfusion imaging), emission computed tomography (positron emission tomography (PET), single-photon emission computed tomography (SPECT)), transcranial doppler ultrasonography (TCD), and retinal microvascular imaging (optical coherence tomography imaging, computer-assisted methods for evaluating retinal vasculature). [ABSTRACT FROM AUTHOR]

Glycinal (HCOCH 2 NH 2 ) and acetamide (CH 3 CONH 2 ) are simple molecular building blocks of biomolecules in prebiotic chemistry, though their origin on early Earth and formation in interstellar media remain a mystery. These molecules are formed with their tautomers in low temperature interstellar model ices upon interaction with simulated galactic cosmic rays. Glycinal and acetamide are accessed via barrierless radical-radical reactions of vinoxy (⋅CH 2 CHO) and acetyl (⋅C(O)CH 3 ), and then undergo keto-enol tautomerization. Exploiting tunable photoionization reflectron time-of-flight mass spectroscopy and photoionization efficiency (PIE) curves, these results demonstrate fundamental reaction pathways for the formation of complex organics through non-equilibrium ice reactions in cold molecular cloud environments. These molecules demonstrate an unconventional starting point for abiotic synthesis of organics relevant to contemporary biomolecules like polypeptides and cell membranes in deep space., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Astrocytes are highly efficient homeostatic glial cells playing a crucial role in optimal brain functioning and homeostasis. Astrocytes respond to changes in brain homoeostasis following central nervous system (CNS) injury/diseased state by a specific defence mechanism called reactive astrogliosis. Recent studies have implicated and placed reactive astrogliosis in the centre of pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. The AD biomarker field is evolving rapidly with new findings providing strong evidence which supports the notion that a reactive astrogliosis is an early event in the time course of AD progression which may precede other pathological hallmarks of AD. Clinical/translational in vivo PET and in vitro postmortem brain imaging studies demonstrated 'a first and second wave' of reactive astrogliosis in AD with distinct close-loop relationships with other pathological biomarkers at different stages of the disease. At the end stages, reactive astrocytes are found to be associated, or in proximity, with amyloid plaque and tau pathological deposits in postmortem AD brains. Several new PET-tracers, which are being in pipeline and validated at a very fast pace for mapping and visualising reactive astrogliosis in the brain, will provide further invaluable mechanistic insights into AD and other non-AD dementia pathologies. The complementary roles of microglia and astrocyte activation in AD progression, along with the clinical value of new fluid astrocytes biomarkers in the context of existing biomarkers, are the latest avenue that needs further exploration., (© 2022 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Introduction: Relying on magnetic resonance imaging (MRI) for quantification of positron emission tomography (PET) images may limit generalizability of the results. We evaluated several MRI-free approaches for amyloid beta (Aβ) and tau PET quantification relative to MRI-dependent quantification cross-sectionally and longitudinally., Methods: We compared baseline MRI-free and MRI-dependent measurements of Aβ PET ([18F]florbetapir [FBP], N = 1290, [18F]florbetaben [FBB], N = 290) and tau PET ([18F]flortaucipir [FTP], N = 768) images with respect to continuous and dichotomous agreement, effect sizes of Aβ+ impaired versus Aβ- unimpaired groups, and longitudinal standardized uptake value ratio (SUVR) slopes in a subset of individuals., Results: The best-performing MRI-free approaches had high continuous and dichotomous agreement with MRI-dependent SUVRs for Aβ PET and temporal flortaucipir (R 2 ≥0.95; ± agreement ≥92%) and for Alzheimer's disease-related effect sizes; agreement was slightly lower for entorhinal flortaucipir and longitudinal slopes., Discussion: There is no consistent loss of baseline or longitudinal AD-related signal with MRI-free Aβ and tau PET image quantification., (© 2022 the Alzheimer's Association.)

Cognitive reserve (CR) and busyness can boost memory, whereas stress can impair memory. Nevertheless, extant research has not yet examined busyness in conjunction with CR and stress, nor whether CR or stress moderate the relationship between busyness and episodic memory. Middle-aged and older adult participants (N = 71; ages 50-74; 31% African-American) answered lifestyle questionnaires and completed a visual paired-associate memory fMRI task. Dimension reduction techniques identified two latent CR factors-personal CR (own education; occupation complexity; socioeconomic status) and parental education (mother's/father's education), and identified two latent stress factors-external stress (neighborhood stress/violence; financial strain) and personal stress (perceived stress; work/personal stress). We cast these latent factors into a series of regression models, revealing that (1) in isolation, higher busyness predicted better episodic memory, (2) higher external stress predicted worse memory, (3) both greater personal CR and greater parental education predicted better memory, (4) busyness did not interact with stress nor with CR, and (5) in a combined model, higher parental education and lower external stress were significant independent predictors. Neuroimaging data revealed that higher CR was associated with more efficient brain activity in the hippocampus and posterior cingulate during successful episodic memory retrieval, whereas higher personal stress was associated with heightened activity in the precuneus. No interactions or main effects of busyness were observed for the fMRI data. Thus, although busyness was associated with superior episodic memory, busyness did not modulate brain activity during episodic memory retrieval, nor did CR or stress moderate the relationship between busyness and associative memory., Competing Interests: Declarations. Ethics approval: This study was approved by the institutional review board (IRB) at the University of Alabama. Consent to participate: All participants provided written informed consent and were treated within the ethical guidelines of the American Psychological Association (APA) and the Declaration of Helsinki. Consent for publication: Not applicable. No identifying personal information is reported. Conflicts of interest/competing interests: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Psychonomic Society, Inc.)

Objective: This study aims to develop and validate a machine learning model for identifying individuals within the nursing population experiencing severe subjective cognitive decline (SCD) during the menopause transition, along with their associated factors., Methods: A secondary analysis was performed using cross-sectional data from 1,264 nurses undergoing the menopause transition. The data set was randomly split into training (75%) and validation sets (25%), with the Bortua algorithm employed for feature selection. Seven machine learning models were constructed and optimized. Model performance was assessed using area under the receiver operating characteristic curve, accuracy, sensitivity, specificity, and F1 score. Shapley Additive Explanations analysis was used to elucidate the weights and characteristics of various factors associated with severe SCD., Results: The average SCD score among nurses in the menopause transition was (5.38 ± 2.43). The Bortua algorithm identified 13 significant feature factors. Among the seven models, the support vector machine exhibited the best overall performance, achieving an area under the receiver operating characteristic curve of 0.846, accuracy of 0.789, sensitivity of 0.753, specificity of 0.802, and an F1 score of 0.658. The two variables most strongly associated with SCD were menopausal symptoms and the stage of menopause., Conclusions: The machine learning models effectively identify individuals with severe SCD and the related factors associated with severe SCD in nurses during the menopause transition. These findings offer valuable insights for the management of cognitive health in women undergoing the menopause transition., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2025 by The Menopause Society.)

Nowadays, presynaptic dopaminergic positron emission tomography, which assesses deficiencies in dopamine synthesis, storage, and transport, is widely utilized for early diagnosis and differential diagnosis of parkinsonism. This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism. We conducted a thorough literature search using reputable databases such as PubMed and Web of Science. Selection criteria involved identifying peer-reviewed articles published within the last 5 years, with emphasis on their relevance to clinical applications. The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis. Moreover, when employed in conjunction with other imaging modalities and advanced analytical methods, presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker. This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion. In summary, the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials, ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

The revised biomarker framework for diagnosis and staging of Alzheimer's disease (AD) relies on amyloid beta (Aβ) and tau pathologies as core markers, and markers for adjacent pathophysiology, such as neurodegeneration and inflammation. Many of the core fluid biomarkers are phosphorylated tau (p-tau) fragments, with p-tau217 showing a prominent association with Aβ and tau. While positron emission tomography (PET) imaging is well established, plasma p-tau assays are newer and likely to reduce the use of expensive, and less accessible cerebrospinal fluid and PET imaging tests, thereby promoting wider access to AD screening. There is a need for greater understanding of how the various plasma p-tau species reflect different pathological processes of AD and how different immunoassays perform. This review surveys the available immunoassays and highlights their strengths and limitations in different contexts of use. Assays need to be standardized to maximize their impact on AD clinical research, and patient diagnosis and management. HIGHLIGHTS: Different plasma phosphorylated tau (p-tau) species reflect different pathological processes of Alzheimer's disease (AD), with p-tau231 showing the greatest association with the earliest increases in brain amyloid beta (Aβ) accumulation, while p-tau217 shows greater association with both brain Aβ and early tau pathology, and other p-tau and tau fragment species show greater association with later stages of brain tau pathology. Plasma p-tau217 has proven to be an excellent biomarker for AD pathology due to its close association with both brain Aβ and tau pathology, as well as its large dynamic range. Many different assays with varying performance exist for the same p-tau species, with mass spectrometry assays performing uniformly well, and several immunoassays achieving comparable performance. "Round robin" head-to-head studies have been performed to compare different assays for several key plasma biomarkers, including p-tau181 and p-tau217, but additional head-to-head studies are needed, especially for new analytes and for measuring performance in diverse populations. Plasma immunoassays have the potential to increase accessibility of early diagnostic testing for a broad population, including diverse historically under-represented and under-served populations, due to the potential to be implemented globally, including in primary care settings; however, further research is needed to validate the optimal cutoffs for each assay for real-world clinical usage. Eventually, clinical implementation of a two-step workflow may allow standalone use of plasma testing in certain contexts, minimizing the need for confirmation with costly and less accessible cerebrospinal fluid/positron emission tomography testing., (© 2024 Janssen Global Services, LLC, a Johsonson & Johnson Company. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

This review examines the significant role of Atomic Force Microscopy (AFM) in neurobiological research and its emerging clinical applications in diagnosing neurological disorders and central nervous system (CNS) tumours. AFM, known for its nanometre-scale resolution and piconewton-scale force sensitivity, offers ground breaking insights into the biomechanical properties of brain cells and tissues and their interactions within their microenvironment. This review delves into the application of AFM in non-clinical settings, where it characterizes molecular, cellular, and tissue-level aspects of neurological disorders in experimental models. This includes studying ion channel distribution, neuron excitability in genetic disorders, and axonal resistance to mechanical injury. In the clinical context, this article emphasizes AFM's potential in early detection and monitoring of neurodegenerative diseases, such as Alzheimer's Disease (AD), Parkinson's Disease (PD) and amyotrophic lateral sclerosis (ALS), through biomarker characterization in biofluids such as cerebrospinal fluid and blood. It also examines the use of AFM in enhancing the grading and treatment of CNS tumours by assessing their stiffness, providing a more detailed analysis than traditional histopathological methods. Despite its promise, this review acknowledges challenges in integrating AFM into clinical practice, such as sample heterogeneity and data analysis complexity, and discusses emerging solutions such as machine learning and neural networks to overcome these hurdles. These advancements, combined with commercial nanotechnology platforms, herald a new era in personalized treatment strategies for management, treatment and diagnosis of neurological disorders. Highlights: • Focus on AFM's unique capabilities in neurobiology for detailed biomechanical analysis of brain tissues and cells. • Explore AFM's clinical potential in diagnosing neurodegenerative diseases and improving current CNS tumour grading system. • Address challenges in clinical integration of AFM and discusses potential solutions. [ABSTRACT FROM AUTHOR]

Background: Wheat is staple diet for majority of people of world and requires several nutrients for optimum growth like Nitrogen, Potassium and Zinc etc. These nutrients when added in the form of chemical fertilizers definitely increase production but at the cost of negative impact on soil, air, water and living beings. Nanoformulations can provide a possible solution to this problem. The current study tried to assess the impact of foliar application of Nano-N, K, Zn on morphological and yield related parameters of wheat. Methods: Wheat plants were grown up to harvesting stage for two consecutive years from 2018 to 2020. Pots grown plants were treated with three different concentrations of Nano-N, K, Zn and bulk/chemical N, K, Zn along-with a control setup having no external nutrients supplement. Several morphological and yield related parameters were recorded. Result: Application of Nano-N, K, Zn resulted in statistically significant increase in plant height, seeds per spike, root length, 100 seed weight, yield and biomass accumulation compared to the control and bulk/chemical N, K, Zn. Highest yield per pot of 23.87 g was obtained under nano-N, K, Zn treatment while yield under bulk fertilizers and control setup was only 7.54 g and 4.38 g respectively. Our work presents a novel combination of nitrogen, potassium and zinc nanofertilizers which not only increase quality of wheat produce but also environment friendly too. [ABSTRACT FROM AUTHOR]

Sovereign immunity statutes set the boundaries of liability for tortious conduct by state government actors. Legislatures can shield state entities and agents from liability for a wide range of tortious conduct. They can even--as some states have--waive immunity to the extent of liability insurance coverage. These restrictive statutory immunity schemes can facilitate discretion and prevent the overdeterrence of helpful conduct. But by preventing state courts from hearing certain claims of tortious conduct, such schemes effectively leave injured plaintiffs in the lurch and future misconduct undeterred. This Note argues that legislatures should allow courts more leeway to set the standard of care for state government tortfeasors. Stripping courts of their capacity to adjudicate cases of garden-variety misconduct by government actors is misguided. By applying the "public duty doctrine"--a default rule that the government owes no general duty of care in tort to the public at large--courts can negotiate the interests that animate restrictive sovereign immunity statutes. This court-centered approach would fill gaps in civil damages liability under federal constitutional law that otherwise leave government negligence unremedied and undeterred. Moreover, it would let courts adapt the common law to define the scope of the government's duties to the public. [ABSTRACT FROM AUTHOR]

Astrocytes primarily maintain physiological brain homeostasis. However, under various pathological conditions, they can undergo morphological, transcriptomic, and functional transformations, collectively referred to as reactive astrogliosis. Recent studies have accumulated lines of evidence that reactive astrogliosis plays a crucial role in the pathology of Alzheimer's disease (AD). In particular, monoamine oxidase B, a mitochondrial enzyme mainly expressed in astrocytes, significantly contributes to neuronal dysfunction and neurodegeneration in AD brains. Moreover, it has been reported that reactive astrogliosis precedes other pathological hallmarks such as amyloid-beta plaque deposition and tau tangle formation in AD. Due to the early onset and profound impact of reactive astrocytes on pathology, there have been extensive efforts in the past decade to visualize these cells in the brains of AD patients using positron emission tomography (PET) imaging. In this review, we summarize the recent studies regarding the essential pathological importance of reactive astrocytes in AD and their application as a target for PET imaging. [ABSTRACT FROM AUTHOR]

Neuroinflammation is associated with the pathophysiologies of neurodegenerative and psychiatric disorders. Evaluating neuroinflammation using positron emission tomography (PET) plays an important role in the early diagnosis and determination of proper treatment of brain diseases. To quantify neuroinflammatory responses in vivo, many PET tracers have been developed using translocator proteins, imidazole-2 binding site, cyclooxygenase, monoamine oxidase-B, adenosine, cannabinoid, purinergic P2X7, and CSF-1 receptors as biomarkers. In this review, we introduce the latest developments in PET tracers that can image neuroinflammation, focusing on clinical trials, and further consider their current implications. [ABSTRACT FROM AUTHOR]

Inleiding In de Verenigde Staten zijn aducanumab en lecanemab voor de ziekte van Alzheimer geregistreerd. In Europa is de registratie van aducanumab afgewezen door het EMA en is de registratieprocedure voor lecanemab en donanemab gaande. In dit artikel worden de onderzoeken naar de werkzaamheid en bijwerkingen van deze nieuwe amyloïde monoklonale antilichamen besproken. Methoden In de literatuur werden gerandomiseerde dubbelblinde placebogecontroleerde onderzoeken gevonden die de werkzaamheid en veiligheid van aducanumab, lecanemab en donanemab onderzochten. De primaire uitkomstmaat was de verandering in de ʻClinical Dementia Rating-Sum of Boxes’ (CDR-SB)-score tussen de start van het onderzoek en het einde na 78 weken. De bijwerkingen werden ook geanalyseerd. Resultaten Aducanumab werd in twee studies onderzocht, die na een futiliteitsanalyse werden gestaakt. Tot dat moment was in de EMERGE-studie de CDR-SB verandering ten opzichte van placebo -0,39 (95% betrouwbaarheidsinterval (BI) -0,69 tot -0,09) en in de ENGAGE-studie +0,03 (-0,26 tot 0,33). In de CLARITY ADstudie met lecanemab was de CDR-SB verandering ten opzichte van placebo -0,45 (-0,67 tot -0,23). In de TRAILBLAZER-ALZ 2-studie met donanemab was deze -0,67 (-0,92 tot -0,40). Voor lecanemab en donanemab duidt deze op een verminderde cognitieve achteruitgang van 27% tot 29% ten opzichte van placebo. Een veel voorkomende bijwerking waarbij op een MRI oedeem of bloeding gerelateerde afwijkingen (ARIA) te zien zijn, kan zonder symptomen verlopen, maar kan ook fataal aflopen. Deze meest gevreesde bijwerking kwam in de monoklonale antilichaamgroepen bij 12% tot 35% voor en in de placebogroepen bij 2% tot 8%. In enkele gevallen leidde dit tot overlijden. Conclusie De gevonden verminderde cognitieve achteruitgang bij behandeling met een amyloïde monoklonaal antilichaam is statistisch significant, maar niet klinisch relevant ten opzichte van placebo. Door de aanwezigheid van de bijwerking ARIA is de balans tussen de werking en bijwerkingen negatief. Er is geen plaats voor deze nieuwe middelen bij de ziekte van Alzheimer. [ABSTRACT FROM AUTHOR]

Niemann Pick disease B (NPB) often presents with hepatosplenomegaly and lung pathological changes, but it usually does not present with central nervous system symptoms. This report presents the unique case of a 21-year-old woman with a 10-year history of hard skin and hepatosplenomegaly. Genetic sequencing revealed NPB and also suggested Segawa syndrome. Although symptomatic supportive treatments were administered in an attempt to improve muscle tone and treat the skin sclerosis, their efficacy was not satisfactory, and the patient refused further treatment. This case provides several noteworthy findings. First, although NPB and Segawa syndrome are rare, both are autosomal recessive inherited diseases that share common clinical symptoms and imaging manifestations. Second, when NPB and Segawa syndrome are highly suspected, screening for tyrosine hydroxylase (TH) and sphingomyelin phosphodiesterase-1 (SMPD1) gene mutations is critical to determine an accurate diagnosis. Finally, early diagnosis and comprehensive therapies are crucial for improving the prognosis of patients with NPB and Segawa syndrome. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders such as Alzheimer's disease (AD) represent an increasingly significant public health concern. As clinical diagnosis faces challenges, biomarkers are becoming increasingly important in research, trials, and patient assessments. While biomarkers like amyloid‐β peptide, tau proteins, CSF levels (Aβ, tau, and p‐tau), and neuroimaging techniques are commonly used in AD diagnosis, they are often limited and invasive in monitoring and diagnosis. For this reason, blood‐based biomarkers are the optimal choice for detecting neurodegeneration in brain diseases due to their noninvasiveness, affordability, reliability, and consistency. This literature review focuses on plasma neurofilament light (NfL) and CSF NfL as blood‐based biomarkers used in recent AD diagnosis. The findings revealed that the core CSF biomarkers of neurodegeneration (T‐tau, P‐tau, and Aβ42), CSF NFL, and plasma T‐tau were strongly associated with Alzheimer's disease, and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Elevated levels of plasma and cerebrospinal fluid NfL were linked to decreased [18F]FDG uptake in corresponding brain areas. In participants with Aβ positivity (Aβ+), NfL correlated with reduced metabolism in regions susceptible to Alzheimer's disease. In addition, CSF NfL levels correlate with brain atrophy and predict cognitive changes, while plasma total tau does not. Plasma P‐tau, especially in combination with Aβ42/Aβ40, is promising for symptomatic AD stages. Though not AD‐exclusive, blood NfL holds promise for neurodegeneration detection and assessing treatment efficacy. Given the consistent levels of T‐tau, P‐tau, Aβ42, and NFL in CSF, their incorporation into both clinical practice and research is highly recommended. [ABSTRACT FROM AUTHOR]

Background: Plasma amyloid-β (Aβ) has emerged as an important tool to detect risks of Alzheimer's disease and related dementias, although research in diverse populations is lacking. Objective: We compared plasma Aβ42/40 by race with dementia risk over 15 years among Black and White older adults. Methods: In a prospective cohort of 997 dementia-free participants (mean age 74±2.9 years, 55% women, 54% Black), incident dementia was identified based on hospital records, medication, and neurocognitive test over 15 years. Plasma Aβ42/40 was measured at Year 2 and categorized into low, medium, and high tertile. We used linear regression to estimate mean Aβ42/40 by race and race-stratified Cox proportional hazards models to assess the association between Aβ42/40 tertile and dementia risk. Results: Black participants had a lower age-adjusted mean Aβ 42/40 compared to White participants, primarily among APOE ɛ4 non-carriers (Black: 0.176, White: 0.185, p = 0.035). Among Black participants, lower Aβ 42/40 was associated with increased dementia risk: 33% in low (hazard ratios [HR] = 1.77, 95% confidence interval 1.09–2.88) and 27% in medium tertile (HR = 1.67, 1.01–2.78) compared with 18% in high Aβ 42/40 tertile; Increased risks were attenuated among White participants: 21% in low (HR = 1.43, 0.81–2.53) and 23% in medium tertile (HR = 1.27, 0.68–2.36) compared with 15% in high Aβ 42/40 tertile. The interaction by race was not statistically significant. Conclusions: Among community-dwelling, non-demented older adults, especially APOE ɛ4 non-carriers, Black individuals had lower plasma Aβ 42/40 and demonstrated a higher dementia risk with low Aβ42/40 compared with White individuals. [ABSTRACT FROM AUTHOR]

Background: While various biomarkers of Alzheimer's disease (AD) have been associated with general cognitive function, their association to visual-perceptive function across the AD spectrum warrant more attention due to its significant impact on quality of life. Thus, this study explores how AD biomarkers are associated with decline in this cognitive domain. Objective: To explore associations between various fluid and imaging biomarkers and visual-based cognitive assessments in participants across the AD spectrum. Methods: Data from participants (N = 1,460) in the Alzheimer's Disease Neuroimaging Initiative were analyzed, including fluid and imaging biomarkers. Along with the Mini-Mental State Examination (MMSE), three specific visual-based cognitive tests were investigated: Trail Making Test (TMT) A and TMT B, and the Boston Naming Test (BNT). Locally estimated scatterplot smoothing curves and Pearson correlation coefficients were used to examine associations. Results: MMSE showed the strongest correlations with most biomarkers, followed by TMT-B. The p-tau181/Aβ1–42 ratio, along with the volume of the hippocampus and entorhinal cortex, had the strongest associations among the biomarkers. Conclusions: Several biomarkers are associated with visual processing across the disease spectrum, emphasizing their potential in assessing disease severity and contributing to progression models of visual function and cognition. [ABSTRACT FROM AUTHOR]

Background: Degeneration of cholinergic basal forebrain (BF) neurons characterizes Alzheimer's disease (AD). However, what role the BF plays in the dynamics of AD pathophysiology has not been investigated precisely. Objective: To investigate the baseline and longitudinal roles of BF along with core neuropathologies in AD. Methods: In this retrospective cohort study, we enrolled 113 subjects (38 amyloid [Aβ]-negative cognitively unimpaired, 6 Aβ-positive cognitively unimpaired, 39 with prodromal AD, and 30 with AD dementia) who performed brain MRI for BF volume and cortical thickness, 18F-florbetaben PET for Aβ, 18F-flortaucipir PET for tau, and detailed cognitive testing longitudinally. We investigated the baseline and longitudinal association of BF volume with Aβ and tau standardized uptake value ratio and cognition. Results: Cross-sectionally, lower BF volume was not independently associated with higher cortical Aβ, but it was associated with tau burden. Tau burden in the orbitofrontal, insular, lateral temporal, inferior temporo-occipital, and anterior cingulate cortices were associated with progressive BF atrophy. Lower BF volume was associated with faster Aβ accumulation, mainly in the prefrontal, anterior temporal, cingulate, and medial occipital cortices. BF volume was associated with progressive decline in language and memory functions regardless of baseline Aβ and tau burden. Conclusions: Tau deposition affected progressive BF atrophy, which in turn accelerated amyloid deposition, leading to a vicious cycle. Also, lower baseline BF volume independently predicted deterioration in cognitive function. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative condition that displays a high prevalence in Lebanon causing a local burden in healthcare and socio-economic sectors. Unfortunately, the lack of prevalence studies and clinical trials in Lebanon minimizes the improvement of AD patient health status. In this review, we include over 155 articles to cover the different aspects of AD ranging from mechanisms to possible treatment and management tools. We highlight some important modifiable and non-modifiable risk factors of the disease including genetics, age, cardiovascular diseases, smoking, etc. Finally, we propose a hypothetical genetic synergy model between APOE4 and TREM2 genes which constitutes a potential early diagnostic tool that helps in reducing the risk of AD based on preventative measures decades before cognitive decline. The studies on AD in Lebanon and the Middle East are scarce. This review points out the importance of genetic mapping in the understanding of disease pathology which is crucial for the emergence of novel diagnostic tools. Hence, we establish a rigid basis for further research to identify the most influential genetic and environmental risk factors for the purpose of using more specific diagnostic tools and possibly adopting a local management protocol. [ABSTRACT FROM AUTHOR]

Purpose: Bayesian penalised likelihood (BPL) reconstruction, which incorporates point-spread-function (PSF) correction, provides higher signal-to-noise ratios and more accurate quantitation than conventional ordered subset expectation maximization (OSEM) reconstruction. However, applying PSF correction to brain PET imaging is controversial due to Gibbs artefacts that manifest as unpredicted cortical uptake enhancement. The present study aimed to validate whether BPL without PSF would be useful for amyloid PET imaging. Methods: Images were acquired from Hoffman 3D brain and cylindrical phantoms for phantom study and 71 patients administered with [18F]flutemetamol in clinical study using a Discovery MI. All images were reconstructed using OSEM, BPL with PSF correction, and BPL without PSF correction. Count profile, %contrast, recovery coefficients (RCs), and image noise were calculated from the images acquired from the phantoms. Amyloid β deposition in patients was visually assessed by two physicians and quantified based on the standardised uptake value ratio (SUVR). Results: The overestimated radioactivity in profile curves was eliminated using BPL without PSF correction. The %contrast and image noise decreased with increasing β values in phantom images. Image quality and RCs were better using BPL with, than without PSF correction or OSEM. An optimal β value of 600 was determined for BPL without PSF correction. Visual evaluation almost agreed perfectly (κ = 0.91–0.97), without depending on reconstruction methods. Composite SUVRs did not significantly differ between reconstruction methods. Conclusion: Gibbs artefacts disappeared from phantom images using the BPL without PSF correction. Visual and quantitative evaluation of [18F]flutemetamol imaging was independent of the reconstruction method. The BPL without PSF correction could be the standard reconstruction method for amyloid PET imaging, despite being qualitatively inferior to BPL with PSF correction for [18F]flutemetamol amyloid PET imaging. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are potential risk factors for the development of dementia including Alzheimer's disease (AD) in later life. The findings of studies investigating this question are inconsistent though. Objective: To investigate if these inconsistencies are caused by the existence of subgroups with different vulnerability for AD pathology and if these subgroups are characterized by atypical tau load/atrophy pattern. Methods: The MRI and PET data of 89 subjects with or without previous TBI and/or PTSD from the DoD ADNI database were used to calculate an age-corrected gray matter tau mismatch metric (ageN-T mismatch-score and matrix) for each subject. This metric provides a measure to what degree regional tau accumulation drives regional gray matter atrophy (matrix) and can be used to calculate a summary score (score) reflecting the severity of AD pathology in an individual. Results: The ageN-T mismatch summary score was positively correlated with whole brain beta-amyloid load and general cognitive function but not with PTSD or TBI severity. Hierarchical cluster analysis identified five different spatial patterns of tau-gray matter interactions. These clusters reflected the different stages of the typical AD tau progression pattern. None was exclusively associated with PTSD and/or TBI. Conclusions: These findings suggest that a) although subsets of patients with PTSD and/or TBI develop AD-pathology, a history of TBI or PTSD alone or both is not associated with a significantly higher risk to develop AD pathology in later life. b) remote TBI or PTSD do not modify the typical AD pathology distribution pattern. [ABSTRACT FROM AUTHOR]

The complex conformational panorama of binary 4,4,4-trifluoro-1-butanol (TFB) aggregates was investigated using chirped-pulse Fourier transform microwave spectroscopy, aided by conformational searches using CREST (Conformer-Rotamer Ensemble Sampling Tool) and quantum chemistry calculations. From nearly 1500 initial dimer geometries, 16 most stable binary candidates were obtained within a relative energy window of ∼4 kJ mol−1. Rotational spectra of five binary conformers were experimentally observed in supersonic expansion and assigned. Interestingly, three out of the five observed binary conformers are composed solely of monomer conformers, which were not observed in their isolated gas phase forms in jet expansion. In addition, an observed dimer that is made exclusively of the most stable TFB monomer subunits does not correspond to the global minimum. The intricate kinetically and thermodynamically controlled dimer formation mechanisms are discussed, and a modified kinetic-thermodynamic model was developed, providing conformational abundances that are in good agreement with the experiment. Subsequent non-covalent interaction analyses reveal that the observed conformers are held together by one primary O–H⋯O hydrogen bond and secondary intermolecular C–H⋯O, C–H⋯F, and/or O–H⋯F interactions, as well as C–H⋯H–C London dispersion interactions between the methylene groups. Further symmetry-adapted perturbation theory analyses of the TFB dimer conformers and related alcohol dimers reveal a considerable rise in dispersion contributions with increasing n-alkyl carbon chain length and highlight the role of dispersion interactions in preferentially stabilizing the global minimum of the TFB dimer. [ABSTRACT FROM AUTHOR]

Introduction: Plasma Aβ42/40 ratio can help predict amyloid PET status, but its clinical utility in Alzheimer's disease (AD) assessment is unclear. Methods: Aβ42/40 ratio was measured by LC-MS/MS for 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and for 6,192 consecutive clinical specimens submitted for Aβ42/40 testing. Results: High diagnostic sensitivity and negative predictive value (NPV) for Aβ- PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aβ42/40 values for individuals with positive vs. negative Aβ-PET results. Assuming a moderate prevalence of Aβ-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients' cognitive impairment and help reduce PET evaluation by about 40%. Conclusion: High-throughput plasma Aβ42/40 LC-MS/MS assays can help identify patients with low likelihood of AD pathology, which can reduce PET evaluations, allowing for cost savings. [ABSTRACT FROM AUTHOR]

Due to worldwide demographic change, the number of older persons in the population is increasing. Aging is accompanied by changes of sleep structure, deposition of beta-amyloid (Aß) and tau proteins and vascular changes and can turn into mild cognitive impairment (MCI) as well as dementia. Sleep disorders are discussed both as a risk factor for and as a consequence of MCI/dementia. Cross-sectional and longitudinal population-based as well as case-control studies revealed sleep disorders, especially sleep-disorderded breathing (SDB) and excessive or insufficient sleep durations, as risk factors for all-cause MCI/dementia. Regarding different dementia types, SDB was especially associated with vascular dementia while insomnia/insufficient sleep was related to an increased risk of Alzheimer's disease (AD). Scarce and still inconsistent evidence suggests that therapy of sleep disorders, especially continuous positive airway pressure (CPAP) in SDB, can improve cognition in patients with sleep disorders with and without comorbid dementia and delay onset of MCI/dementia in patients with sleep disorders without previous cognitive impairment. Regarding potential pathomechanisms via which sleep disorders lead to MCI/dementia, disturbed sleep, chronic sleep deficit and SDB can impair glymphatic clearance of beta-amyloid (Aß) and tau which lead to amyloid deposition and tau aggregation resulting in changes of brain structures responsible for cognition. Orexins are discussed to modulate sleep and Aß pathology. Their diurnal fluctuation is suppressed by sleep fragmentation and the expression suppressed at the point of hippocampal atrophy, contributing to the progression of dementia. Additionally, sleep disorders can lead to an increased vascular risk profile and vascular changes such as inflammation, endothelial dysfunction and atherosclerosis which can foster neurodegenerative pathology. There is ample evidence indicating that changes of sleep structure in aging persons can lead to dementia and also evidence that therapy of sleep disorder can improve cognition. Therefore, sleep disorders should be identified and treated early. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The Finnish Geriatric Intervention Study (FINGER) led to the global dementia risk reduction initiative: World‐Wide FINGERS (WW‐FINGERS). As part of WW‐FINGERS, the Australian AU‐ARROW study mirrors aspects of FINGER, as well as US‐POINTER. METHOD: AU‐ARROW is a randomized, single‐blind, multisite, 2‐year clinical trial (n = 600; aged 55–79). The multimodal lifestyle intervention group will engage in aerobic exercise, resistance training and stretching, dietary advice to encourage MIND diet adherence, BrainHQ cognitive training, and medical monitoring and health education. The Health Education and Coaching group will receive occasional health education sessions. The primary outcome measure is the change in a global composite cognitive score. Extra value will emanate from blood biomarker analysis, positron emission tomography (PET) imaging, brain magnetic resonance imaging (MRI), and retinal biomarker tests. DISCUSSION: The finalized AU‐ARROW protocol is expected to allow development of an evidence‐based innovative treatment plan to reduce cognitive decline and dementia risk, and effective transfer of research outcomes into Australian health policy. Highlights: Study protocol for a single‐blind, randomized controlled trial, the AU‐ARROW Study.The AU‐ARROW Study is a member of the World‐Wide FINGERS (WW‐FINGERS) initiative.AU‐ARROW's primary outcome measure is change in a global composite cognitive score.Extra significance from amyloid PET imaging, brain MRI, and retinal biomarker tests.Leading to development of an innovative treatment plan to reduce cognitive decline. [ABSTRACT FROM AUTHOR]

INTRODUCTION: This study investigated whether self‐reported sleep quality is associated with brain amyloid beta (Aβ) accumulation. METHODS: Linear mixed effect model analyses were conducted for 189 cognitively unimpaired (CU) older adults (mean ± standard deviation 74.0 ± 6.2; 53.2% female), with baseline self‐reported sleep data, and positron emission tomography‐determined brain Aβ measured over a minimum of three time points (range 33.3–72.7 months). Analyses included random slopes and intercepts, interaction for apolipoprotein E (APOE) ε4 allele status, and time, adjusting for sex and baseline age. RESULTS: Sleep duration <6 hours, in APOE ε4 carriers, and sleep efficiency <65%, in the whole sample and APOE ε4 non‐carriers, is associated with faster accumulation of brain Aβ. DISCUSSION: These findings suggest a role for self‐reported suboptimal sleep efficiency and duration in the accumulation of Alzheimer's disease (AD) neuropathology in CU individuals. Additionally, poor sleep efficiency represents a potential route via which individuals at lower genetic risk may progress to preclinical AD. Highlights: In cognitively unimpaired older adults self‐report sleep is associated with brain amyloid beta (Aβ) accumulation.Across sleep characteristics, this relationship differs by apolipoprotein E (APOE) genotype.Sleep duration <6 hours is associated with faster brain Aβ accumulation in APOE ε4 carriers.Sleep efficiency < 65% is associated with faster brain Aβ accumulation in APOE ε4 non‐carriers.Personalized sleep interventions should be studied for potential to slow Aβ accumulation. [ABSTRACT FROM AUTHOR]

Background: Standard methods for deriving Centiloid scales from amyloid PET images are time-consuming and require considerable expert knowledge. We aimed to develop a deep learning method of automating Centiloid scale calculations from amyloid PET images with 11C-Pittsburgh Compound-B (PiB) tracer and assess its applicability to 18F-labeled tracers without retraining. Methods: We trained models on 231 11C-PiB amyloid PET images using a 50-layer 3D ResNet architecture. The models predicted the Centiloid scale, and accuracy was assessed using mean absolute error (MAE), linear regression analysis, and Bland–Altman plots. Results: The MAEs for Alzheimer's disease (AD) and young controls (YC) were 8.54 and 2.61, respectively, using 11C-PiB, and 8.66 and 3.56, respectively, using 18F-NAV4694. The MAEs for AD and YC were higher with 18F-florbetaben (39.8 and 7.13, respectively) and 18F-florbetapir (40.5 and 12.4, respectively), and the error rate was moderate for 18F-flutemetamol (21.3 and 4.03, respectively). Linear regression yielded a slope of 1.00, intercept of 1.26, and R2 of 0.956, with a mean bias of −1.31 in the Centiloid scale prediction. Conclusions: We propose a deep learning means of directly predicting the Centiloid scale from amyloid PET images in a native space. Transferring the model trained on 11C-PiB directly to 18F-NAV4694 without retraining was feasible. [ABSTRACT FROM AUTHOR]

This review article focuses on the upstream pertinent pathophysiology leading to neurodegenerative disease. Specifically, the nexus appears to be blood–brain barrier (BBB) leakiness resulting in a two-prong inflammatory disease spectrum damaging the microvasculature and corrupting protein synthesis and degradation with accumulating misfolded toxic proteins. The suboptimal results of removing misfolded proteins mean a new approach to disease in the preclinical state is required aimed at other targets. Validated noninvasive imaging and serologic biomarkers of early preclinical disease implemented in the high-risk patient cohort along with periodic surveillance once effective treatments are developed will be required. This review discusses the physiology and pathophysiology of the BBB, new MRI imaging techniques identifying the leak, and altered fluid dynamic effects in the preclinical state. The risk factors for disease development, preventative measures, and potential treatment targets are also discussed. [ABSTRACT FROM AUTHOR]