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Objective As large-scale medical imaging studies are becoming more common, there is an increasing reliance on automated software to extract quantitative information from these images. As the size of the cohorts keeps increasing with large studies, there is a also a need for tools that allow results from automated image processing and analysis to be presented in a way that enables fast and efficient quality checking, tagging and reporting on cases in which automatic processing failed or was problematic. Materials and methods MilxXplore is an open source visualization platform, which provides an interface to navigate and explore imaging data in a web browser, giving the end user the opportunity to perform quality control and reporting in a user friendly, collaborative and efficient way. Discussion Compared to existing software solutions that often provide an overview of the results at the subject's level, MilxXplore pools the results of individual subjects and time points together, allowing easy and efficient navigation and browsing through the different acquisitions of a subject over time, and comparing the results against the rest of the population. Conclusions MilxXplore is fast, flexible and allows remote quality checks of processed imaging data, facilitating data sharing and collaboration across multiple locations, and can be easily integrated into a cloud computing pipeline. With the growing trend of open data and open science, such a tool will become increasingly important to share and publish results of imaging analysis. [ABSTRACT FROM AUTHOR]

Background: The introduction of therapeutics for Alzheimer's disease has led to increased interest in precisely quantifying amyloid-β (Aβ) burden for diagnosis, treatment monitoring, and further clinical research. Recent positron emission tomography (PET) hardware innovations including digital detectors have led to superior resolution and sensitivity, improving quantitative accuracy. However, the effect of PET scanner on Centiloid remains relatively unexplored and is assumed to be minimized by harmonizing PET resolutions. Objective: To quantify the differences in Centiloid between scanners in a paired cohort. Methods: 36 participants from the Australian Imaging, Biomarker and Lifestyle study (AIBL) cohort were scanned within a year on two scanners. Each participant underwent 18F-NAV4694 imaging on two of the three scanners investigated, the Siemens Vision, the Siemens mCT and the Philips Gemini. We compared Aβ Centiloid quantification between scanners and assessed the effectiveness of post-reconstruction PET resolution harmonization. We further compared the scanner differences in target sub-regions and with different reference regions to assess spatial variability. Results: Centiloid from the Vision camera was found to be significantly higher compared to the Gemini and mCT; the difference was greater at high-Centiloid levels. Post-reconstruction resolution harmonization only accounted for and corrected ∼20% of the Centiloid (CL) difference between scanners. We further demonstrated that residual differences have effects that vary spatially between different subregions of the Centiloid mask. Conclusions: We have demonstrated that the type of PET scanner that a participant is scanned on affects Centiloid quantification, even when scanner resolution is harmonized. We conclude by highlighting the need for further investigation into harmonization techniques that consider scanner differences. [ABSTRACT FROM AUTHOR]

Background: In older adults with preclinical Alzheimer's disease (AD), learning curves derived from validated psychological learning paradigms are reduced to an extent greater than impairment, or decline, on neuropsychological memory tests. Objective: This study aimed to examine how age, sex, education, mood, and general dementia risk, which also increases risk for preclinical AD, could influence learning curves. Methods: 1050 adults enrolled in the BetterBrains trial completed 10 blocks of ORCA-LLT learning trials over 5 days. Learning curves were derived from improvement in accuracy over trials. Participants also completed questionnaires of demography and mood, and the CAIDE risk score was computed for each participant. Results: Most participants (67%) completed ≥6 blocks of ORCA-LLT. Older age (d = 0.75), lower education (d = 0.50), and higher dementia risk (d = 0.36) were associated significantly with slower learning rates. Conclusions: In older adults, learning curves are influenced subtly by age, education, and dementia risk but not by sex or mood. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes mellitus (T2DM) impact more than 2.5 billion adults worldwide, necessitating innovative therapeutic approaches. Unimolecular polypharmacology, which involves designing single molecules to target multiple receptors or pathways simultaneously, has revolutionized treatment strategies. Blockbuster drugs such as tirzepatide and retatrutide have shown unprecedented success in managing obesity and T2DM, demonstrating superior efficacy compared to conventional single agonists. Tirzepatide, in particular, has garnered tremendous attention for its remarkable effectiveness in promoting weight loss and improving glycemic control, while offering additional cardiovascular and renal benefits. Despite their promises, such therapeutic agents also face challenges that include gastrointestinal side effects, patient compliance issues, and body weight rebound after cessation of the treatment. Nonetheless, the development of these therapies marks a significant leap forward, underscoring the transformative potential of unimolecular polypharmacology in addressing metabolic diseases and paving the way for future innovations in personalized medicine. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic stress disorder (PTSD) is associated with the development of dementia. However, the link between PTSD and preclinical Alzheimer's disease pathology (amyloid β [Aβ]) remains controversial. Moreover, the correlation between the severity of PTSD with Aβ levels remains unknown. Methods: This cross-sectional study sought to investigate the associations of PTSD symptoms with global and regional brain Aβ burden. To this end, data were obtained from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study. In addition, we explored the association between the severity of PTSD symptoms and Aβ levels. Results: A total of 4,228 participants aged 65 to 85 years were included in the final analysis. The results showed that PTSD symptoms were significantly associated with higher global Aβ levels (1.15 ± 0.20 vs. 1.09 ± 0.19; β = 0.056; p < 0.001), after adjusting for covariates. The association between PTSD symptoms and Aβ levels was not affected by sex, age, ApoE genotype, or psychiatric diseases. Similarly, PTSD symptoms were significantly associated with Aβ levels in all subregions, including the anterior cingulate, posterior cingulate, parietal cortex, precuneus, temporal cortex, and frontal cortex. In addition, the group with severe PTSD symptoms (1.22 ± 0.24) exhibited higher global Aβ levels than the groups with moderate (1.14 ± 0.19) or mild (1.12 ± 0.20) symptoms or the control (1.08 ± 0.18), with p < 0.001. Conclusion: The findings imply a close relationship between PTSD and brain Aβ levels, irrespective of sex, age, ApoE genotype, or psychiatric diseases. More well-designed studies are needed to further explore the relationship and mechanism underlying the association between PTSD and Aβ burden. [ABSTRACT FROM AUTHOR]

An incurable neurogenerative illness, Alzheimer's disease, is the cause of most global health, medical, and social disasters. The two main symptoms are cognitive impairment and neuronal loss. Current medications that target tau protein tangles and Aβ plaques are not very effective because they only slow the symptoms of AD and do not repair damaged cells. Stem cell-based treatments, however, present an alternative strategy in the treatment of AD. They have the capacity to divide into specialized adult cells, have self-renewal abilities, and multiplication. Stem cells can now be employed as a donor source for cell therapy due to developments in stem cell technology. This review covers preclinical and clinical updates on studies based on targeting the tau protein tangles and Aβ plaque, as well as four types of stem cells employed in AD treatment. The review also outlines the two basic pathologic aspects, tau protein tangles and Aβ plaques, of AD. [ABSTRACT FROM AUTHOR]

Purpose of Review: Obstructive Sleep Apnea (OSA) is a frequent comorbidity in patients with Alzheimer's Disease (AD). This narrative review critically examines current evidence on the relationship between OSA and AD, discussing their shared pathogenic mechanisms. Furthermore, the review focuses on the rationale, effectiveness, and feasibility of Continuous Positive Airway Pressure (CPAP) treatment in patients with comorbid OSA and mild cognitive impairment (MCI) or dementia due to AD. Finally, this review provides clinicians with a practical approach for the proper diagnosis, and management of OSA in patients with AD either in the context of memory clinics and sleep medicine centers. Recent Findings: Chronic intermittent hypoxia, glymphatic system failure and sleep disruption are the most important mechanisms connecting OSA to AD pathophysiology. Randomized clinical trials and observational studies show that OSA treatment with CPAP in patients with AD results in improvement of daytime vigilance, mood and executive functions as well as sleep consolidation. Moreover, it has been shown that CPAP has a mild potential effect on cognitive trajectories over time. Interestingly, adherence rates to CPAP treatment are similar to those reported in the general population. Summary: Patients with MCI and AD dementia should be screened for the presence of OSA as part of the routinary clinical evaluation. Given its proven efficacy and feasibility, treatment with CPAP should be offered in patients with comorbid AD and moderate-severe OSA and a proper follow-up should be established to ensure treatment compliance and tolerability. [ABSTRACT FROM AUTHOR]

Background: Regular physical activity plays a crucial role in modulating cellular metabolism and mitigating the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Multiple Sclerosis. Objective: The objective of this review is to evaluate the molecular mechanisms by which exercise influences cellular metabolism, with a focus on its potential as a therapeutic intervention for neurological disorders. Methods: A comprehensive literature review was conducted using peer-reviewed scientific articles, with a focus on the period between 2015 and 2024, to analyze the effects of exercise on mitochondrial function, oxidative stress, and metabolic health. Results: The findings indicate that exercise promotes mitochondrial biogenesis, enhances oxidative phosphorylation, and reduces reactive oxygen species, contributing to improved energy production and cellular resilience. These metabolic adaptations are associated with delayed disease progression and reduced symptoms in patients with neurodegenerative conditions. Additionally, integrating exercise with nutritional strategies may further enhance therapeutic outcomes by addressing metabolic disturbances comprehensively. Conclusions: This review concludes that personalized exercise protocols should be developed to optimize metabolic benefits for patients with neurological diseases, while future research should focus on biomarker development for individualized treatment approaches. These findings highlight the importance of non-pharmacological interventions in managing neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background/Objectives: Cardiovascular disease (CVD) and Alzheimer's disease (AD) are two diseases highly prevalent in the aging population and often co-occur. The exact relationship between the two diseases is uncertain, though epidemiological studies have demonstrated that CVDs appear to increase the risk of AD and vice versa. This scoping review aims to examine the current identified overlapping genetics between CVDs and AD at the individual gene level and at the shared pathway level. Methods: Following PRISMA-ScR guidelines for a scoping review, we searched the PubMed and Scopus databases from 1990 to October 2024 for articles that involved (1) CVDs, (2) AD, and (3) used statistical methods to parse genetic relationships. Results: Our search yielded 2918 articles, of which 274 articles passed screening and were organized into two main sections: (1) evidence of shared genetic risk; and (2) shared mechanisms. The genes APOE, PSEN1, and PSEN2 reportedly have wide effects across the AD and CVD spectrum, affecting both cardiac and brain tissues. Mechanistically, changes in three main pathways (lipid metabolism, blood pressure regulation, and the breakdown of the blood–brain barrier (BBB)) contribute to subclinical and etiological changes that promote both AD and CVD progression. However, genetic studies continue to be limited by the availability of longitudinal data and lack of cohorts that are representative of diverse populations. Conclusions: Highly penetrant familial genes simultaneously increase the risk of CVDs and AD. However, in most cases, sets of dysregulated genes within larger-scale mechanisms, like changes in lipid metabolism, blood pressure regulation, and BBB breakdown, increase the risk of both AD and CVDs and contribute to disease progression. [ABSTRACT FROM AUTHOR]

Florbetaben (FBB) is a radiopharmaceutical approved by the FDA and EMA in 2014 for the positron emission tomography (PET) imaging of brain amyloid deposition in patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD) or other causes of cognitive decline. Initially, the clinical adoption of FBB PET faced significant barriers, including reimbursement challenges and uncertainties regarding its integration into diagnostic clinical practice. This review examines the progress made in overcoming these obstacles and describes the concurrent evolution of the diagnostic landscape. Advances in quantification methods have further strengthened the traditional visual assessment approach. Over the past decade, compelling evidence has emerged, demonstrating that amyloid PET has a strong impact on AD diagnosis, management, and outcomes across diverse clinical scenarios, even in the absence of amyloid-targeted therapies. Amyloid PET imaging has become essential in clinical trials and the application of new AD therapeutics, particularly for confirming eligibility criteria (i.e., the presence of amyloid plaques) and monitoring biological responses to amyloid-lowering therapies. Since its approval, FBB PET has transitioned from a purely diagnostic tool aimed primarily at excluding amyloid pathology to a critical component in AD drug development, and today, it is essential in the diagnostic workup and therapy management of approved AD treatments. [ABSTRACT FROM AUTHOR]

Background: To establish simple screening tests to suspect Alzheimer's disease (AD) pathology, the clinical sign "head-turning sign" (HTS), which is a patient's behavior of turning their head towards their partner to seek assistance with questions posed by the examiner during the interview, and the simple screening questionnaire for dementia named "Neucop-Q" were validated in participants diagnosed with amyloid and tau positron emission tomography (PET). Methods: We enrolled 155 patients: 47 cognitive normal, 36 with mild cognitive impairment, 64 with dementia, and 8 with psychiatric disorders. All participants underwent Neucop-Q [three questions: Consciousness/self-awareness of cognitive disabilities (C) normal/impaired (nor/imp), Pleasure/pastime (P) nor/imp, and News/knowledge on current topics (N) nor/imp] and amyloid/tau PET. Additionally, we measured plasma amyloid β (Aβ) 42/40 ratio, phosphorylated tau 181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) levels and compared with HTS and Neucop-Q results. Results: The specificity and positive predictive value (PPV) of HTS positivity (HTSpos) were the highest (amyloid PET: 0.930 and 0.870, tau PET: 0.944 and 0.957, respectively), while Cimp and Nimp had a high negative predictive value (NPV) for amyloid PET (negativity) (0.750 and 0.725). Pimp showed high specificity for predicting non-AD tau positivity among non-AD participants without amyloid PET positivity (0.854). To validate these findings with PET results, we examined the correlation between well-established AD blood biomarkers and results obtained from these screening tests. HTSpos, Cimp, and Nimp were strongly associated with Aβ42/40 ratio (P < 0.0001, P = 0.0022, and P = 0.001), pTau181 (P < 0.0001, P = 0.0095, and P = 0.001), GFAP (P = 0.0372, P = 0.0088, and P = 0.0002), and amyloid PET Centiloid (P < 0.0001, P = 0.0210, and P = 0.0006), whereas Pimp increased neuroinflammation (GFAP; P = 0.0061) and was associated with non-AD tauopathy. The combination of Neucop-Q questions showed that Cimp/Pnor/Nimp subjects have the highest specificity and PPV (0.972 and 0.833) and were strongly associated with Aβ42/40 ratio (P = 0.0006), pTau181 (P = 0.0006), and amyloid PET Centiloid (P < 0.0001). Conclusion: HTSpos, Cimp, and Nimp have diagnostic utility in suspecting MCI due to AD and AD, and Pimp has diagnostic value in non-AD tauopathy. HTSpos, Cimp, and Nimp were associated with biomarkers of Aβ pathology. HTS and Neucop-Q may serve as powerful first-line screening in memory clinics. Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) under registration numbers 000032027 (Registration date: 2018/03/31) and 000030248 (Registration date: 2018/01/01). [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the characteristics of individuals with amyloid levels below the threshold. To achieve this, we differentiated between two groups: those with global amyloid negativity but focal deposition [G(–)F(+)] and those without focal deposition [G(–)F(–)]. Materials and methods: A total of 2,677 participants were diagnosed with cognitive unimpairment (CU) or mild cognitive impairment (MCI). MRI-based regional centiloid (CL) values were used to establish threshold values for each brain region. After applying a cutoff of 20 rdcCL to identify amyloid positivity, participants who were globally amyloid-negative were grouped into three categories: those who showed focal amyloid uptake [G(–)F(+)], individuals without focal amyloid deposition but with relatively high CL(HC) levels comparable to those in the focal uptake group [G(–)F(–) HC)], and those with relatively low CL(LC) levels [G(–)F(–) LC]. We compared the neuropsychological test results and brain structural changes between these groups using ANCOVA. Results: The G(–)F(+) group demonstrated a lower cortical thickness (P < 0.001) than the G(–)F(–) HC group. In neuropsychological tests, the G(–)F(+) group exhibited lower the Seoul Verbal Learning Test delayed recall (SVLT-DR) and Mini Mental State Examination (MMSE), and showed progressed clinical status in the clinical dementia rating–sum of boxes (CDR-SOB) compared to the G(–)F(–) HC group (P < 0.001). The subsequent sensitivity analyses confirmed the persistence of these findings. Conclusions: Individuals with focal amyloid deposition [G(–)F(+)] exhibited higher rates of cognitive impairment compared to patients with similar levels of amyloid, underscoring the importance of monitoring the progression of focal uptake, even when it remains below the amyloid threshold. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21 (trisomy 21 or T21) and is associated with an increased risk of early-onset Alzheimer's disease (AD), also known as DS-associated AD (DSAD). Individuals with DS typically develop amyloid neuropathology in their late-thirties to early-forties and the mean age of onset of clinical dementia is approximately 55 years. Recent advances in AD clinical research have focused on monoclonal antibodies (mAbs) targeting amyloid-β (Aβ) plaques as a potential therapeutic approach. Therefore, there has been guarded enthusiasm about using anti-amyloid mAbs in the prevention/treatment of DSAD. This narrative review and perspective explores the current understanding of amyloid pathology in AD and DSAD, the rationale for using anti-amyloid mAbs in the treatment of DSAD, and the challenges and opportunities for research toward the application of this therapeutic strategy to older adults with DS. [ABSTRACT FROM AUTHOR]

With the advent of PET imaging in 1976, 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-PET became the preferred method for in vivo investigation of cerebral processes, including regional hypometabolism in Alzheimer's disease. With the emergence of amyloid-PET tracers, [11C]Pittsburgh Compound-B in 2004 and later [18F]florbetapir, [18F]florbetaben, and [18F]flumetamol, amyloid-PET has replaced FDG-PET in Alzheimer's disease anti-amyloid clinical trial treatments to ensure "amyloid positivity" as an entry criterion, and to measure treatment-related decline in cerebral amyloid deposits. MRI has been used to rule out other brain diseases and screen for 'amyloid-related imaging abnormalities' (ARIAs) of two kinds, ARIA-E and ARIA-H, characterized by edema and micro-hemorrhage, respectively, and, to a lesser extent, to measure changes in cerebral volumes. While early immunotherapy trials of Alzheimer's disease showed no clinical effects, newer monoclonal antibody trials reported decreases of 27% to 85% in the cerebral amyloid-PET signal, interpreted by the Food and Drug Administration as amyloid removal expected to result in a reduction in clinical decline. However, due to the lack of diagnostic specificity of amyloid-PET tracers, amyloid positivity cannot prevent the inclusion of non-Alzheimer's patients and even healthy subjects in these clinical trials. Moreover, the "decreasing amyloid accumulation" assessed by amyloid-PET imaging has questionable quantitative value in the presence of treatment-related brain damage (ARIAs). Therefore, future Alzheimer's clinical trials should disregard amyloid-PET imaging and focus instead on assessment of regional brain function by FDG-PET and MRI monitoring of ARIAs and brain volume loss in all trial patients. [ABSTRACT FROM AUTHOR]

Assessing imaging biomarker in the prodromal and early phases of Parkinson's disease (PD) is of great importance to ensure an early and safe diagnosis. In the last decades, imaging modalities advanced and are now able to assess many different aspects of neurodegeneration in PD. MRI sequences can measure iron content or neuromelanin. Apart from SPECT imaging with Ioflupane, more specific PET tracers to assess degeneration of the dopaminergic system are available. Furthermore, metabolic PET patterns can be used to anticipate a phenoconversion from prodromal PD to manifest PD. In this regard, it is worth mentioning that PET imaging of inflammation will gain significance. Molecular imaging of neurotransmitters like serotonin, noradrenaline and acetylcholine shed more light on non-motor symptoms. Outside of the brain, molecular imaging of the heart and gut is used to measure PD-related degeneration of the autonomous nervous system. Moreover, optical coherence tomography can noninvasively detect degeneration of retinal fibers as a potential biomarker in PD. In this review, we describe these state-of-the-art imaging modalities in early and prodromal PD and point out in how far these techniques can and will be used in the future to pave the way towards a biomarker-based staging of PD. [ABSTRACT FROM AUTHOR]

Identifying biomarkers for Alzheimer's disease (AD) is crucial, due to its complex pathology, which involves dysfunction in lipid transport, contributing to neuroinflammation, synaptic loss, and impaired amyloid-β clearance. Nuclear magnetic resonance (NMR) is able to quantify and stratify lipoproteins. The study investigated lipoproteins in blood from AD patients, aiming to evaluate their diagnostic potential. Serum and plasma were collected from AD patients (n = 25) and healthy individuals (n = 25). We conducted a comprehensive lipoprotein profiling on serum samples using NMR spectroscopy, analysing 112 lipoprotein subfractions. In plasma, we measured unspecific markers of neuronal damage and AD hallmark proteins using single molecule array technology. Additionally, clinical data and cerebrospinal fluid biomarker levels were also collected to enrich our data. Our findings, after adjusting for age and sex differences, highlight significant alterations in two specific lipoproteins; high-density lipoprotein (HDL)-1 Apo-A2 (H1A2) and HDL-2 Apo-A2 (H2A2), both with area under the curve (AUC) values of 0.67, 95% confidence interval (CI) = 0.52–0.82). These results indicate that these lipoprotein subfractions may have potential as indicators of AD-related metabolic changes. [ABSTRACT FROM AUTHOR]

Background: In the central nervous system, type 2 vesicular monoamine transporters (VMAT2) are responsible for the reuptake of monoamines from synaptic junction back to pre-synaptic terminal vesicles. These transporters are functionally crucial as they reflect the integrity of monoamine neurons. D6-[18F]FP-(+)-DTBZ, a novel deuterated VMAT2 radioligand, has shown promise as a potential PET tracer for the diagnosis of Parkinson's disease (PD). This study evaluates the biodistribution and dosimetry of D6-[18F]FP-(+)-DTBZ and includes a head-to-head comparison with its non-deuterated version, [18F]FP-(+)-DTBZ (AV-133), in healthy individuals and PD patients. Results: The automated synthesis of D6-[18F]FP-(+)-DTBZ using the SPE method was accomplished in 35 min, yielding a high radiochemical purity (> 99%) and high radiochemical yields (35 ± 5%). The biodistribution and dosimetry study indicated an effective dose of 37.1 ± 7.2 μSv/MBq, with the liver receiving the highest radiation dose (289.6 ± 42.1 μGy/MBq), followed by pancreas (185.2 ± 29.1 μGy/MBq). Brain imaging with D6-[18F]FP-(+)-DTBZ exhibited a significantly increased uptake in VMAT2-rich regions, particularly the striatum. In a head-to-head comparison between [18F]FP-(+)-DTBZ and D6-[18F]FP-(+)-DTBZ, the latter exhibited approximately 15% higher SUVR in the caudate, putamen, and nucleus accumbens. Preliminary studies in PD patients showed a substantial reduction in VMAT2 uptake in the striatum, with the most pronounced decrease observed in the putamen (a 53% decline). Conclusions: D6-[18F]FP-(+)-DTBZ is a safe and improved VMAT2-specific imaging agent, which may be suitable for diagnosing PD by evaluating changes in VMAT2 binding of monoamine neurons in the brain. Trial registration Chinese Clinical Trial Registry, ChiCTR2200057218, Registered 16 August 2021, https://www.chictr.org.cn/bin/project/edit?pid=142725. [ABSTRACT FROM AUTHOR]

Sensory stimulations at 40 Hz gamma (but not any other frequency), have shown promise in reversing Alzheimer's disease (AD)-related pathologies. What distinguishes 40 Hz? We hypothesized that stimuli at 40 Hz might summate more efficiently (temporal summation) or propagate more efficiently between cortical layers (vertically), or along cortical laminas (horizontally), compared to inputs at 20 or 83 Hz. To investigate these hypotheses, we used brain slices from AD mouse model animals (5xFAD). Extracellular (synaptic) stimuli were delivered in cortical layer 4 (L4). Leveraging a fluorescent voltage indicator (VSFP) expressed in cortical pyramidal neurons, we simultaneously monitored evoked cortical depolarizations at multiple sites, at 1 kHz sampling frequency. Experimental groups (AD-Female, CTRL-Female, AD-Male, and CTRL-Male) were tested at three stimulation frequencies (20, 40, and 83 Hz). Despite our initial hypothesis, two parameters—temporal summation of voltage waveforms and the strength of propagation through the cortical neuropil—did not reveal any distinct advantage of 40 Hz stimulation. Significant physiological differences between AD and Control mice were found at all stimulation frequencies tested, while the 40 Hz stimulation frequency was not remarkable. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Widowhood and divorce are extremely stressful life events that are associated with dementia, but the neurobiological underpinnings of this risk remain unknown. Amyloid beta (Aβ) load may explain influences of chronic stress, commonly seen in disruptive marital transitions, on cognitive decline. METHODS: We examined whether Aβ quantified by tracer uptake on positron emission tomography mediates associations between marital dissolution and executive functioning and episodic memory performance using data from 543 cognitively normal (CN) participants from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: Marriage dissolution was associated with increased Aβ burden (β = 0.56; P = 0.015) and worse memory performance (β = –0.09; P = 0.003). Aβ levels were a significant mediator for the relationship between marriage dissolution and memory (average causal mediation effect = –0.007; P = 0.029). DISCUSSION: Findings suggest that stressful life events, such as the dissolution of one's marriage, might exert an effect on Alzheimer's disease proteinopathy, which may subsequently influence poor cognition. Highlights: Marital dissolution was associated with increased amyloid beta (Aβ) and memory declines.Aβ burden mediated associations between marital dissolution and memory.Findings were robust to potential non‐linear influences of age.Mediation results were not observed when stratifying marital groups by sex. [ABSTRACT FROM AUTHOR]

Despite their chemical simplicity, the spectroscopic investigation of light hydrides, such as hydrogen sulfide, is challenging due to strong hyperfine interactions and/or anomalous centrifugal-distortion effects. Several hydrides have already been detected in the interstellar medium, and the list includes H2S and some of its isotopologues. Astronomical observation of isotopic species and, in particular, those bearing deuterium is important to gain insights into the evolutionary stage of astronomical objects and to shed light on interstellar chemistry. These observations require a very accurate knowledge of the rotational spectrum, which is so far limited for mono-deuterated hydrogen sulfide, HDS. To fill this gap, high-level quantum-chemical calculations and sub-Doppler measurements have been combined for the investigation of the hyperfine structure of the rotational spectrum in the millimeter- and submillimeter-wave region. In addition to the determination of accurate hyperfine parameters, these new measurements together with the available literature data allowed us to extend the centrifugal analysis using a Watson-type Hamiltonian and a Hamiltonian-independent approach based on the Measured Active Ro-Vibrational Energy Levels (MARVEL) procedure. The present study thus permits to model the rotational spectrum of HDS from the microwave to far-infrared region with great accuracy, thereby accounting for the effect of the electric and magnetic interactions due to the deuterium and hydrogen nuclei. [ABSTRACT FROM AUTHOR]

Ketoaldehydes are key intermediates in biochemical processes including carbohydrate, lipid, and amino acid metabolism. Despite their crucial role in the interstellar synthesis of essential biomolecules necessary for the Origins of Life, their formation mechanisms have largely remained elusive. Here, we report the first bottom-up formation of methylglyoxal (CH3C(O)CHO)—the simplest ketoaldehyde—through the barrierless recombination of the formyl (HĊO) radical with the acetyl (CH3ĊO) radical in low-temperature interstellar ice analogs upon exposure to energetic irradiation as proxies of galactic cosmic rays. Utilizing vacuum ultraviolet photoionization reflectron time-of-flight mass spectrometry and isotopic substitution studies, methylglyoxal and its enol tautomer 2-hydroxypropenone (CH3C(OH)CO) were identified in the gas phase during the temperature-programmed desorption of irradiated carbon monoxide–acetaldehyde (CO–CH3CHO) ices, suggesting their potential as promising candidates for future astronomical searches. Once synthesized in cold molecular clouds, methylglyoxal can serve as a key precursor to sugars, sugar acids, and amino acids. Furthermore, this work provides the first experimental evidence for tautomerization of a ketoaldehyde in interstellar ice analogs, advancing our fundamental knowledge of how ketoaldehydes and their enol tautomers can be synthesized in deep space. [ABSTRACT FROM AUTHOR]

Background: Several blood-based biomarkers offer the opportunity of in vivo detection of brain pathology and neurodegeneration in Alzheimer disease with high specificity and sensitivity, but the performance of amyloid-β (Aβ) measurements remains under evaluation. Autosomal dominant Alzheimer disease (ADAD) with mutations in PSEN1, PSEN2 and APP can be studied as a model for sporadic Alzheimer disease. However, clarifying the genetic effects on the Aβ-levels in different matrices such as cerebrospinal fluid or plasma is crucial for generalizability and utility of data. We aimed to explore plasma Aβ concentrations over the Alzheimer disease continuum in a longitudinal cohort of genetic Alzheimer disease. Methods: 92 plasma samples were collected from at-risk individuals (n = 47) in a Swedish cohort of ADAD, including 18 mutation carriers (13 APPswe (p.KM670/671NL) MC), 5 PSEN1 (p.H163Y) MC) and 29 non-carriers (NC) as the reference group. Concentrations of Aβ1–38, Aβ1–40 and Aβ1–42 were analyzed in plasma using immunoprecipitation coupled to tandem liquid chromatography mass spectrometry (IP-LC-MS/MS). Cross-sectional and repeated-measures data analyses were investigated family-wise, applying non-parametric tests as well as mixed-effects models. Results: Cross-sectional analysis at baseline showed more than a 3-fold increase in all plasma Aβ peptides in APPswe MC, regardless of clinical status, compared to controls (p < 0.01). PSEN1 (p.H163Y) presymptomatic MC had a decrease of plasma Aβ1–38 compared to controls (p < 0.05). There was no difference in Aβ1–42/1–40 ratio between APPswe MC (PMC and SMC), PSEN1 MC (PMC) and controls at baseline. Notably, both cross-sectional data and repeated-measures analysis suggested that APPswe MC have a stable Aβ1–42/1–40 ratio with increasing age, in contrast to the decrease seen with aging in both controls and PSEN1 (p.H163Y) MC. Conclusion: These data show very strong mutation-specific effects on Aβ profiles in blood, most likely due to a ubiquitous production outside of the CNS. Hence, analyses in an unselected clinical setting might unintentionally disclose genetic status. Furthermore, our findings suggest that the Aβ ratio might be a poor indicator of brain Aβ pathology in selected genetic cases. The very small sample size is a limitation that needs to be considered but reflects the scarcity of longitudinal in vivo data from genetic cohorts. [ABSTRACT FROM AUTHOR]

The formation of double-emulsions or core/shell microdroplets in microchannels, essential for various chemical applications, traditionally relies on costly and time-consuming laboratory methods. In this regard, computational fluid dynamics (CFD) and artificial neural network (ANN) techniques were employed. The present study developed ANN models to predict the relationship between shell thickness and double-emulsion size in a double-T microchannel, using two datasets comprising 180 experimental and CFD data points. Assessing this relationship involved analyzing various input factors, including the Capillary, Weber (case A), and Reynolds numbers (case B) of the core, shell, and continuous phases. Among twelve training algorithms and four activation functions, the Levenberg–Marquardt (LM) algorithm with sigmoidal activation functions (Tansig and Logsig), in contrast to the linear activation functions (Poslin and Purelin), achieved the highest predictive accuracy. Additionally, the predictive accuracy of ANN models was found to be significantly improved when trained using a combination of capillary and Weber numbers, as opposed to models trained only using capillary, Weber, and Reynolds numbers. The optimal neural network architectures were [10 5] neurons for case A (tansig and logsig) and [8] neurons for case B (tansig), yielding coefficients of determination (R2) of 0.99 and 0.98, respectively. These models demonstrated high precision and effective generalization, evidenced by statistical measures such as R2, MSE, RMSE, AAD, %AARD, and computational time. Moreover, their ability to generalize within the training dataset further substantiates their predictive capacity. [ABSTRACT FROM AUTHOR]

While trans-glyoxal may not be easily observable in astronomical sources through either IR or radioastronomy due to its C2h symmetry, its cis conformer along with the cyc-H2COCO epoxide isomer should be ready targets for astrochemical detection. The present quantum chemical study shows that not only are both molecular isomers strongly polar, they also have notable IR features and low isomerisation energies of 4.1 kcal mol−1 and 10.7 kcal mol−1, respectively. These three isomers along with two other C2O2H2 isomers have had their full set of fundamental vibrational frequencies and spectroscopic constants characterised herein. These isomers have previously been shown to occur in simulated astrophysical ices making them worthy targets of astronomical search. Furthermore, the hybrid quartic force field (QFF) approach utilized herein to produce the needed spectral data has a mean absolute percent error compared to the experimentally-available, gas phase fundamental vibrational frequencies of 0.6% and rotational constants to better than 0.1%. The hybrid QFF is defined from explicitly correlated coupled cluster theory at the singles, doubles, and perturbative triples level [CCSD(T)-F12b] including core electron correlation and a canonical CCSD(T) relativity correction for the harmonic (quadratic) terms in the QFF and simple CCSD(T)-F12b/cc-pVDZ energies for the cubic and quartic terms, the so-called "F12-TcCR+DZ QFF." This method is producing spectroscopically-accurate predictions for both fundamental vibrational frequencies and principal spectroscopic constants. Hence, the values computed in this work should be notably accurate and, hence, exceptionally useful to the spectroscopy and astrochemistry communities. [ABSTRACT FROM AUTHOR]

Background: Tau accumulation in Alzheimer's disease is associated with short term clinical progression and faster rates of cognitive decline in individuals with high amyloid-β deposition. Defining an optimal threshold of tau accumulation predictive of cognitive decline remains a challenge. Objective: We tested the ability of regional tau PET sensitivity and specificity thresholds to predict longitudinal cognitive decline. We also tested the predictive performance of thresholds in the proposed new NIA-AA biological staging for Alzheimer's disease where multiple levels of tau positivity are used to stage participants. Methods: 18F-flortaucipir scans from 301 non-demented participants were processed and sampled. Four cognitive measures were assessed longitudinally. Regional standardized uptake value ratios were split into infra- and suprathreshold groups at baseline using previously derived thresholds. Survival analysis, log rank testing, and Generalized Estimation Equations assessed the relationship between the application of regional sensitivity/specificity thresholds and change in cognitive measures as well as tau threshold performance in predicting cognitive decline within the new NIA-AA biological staging. Results: The meta temporal region was best for predicting risk of short-term cognitive decline in suprathreshold, as compared to infrathreshold participants. When applying multiple levels of tau positivity, each subsequent level of tau identified cognitive decline at earlier timepoints. Conclusions: When using 18F-flortaucipir, meta temporal suprathreshold classification was associated with increased risk of cognitive decline, suggesting that abnormal tau deposition in the cortex predicts decline. Likewise, the application of multiple levels of tau clearly predicts the distinctive cognitive trajectories in the new NIA-AA biological staging framework. [ABSTRACT FROM AUTHOR]

Background: Blood inflammatory biomarkers have emerged as important tools for diagnosing, assessing treatment responses, and predicting neurodegenerative diseases. This study evaluated the associations between blood inflammatory biomarkers and brain tissue volume loss in elderly people. Methods: This study included 111 participants (age 67.86 ± 8.29 years; 32 men and 79 women). A battery of the following blood inflammatory biomarkers was measured, including interleukin 1-beta (IL1β), NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), monomer Aβ42 (mAβ), oligomeric Aβ42 (oAβ), miR155, neurite outgrowth inhibitor A (nogo-A), phosphorylated tau (P-tau), and total tau (T-tau). Three-dimensional T1-weight images (3D T1WI) of all participants were prospectively obtained and segmented into gray matter and white matter to measure the gray matter volume (GMV), white matter volume (WMV), and gray-white matter boundary tissue volume (gwBTV). The association between blood biomarkers and tissue volumes was assessed using voxel-based and region-of-interest analyses. Results: GMV and gwBTV significantly decreased as the levels of IL1β and T-tau increased, while no significant association was found between the level of P-tau and the three brain tissue volumes. Three brain tissue volumes were negatively correlated with the levels of IL1β, P-tau, and T-tau in the hippocampus. Specifically, IL1β and T-tau levels showed a distinct negative association with the three brain tissue volume losses in the hippocampus. In addition, gwBTV was negatively associated with the level of NLRP3. Conclusion: The observed association between brain tissue volume loss and elevated levels of IL1β and T-tau suggests that these biomarkers in the blood may serve as potential biomarkers of cognitive impairment in elderly people. Thus, IL1β and T-tau could be used to assess disease severity and monitor treatment response after diagnosis in elderly people who are at risk of cognitive decline. [ABSTRACT FROM AUTHOR]

The performance and operational stability of perovskite‐based devices heavily rely on the interfacial properties between the photoactive perovskite layer and charge transport layers. Understanding the theoretical relationship between surface/interface dipoles and surface energetics is crucial for scientific understanding and practical applications. In this study, a method is applied that bridges classical electromagnetism and modern atomistic approaches. The impact of dipolar ligand molecules functionalizing the FASnI3 perovskite surface is investigated, with inspection of the interplay between surface dipole, charge transfer, and local strain effect, and corresponding shifts in the valence level. The results reveal that the contribution of individual molecular entities to surface dipoles and electric susceptibilities follows an essentially additive behavior. The influence of F doping usually used to mitigate Sn oxidation in Sn‐based layer for photovoltaic applications, is also discussed. Furthermore, the findings are compared with predictions from classical approaches employing a capacitor model that links the induced vacuum level shift and the molecular dipole moment. The insights gained from the study provide theoretical guidelines for fine‐tuning the work functions of materials, thus enabling effective interfacial engineering in this class of semiconductors. [ABSTRACT FROM AUTHOR]

Background: Higher midlife physical activity engagement has been associated with lower dementia risk in late life. However, the underlying mechanisms contributing to the protective effect remain unclear. Objective: The goal of the current study was to evaluate the associations of physical activity with cerebral amyloid-β (Aβ) and tau in a predominately middle-aged community-based cohort, as well as to explore whether the associations differ by sex or age. Methods: Participants from the Framingham Heart Study underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Total physical activity levels were evaluated by self-report using the Physical Activity Index (PAI). Cross-sectional associations between total PAI with regional Aβ and tau PET retention were evaluated using linear regression models adjusted for demographic and cardiovascular risk factors. Interactions with sex and age group were examined and stratified analyses were performed when significant. FDR-correction for multiple comparisons was applied. Results: The sample included 354 participants (mean age 53±8 years, 51% female). Higher total PAI scores were associated with lower entorhinal cortex tau PET binding (β (SE) = –0.021(0.008), p = 0.049). There were significant interactions with sex. In men alone, total PAI inversely associated with entorhinal cortex (β (SE) = –0.035(0.009), p = 0.001), inferior temporal (β (SE) = –0.029(0.010), p = 0.012), and rhinal cortex tau(β (SE) = –0.033(0.010), p = 0.002). Conclusions: The results suggest that higher midlife physical activity engagement may confer resistance to tau pathology. However, the effects may vary based on sex, highlighting the importance of better understanding and tailoring lifestyle interventions to address sex disparities. [ABSTRACT FROM AUTHOR]

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]