bluuebunny/crossref_metadata_2025 huggingface dataset:
CSF biomarkers of immune activation and Alzheimer’s disease for predicting cognitive impairment risk in the elderly
Authors: Shue Francis , White Launia J , Hendrix Rachel , Ulrich Jason D , Henson Rachel L. , Knight William C. , Martens Yuka A , Wang Ni , Roy Bhaskar , Starling Skylar C , Ren Yingxue , Xiong Chengjie , Asmann Yan W. , Syrjanen Jeremy A. , Vassilaki Maria , Mielke Michelle M. , Cruchaga Carlos , Holtzman David M. , Bu Guojun , Petersen Ronald C. , Heckman Michael G. , Kanekiyo Takahisa
Published: January 2025

Background

The immune system is substantially involved in the development and progression of age‐related cognitive decline and Alzheimer’s disease (AD).

Method

As genetic and environmental factors interactively impact these conditions, we investigated how risk factors such as APOE genotype, age, and sex influence immune activation markers and AD biomarkers in cerebrospinal fluid (CSF) in elderly individuals enrolled in the Mayo Clinic Study of Aging cohort. Among cognitively unimpaired individuals aged over 65 at the baseline visit (N=298), we measured 365 CSF immune activation markers using the proximity extension assay.

Result

We found that age, sex, and diabetes status are associated with altered CSF levels of immune activation markers independently of other factors. For CSF AD biomarkers, we observed significant positive correlations between age and total tau, phosphorylated tau‐181 (p‐tau181), neurofilament light (NfL), and YKL40. APOE4 was also associated with lower Aβ42 and higher SNAP25 in CSF. We further examined whether baseline visit variables can predict cognitive decline, represented by the conversion from CDR=0 to CDR>0. We found that age, Aβ42, NfL, and REG4 were independently correlated with CDR conversion risk. When the cohort was dichotomized by their median values, older participants with lower Aβ42, higher NfL, and higher REG4 at baseline developed cognitive impairment during the follow up with a c‐index of 0.762 while age alone had a c‐index of 0.699.

Conclusion

Together, our results suggest that assessing CSF immune activation markers and AD biomarkers can improve the prediction of cognitive impairment risk in the elderly.
Elevated plasma neurofilament light and glial fibrillary acidic protein are associated with impaired cerebrovascular reactivity in older adults
Authors: Kapoor Arunima , Dutt Shubir , Nguyen Amy , Gaubert Aimée , Alitin John Paul M , Sible Isabel , Marshall Anisa J , Shenasa Fatemah , Engstrom Allison C , Shao Xingfeng , Martini Alessandra Cadete , Head Elizabeth , Wang Danny JJ , Nation Daniel A.
Published: January 2025

Background

Plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) are markers of axonal and astroglial injury, respectively. Both markers have been proposed as predictive biomarkers of cerebral small vessel disease, with elevated levels indicating higher burden of white matter hyperintensities, lacunar infarcts and cerebral microbleeds. However, to date, no study has examined whether NfL and GFAP levels are associated with dynamic markers of small vessel damage such as cerebrovascular reactivity (CVR)—the ability of cerebral blood vessels to regulate cerebral blood flow (CBF) in response to vasodilatory or vasoconstrictive stimuli. In this study, we examined whether levels of NfL and GFAP are associated with CVR to hypercapnia and hypocapnia.

Method

Independently living older adults (N = 78; mean age = 69.5 years; SD = 8.1; age range 55‐89 years; 35.9% male) free of dementia or clinical stroke were recruited from the community and underwent venipuncture and brain MRI. Plasma levels of NfL, and GFAP were determined using a digital immunoassay. Pseudo‐continuous arterial spin labeling MRI quantified whole brain cerebral perfusion during CVR to hypocapnia (0.1Hz paced breathing; vasoconstriction) and hypercapnia (15s breath holds, vasodilation).

Result

A significant negative association was observed between circulating levels of NfL and global CVR to hypocapnia (r = ‐.26, p = .027) and hypercapnia (r = ‐.23, p = 0.049) as well as GFAP and CVR to hypercapnia (‐.26, p = .025).

Conclusion

This study demonstrates that elevated levels of NfL and GFAP are associated with diminished CVR to hypercapnia and levels of NfL are associated with impaired CVR to hypocapnia. These findings are consistent with prior studies suggesting that plasma NfL and GFAP may serve as biomarkers of cerebral small vessel disease. Given that these markers signify axonal and astroglial injury, these findings also provide insight into the pathophysiological processes underlying cerebrovascular dysfunction, which may contribute to the development of neurodegenerative conditions.
Time‐based measures for quantifying disease modification in Alzheimer’s disease
Authors: Raket Lars Lau
Published: January 2025

Background

The advent of disease‐modifying therapies in Alzheimer’s disease (AD) necessitates a nuanced understanding of how therapies impact disease processes. Over the past decades, AD clinical trials have primarily relied on classical statistical analysis methodology such as the mixed model for repeated measures (MMRM) to estimate treatment effects. These conventional treatment effect quantifications are given as group differences in clinical outcome measures at a single visit. While this classical approach of estimating treatment effects is well established, the resulting quantifications have shortcomings in relation to data utilization, meaningfulness, cumulative benefit summarization, post‐trial implications, and cross‐trial comparability.

Method

Properties of conventional treatment effect quantifications from the MMRM were compared with two time‐based quantifications from the progression model for repeated measures (PMRM)1 and a latent time‐disease progression model. Results were illustrated and compared using data from the TRAILBLAZER‐ALZ 2 trial of donanemab.

Result

The MMRM had fewest assumptions, followed by PMRM and then the laten‐time quantifications. PMRM and latent‐time quantifications utilized information across visits better than the conventional MMRM quantification and produced greater power to detect treatment effects. Compared to conventional quantifications, the time‐based quantifications of treatment effects offered several desirable properties in terms of meaningfulness, cumulative benefit summarization, post‐trial implications, and cross‐trial comparability.

Conclusion

Time‐based estimates, particularly those derived from PMRM and latent time disease progression models, offer a set of desirable properties that complement conventional treatment effect quantifications. This study advocates for the inclusion of time‐based measures in the evaluation of disease modification in AD, providing a more comprehensive and nuanced perspective for guiding future clinical trial methodologies and result interpretations.

References:

1. Raket, L. L. (2022). Progression models for repeated measures: Estimating novel treatment effects in progressive diseases. Statistics in Medicine, 41(28), 5537‐5557.
How to handle use of additional medication for Alzheimer’s Disease during randomised clinical trials?
Authors: Dethlefsen Claus , Johannsen Peter
Published: January 2025

Background

Phase 3 randomized clinical trials within Alzheimer’s Disease (AD) typically last over 18 months. Post‐baseline participants can use additional treatment for Alzheimer’s disease, potentially impacting the cognitive ability as evaluated by the primary endpoint. Consequently, this could overestimate or underestimate the treatment effect, depending on the distribution of usage between treatment arms.

Method

The ICH E9 (R1) addendum’s estimand framework provide a means of precisely defining the clinical question of interest, in particular detailing how intercurrent events such as ‘use of additional AD medication’ should be handled and how to interpret the estimated treatment effect. Donohue et al (2020) suggested to use a treatment policy strategy for initiation of symptomatic treatments, based on the observation that placebo subjects did not experience an improvement after initiation of symptomatic treatment. The EMA guideline for Alzheimer’s disease (2018), recommends using a hypothetical strategy for initiation of symptomatic treatment.

Result

Use of additional AD medication will qualify as an intercurrent event only as long as the medication is considered to have an effect. Symptomatic AD medication is assumed to have no effect when the patient is no longer exposed. Therefore, we suggest to allow for the intercurrent event ‘use of additional AD medication’ to have both a start and a stop date, and, when applying a hypothetical strategy, only measurements that are considered affected by the intercurrent event will be substituted by outcomes corresponding to the hypothetical scenario were additional AD medication has not been initiated.

Conclusion

Using estimands clarifies the interpretation of treatment effects in clinical trials allowing usage of additional AD medication.
Discovery and Preclinical Development of SM15685, a Novel Highly Selective Oral DYRK1A/B Inhibitor as a Potential Therapeutic for Alzheimer’s Disease
Authors: Mak Chi‐Ching , Mittapalli Gopi , Nora Chelsea , Creger Emily , Turner Lewis , Eastman Brian , Hofilena Brian , Vakiti Ramkrishna , Benardo David , Taylor Graeme , Hill John S , Bossard Carine
Published: January 2025

Background

DYRK1A overexpression, common in neurodegenerative diseases like Alzheimer’s (AD), contributes to neurofibrillary tangles via Tau protein hyperphosphorylation and amyloid plaque formation, key AD hallmarks. Therefore, DYRK1A has been regarded as a novel target for neurodegenerative diseases. However, developing DYRK1A selective inhibitors has been a difficult challenge due to the highly conserved ATP‐binding site of protein kinases, particularly among the CMGC family. Here we describe SM15685, a novel highly selective and potent oral DYRK1A/B inhibitor, which reduces Tau hyperphosphorylation both in vitro and in vivo.

Method

Compound selectivity and potency were evaluated in kinase panels and cellular target engagement assays. Tau phosphorylation (pTau) was measured in cell‐based assays. Pharmacokinetics (PK) were evaluated in rodents and pharmacodynamics evaluated in 3‐month‐old JNPL3 female mice (P301L human Tau overexpression) treated orally with SM15685 or Vehicle for 7 days (7 mice/group). pTau at Thr212 was biochemically quantified in subcortical brain and spinal cord fractions.

Result

SM15685 was developed by utilizing structure‐based drug design and via iterative medicinal chemistry optimization cycles to achieve high potency, selectivity against the closely related CLKs and GSK3β, and good oral PK profiles characterized by brain‐penetration. SM15685 selectively and potently inhibited DYRK1A kinase activity (IC50 = 1 nM) with >90% inhibition at 1μM and only inhibited <2% of the full kinome. Selectivity and potency for DYRK1A and DYRK1B were confirmed in cellular target engagement assays (IC50 = 18 and 55 nM, respectively). SM15685 reduced pTau at the Threonine 212 site (IC50 = 14 nM). In pharmacokinetic studies, SM15685 demonstrated high oral bioavailability (%F >70) and good brain‐penetration in rodents (Kpuu >0.6). Compared to vehicle, JNPL3 mice treated with SM15685 at 45mg/kg showed significant reduction of pTau in both subcortical and spinal cord fractions in a pharmacodynamic model (p<0.05, T‐test).

Conclusion

SM15685, a highly selective and potent, oral, brain‐penetrant, DYRK1A/B inhibitor with the ability to significantly reduce Tau phosphorylation, has potential as a treatment for chronic tauopathies such as AD. These studies support further evaluation of SM15685 as a therapeutic option for AD and other diseases characterized by Tau hyperphosphorylation.
Association Between the Retinal Biomarkers and Cognitive Impairment in Community‐dwelling Older Adults in Taiwan
Authors: Chu Ting‐Wen , Hsieh Yi‐Ting , Chiou Jeng‐Min , Liu Yao‐Lin , Chen Jen‐Hau , Chen Yen‐Ching
Published: January 2025

Background

The early detection of preclinical dementia is crucial, prompting investigations into retinal biomarkers using optical coherence tomography (OCT). Inconsistent and limited longitudinal studies have been done to clarify the association between the retinal nerve fiber layer (RNFL) and ganglion cell‐inner plexiform layer (GC‐IPL) thickness and cognitive function over time. This study aims to explore the association between retinal biomarkers and cognitive function over time in non‐demented older adults.

Method

This seven‐year prospective cohort study included 264 non‐demented older adults at baseline (2015‐2017) from the ongoing Taiwan Initiative for Geriatric Epidemiological Research. Cognitive function underwent biennial follow‐ups to 2022, with assessments including global and domain‐specific cognition (memory, attention, executive function, and verbal fluency) measured using the Montreal Cognitive Assessment–Taiwanese version (MoCA‐T) and a battery of neuropsychological tests. Retinal data were collected using OCT at baseline. Generalized linear mixed models were utilized to examine the relationship between the RNFL, GC‐IPL thickness, and cognitive function, adjusting for apolipoprotein E ε4 status, age, sex, education years, and age‐related macular degeneration.

Result

At baseline, the performance of global cognition (MoCA‐T) decreased as GC‐IPL deviated from the mean (77.1 μm) (quadratic GC‐IPL: β= ‐0.32 x 10‐2; 95% CI: ‐0.61 x 10‐2 to ‐0.03 x 10‐2). Similar findings were found for memory performance (quadratic GC‐IPL: β= ‐0.19 x 10‐2; 95% CI: ‐0.31 x 10‐2 to ‐0.06 x 10‐2), and executive function (quadratic GC‐IPL: β= ‐0.07 x 10‐2; 95% CI: ‐0.14 x 10‐2 to ‐0.003 x 10‐2) over seven years. These results remained significant in females after stratification by sex. Notably, no significant association was observed between RNFL thickness and cognition.

Conclusion

We found a non‐linear relation between GC‐IPL thickness and poor performance of global cognition, memory, and executive function, particularly among women. These findings highlight the significance of GC‐IPL thickness as an early biomarker of cognitive impairment, informing strategies for timely intervention in aging populations.
FDG‐PET and Amyloid PET scans: benefits beyond Alzheimer´s Disease. It´s really useful in daily practice? Clinical case review
Authors: Orrego Shenda , Sava Mihaela , Garcia Maria Pilar , Manzano María Sagrario
Published: January 2025

Background

biomarkers are essential in order to make a diagnosis with a high level of accuracy in patients with cognitive and behavior complaints. However, molecular imaging biomarkers not always provide an answer in daily clinical practice.

Methods

retrospective and descriptive study in patients with Amyloid PET (APscans) implemented according to rational use of this technic, between January 2019‐November 2023 in Neurology Department, Infanta Leonor Hospital, Madrid, Spain.

We included: first visit date, type of diagnosis, date, age, sex, neuropsychiatric symptoms, doctor requesting the diagnosis, CT/MRI scans (atrophy or vascular signs), NPS values (GDS),18F‐FDG PET scans (divided into normal, AD pattern, not AD pattern, indeterminate). The study was approved by the Research Committee of ILH. Statistical analysis was made with Dataset and SPSS 22.0.

Results

total of 51 patients (54.9%females) were included. Mean of age 61.058, SD:8.329

The mean of months till diagnosis was 10.82, SD:10.133. 74.5% cases were GDS 3 in the first visit.

Positive APScans:39.22%, negative APScans:50.98%, not made yet:1.96%, not made:7.84%

In the negative APScans only 26.92% could obtain a diagnosis with a high level of accuracy (Lewy body dementia 11.54%; FTD. 15.38%). But in 23.08% the results were not conclusive and the patients remains without a diagnosis in the follow up.

In FDG‐PET‐scans we observed an impairment of glucose metabolism in 72.55% of patients. 58.82% FDG‐PET‐scans have a not AD pattern, being indeterminate in 73.33%.

49.02% patients have history of depression, 3.92% psychosis, sleep disorders 1.96%, anxiety 3.92%, suicidal ideation 1.96%. Positive APScans has depression in 50% of cases vs 57.69% of negatives(p>0.05). Psychosis was present in 10% of positive APScans vs 0% of negatives(p>0.05). These symptoms did not predict the positive or negative results in APScans

In structural neuroimaging we observed 55% of patients with atrophy in MRI scans. A vascular pathology in MRI (lacunar strokes or leukoaraiosis):56.86%. Vascular pathology in structural neuroimaging predicted the higher probability to have a negative APScan (57.69%). Probably the small size could impact in all these results.

Conclusion

In patients with cognitive and behaviour complaints, biomarkers are essential to make a diagnosis. However, when an APScan is negative and FDG‐PET‐scan indeterminate, diagnostic uncertainty, in real life, remains a serious unresolved issue
The Swedish registry for behavioural and psychological symptoms of dementia (BPSD)
Authors: Jönsson Linus , Londos Elisabet , Wibom Moa , Nägga Katarina
Published: January 2025

Background

Behavioural and psychological symptoms (BPSD) are common in major cognitive disorders and an important driver of suffering and high care needs. The Swedish BPSD registry was founded in 2010 to develop an evidence base for quality improvement in the care of patients with BPSD. Here we describe the process of establishing and operating the registry, the patient population included, and data collected since the start of the registry in 2010.

Methods

The Swedish BPSD registry provides a framework for documenting the occurrence of behavioural disturbances, formulating individual caring and treatment plans and following up the patients and capturing health outcomes. Symptoms are recorded by the neuropsychiatric inventory ‐ nursing home (NPI‐NH) scale, and data is entered by trained staff, mainly at institutional care facilities. Triggering factors for BPSD are also recorded, as well as care objectives and targeted symptoms.

Results

Between 2010 and 2023, 324,900 registrations were made in 110,684 persons. The number of patients active in the registry each year is 20‐25,000. Alzheimer’s disease was the most common diagnosis, 33%, followed by vascular dementia 17%, mixed 8%, DLB/PDD in 3% and FTD in 1,5%. Pain was the most cited trigger factor in all symptoms, except for night‐time and appetite/eating disturbances. The most frequently used care objective was affirmation/security, especially to manage agitation/aggression. Median survival was 24.0 months for men, 30.5 months for women.

Conclusions

The Swedish BPSD registry provides a unique view of the final stages in the disease course of dementia, with specific focus on the role of behavioural disturbances and their management. The scale, data completeness, long duration and possibility of linkage to other health registries is to our knowledge unparalleled and a great potential as a resource for data‐driven research.
Exploring the Therapeutic Effect of Perampanel, a Selective AMPA Receptor Antagonist, on Pathophysiological Changes in hAPP‐J20 Transgenic Alzheimer’s Mice
Authors: Liao Keng Ying , Hsin Yue Loong , Han Xu , Chen Wen‐Ying , Liu Wentai
Published: January 2025

Background

The initiation of amyloid plaque deposition signifies a crucial stage in Alzheimer’s disease (AD) progression, which often coincides with the disruption of neural circuits and cognitive decline. While the role of excitatory‐inhibitory balance is increasingly recognized in AD pathophysiology, targeted therapies to modulate this balance remain underexplored. This study investigates the effect of perampanel, a selective non‐competitive AMPA receptor antagonist, in modulating neurophysiological changes in hAPP‐J20 transgenic Alzheimer’s mice.

Method

Perampanel was administered to hAPP‐J20 mice and their age‐matched wildtype littermates, aged 20‐25 weeks, during the critical amyloid plaque deposition period in the hippocampus. We continuously monitored the local field potential of the hippocampal CA1 region using long‐term wireless telemetry (sampled at a rate of 2 kHz), capable of calculating rates of high‐frequency oscillations (HFOs) to gauge potential epileptiform activity. To evaluate cognitive function, Morris water maze test was conducted. Glutamatergic pyramidal cells and GABAergic interneurons was quantified to assess neuronal health, and the hippocampal concentration of neuropeptide Y (NPY) was measured as an indirect indicator of mossy fiber sprouting.

Result

Treatment with perampanel resulted in a significant rescue of GABAergic interneuron depletion and reduced the pathological increase of HFOs, indicative of restored excitatory‐inhibitory balance. In line with the restored excitatory‐inhibitory balance, it also attenuated neuronal sprouting labeled by NPY. Additionally, perampanel administration led to a substantial decrease in amyloid plaque accumulation in the hippocampus, though the observed memory deficit in transgenic mice did not change significantly.

Conclusion

Our findings reveal that perampanel, an established antiseizure medication, exerts multifaceted neuroprotective effects in the AD mouse model. The preservation of interneurons, reduction of pathological neural hyperactivity, and decreased amyloid plaque burden highlighted the potential of targeting glutamatergic pathways as a therapeutic strategy. The study warrants further investigation of perampanel as a promising candidate for ameliorating the pathophysiological and cognitive deficits associated with AD.
The role of the insula predicting memory performance in Alzheimer's disease amyloid positive and negative: a clinical cohort study
Authors: Coleman Michelle M , Haut Marc W , Teixeira Camila Vieira de Ligo , Keith Cierra M , Mehta Rashi , Phelps Holly , Ward Melanie , Miller Mark , Navia R. Osvaldo , Marano Gary D , Wang Xiaofei , Pockl Stephanie , Rajabalee Nafiisah , McCuddy William T , D’Haese Pierre‐Francois , Wilhelmson Kirk
Published: January 2025

Background

Known areas of Alzheimer’s pathology, including the hippocampus, entorhinal cortex and medial temporal cortex, have been well‐demonstrated as demonstrating atrophy in Alzheimer’s disease (AD). Using surface‐based morphometry measures, recent studies have suggested that the insula may play a role in memory function. Differences in patients based on amyloid biomarkers are increasingly being studied, particularly comparing individuals who were clinically diagnosed as AD but have negative amyloid biomarkers with those who are positive for amyloid. Atrophy may be similar in the entorhinal cortex between individuals who are amyloid positive versus amyloid negative, despite differences in memory. Here, we aimed to investigate the role of the insula in memory in a cohort of patients (aMCI and dementia) who were positive for amyloid with those who were negative for amyloid.

Method

We retrospectively analyzed clinical data from 161 aMCI and dementia patients (A+ = 106, A‐ = 55) and 41 healthy participants. Participants completed MRI and cognitive measures. Analysis of cortical thickness and gyrification index of the AD signature areas and the insula were completed using CAT12 and the DKT40 atlas. Memory performance was assessed using the California Verbal Learning Test short form, with long‐delay‐free recall as the variable of interest. Pearson’s correlations and stepwise linear regression were run using signature areas' significant correlations and interactions (adjusted p<0.001).

Result

Significant correlations with memory performance included insula gyrification and entorhinal and inferior parietal thickness (r=.25, r=.23, and r=.22, respectively). The interaction of insula gyrification with entorhinal thickness demonstrated significant results in predicting memory performance, accounting for 11% variance, even controlling for age. The interaction of reduced entorhinal cortex thickness and increased insula gyrification best explains delayed recall.

Conclusion

In our well‐characterized clinical cohort of aMCI and dementia with positive and negative amyloid biomarkers, insula gyrification interaction with entorhinal thickness best predicted memory performance measured by CVLT long delay. This finding suggests that, regardless of amyloid status, reduced entorhinal cortex thickness and increased insula atrophy (measured by gyrification, not thickness), impact delayed memory. Studies are necessary to understand the insula's function in memory as well as gyrification and thickness variations across brain regions and their role in cognition.
New high throughput fully automated plasma p‐Tau217 immunoassay
Authors: Szabo Miklos , Wynveen Paul , Knutson Chris , Salvati Mike , Hoffmann Katie , Curtis Kara , Dumke Ben , Patzlaff Jason , Nichkova‐Doseva Mikaela
Published: January 2025

Background

Hyperphosphorylated Tau is a pathologic hallmark of the neurofibrillary tangles in Alzheimer’s Disease (AD). p‐Tau217 is a promising blood‐based biomarker in AD research, drug development, diagnosis, disease monitoring, and patient care. Several assays for p‐Tau217 in plasma have been previously described, however there is a need to make this test easily available to the clinical laboratories around the world and more accessible to the patients and the clinicians. We describe the development of a precise and highly sensitive plasma phosphorylated Tau (Thr 217) high‐throughput immunoassay on the new Beckman Coulter DxI 9000TM Access Immunoassay Analyzer.

Method

The prototype p‐Tau217 assay is a two‐step sandwich assay using an alkaline phosphatase‐conjugated anti‐tau monoclonal antibody (MAb), with an anti‐p‐Tau217 MAb bound to paramagnetic particles. EDTA plasma sample, reaction buffer, and MAb‐coated particles are incubated and washed. This is followed by addition of the ALP‐conjugate with another incubation and wash step before a chemiluminescent substrate is added. The light generated is directly proportional to the p‐Tau217 concentration in the sample. Through the capabilities of the DxI 9000 analyzer, assay time to first results is ∼48 minutes with a throughput of 225 test/hour. For this study, 66 EDTA plasma samples, consisting of 40 AD and 26 age‐matched healthy controls, were evaluated. Analytical sensitivity (lower limit of quantitation) and discrimination between AD positive and healthy control populations were evaluated.

Result

The prototype p‐Tau217 assay has a targeted analytical measuring range of ∼10 fg/ml to approximately 2000 fg/mL. All (100%) healthy control samples were quantified, and a 20% within‐run lower limit of quantitation (LLOQ) was estimated at 10 fg/mL with a 10% LLOQ estimated at 30 fg/mL. The ratio of the mean concentration of p‐Tau217 in the AD samples (520.9 fg/mL) compared with the mean concentration of p‐Tau217 of the age‐matched healthy controls (129.3 fg/mL) was 4.0.

Conclusion

p‐Tau217 is a promising blood‐based biomarker in AD research, drug development, diagnosis, disease monitoring, and patient care. The prototype p‐Tau217 assay provides fast, highly sensitive, precise, and relatively cost‐effective results in an automated immunoassay on the high‐throughput Beckman Coulter DxI 9000TM Access Immunoassay Analyzer.
Xanthohumol loaded self‐nano emulsifying drug delivery system: Harnessing neuroprotective effects in Alzheimer’s Disease management
Authors: Bashir Bushra , Singh Sachin Kumar , Gulati Monica , Vishwas Sukriti , Dua Kamal
Published: January 2025

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the impairment of cognitive development and disruption of neurocognitive function. This neuropathological condition is marked by neurodegeneration, loss of neural tissue, and the formation of neurofibrillary tangles and Aβ plaques. Various studies reported the utilization of phytoconstituents like fisetin, quercetin, berberine, and xanthohumol for the treatment of AD. Among these phytoconstituents, XH is reported to have neuroprotective effects against AD by attenuating the levels of acetylcholinesterase (AChE) enzyme, accumulated amyloid β, oxidative stress, neuroinflammation, and mitochondrial dysfunction. In addition, XH also acts as senolytic, reducing the impact of cellular aging. Nevertheless, XH exhibits constrained solubility and encounters difficulty in traversing the blood‐brain barrier, thereby diminishing its efficacy in the target sites.

Method

To overcome these challenges, a self‐emulsifying drug delivery system (SNEDDS) for XH was devised, employing quality by design (QbD) based Box‐Behnken design (BBD). SNEDDS offers numerous advantages, encompassing increased drug loading, facile preparation, exceptional stability, as well as enhanced bioavailability and permeability across the blood‐brain barrier.

Result

The optimized XH‐loaded SNEDDS formulation exhibited droplet size, PDI, zeta potential, and drug loading as 40.23nm, 0.2, ‐15Mv, and 98% respectively. The formulation was found to be stable after six months in accelerated stability studies. The formulation underwent various pharmacodynamic studies. Pharmacodynamic studies assessed cognitive and motor functions in rats, revealing significant improvements in cognition with both low and high doses respectively. Additionally, the biochemical investigations revealed that the XH‐loaded SNEDDS effectively decreased the levels AChE enzyme, amyloid β, oxidative stress, and neuroinflammation.

Conclusion

The study demonstrates that the utilization of XH‐loaded SNEDDS for addressing the challenges associated with AD treatment. The optimized XH‐loaded SNEDDS formulation exhibited favorable characteristics and stability, overcoming XH solubility constraints. The results suggest that the SNEDDS approach enhances the bioavailability and permeability of XH, highlighting its potential as a neuroprotective and senolytic agent for AD treatment.
Exploring the Interplay between Carotenoids, Lipid Oxidation, and Cognitive Impairment in Aging
Authors: Dias Irundika HK , Abdullah Sewa , Pickert Lena , Thimm Alexander , Abeysena Dumindri , Deelen Joris , Griffiths Helen R , Polidori Maria Cristina
Published: January 2025

Background

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, memory loss, and impaired daily functioning. As the global population ages, the prevalence of AD continues to rise, emphasising the urgent need for effective preventive and therapeutic strategies. Carotenoids, a group of naturally occurring pigments with antioxidant properties, have gained attention for their potential neuroprotective effects. Carotenoids interrupt the oxidative process by scavenging free radicals and quenching singlet oxygen, ultimately reducing lipid oxidation and preserving the integrity of lipids in biological systems. This project investigated the relationship between blood carotenoid levels, lipid oxidation and their impact on cognitive impairment.

Method

Serum samples were collected from 49 healthy individuals (17 male, 32 female) who are 65 years or older. Serum carotenoids (Retinol, Lutein, Zeaxanthin, Lycopene, Alpha‐Tocopherol, β‐Carotene) were analysed by reversed phase HPLC method using methanol/acetonitrile/water gradient. Method validation was performed to establish linearity, sensitivity, recovery, and accuracy. Lipid oxidation products (oxysterols and oxidised phospholipids) were analysed using targeted mass spectrometry methods developed in our laboratory. Cognitive functions were measured using Montreal Cognitive Assessment, Trail Making Tests, letter fluency, category fluency and CogState.

Result

HPLC assay for carotenoids assay showed a linear dynamic range (R2 > 0.94) of 0.01 µM‐20 µM for the six carotenoids that were tested. High intra‐ and inter‐day precision (CV < 9%) and high concentration accuracy (< 15% absolute error) were observed for the QC plasma samples. Correlation analyses did not show any relationship between cognitive status with serum carotenoids or oxysterols; 7‐ketocholesterol, 7β hydroxycholesterol and 25‐hydroxycholesterol and 27‐hydroxycholesterol). 27‐hydroxycholesterol was increased in individuals >80 years old.

Conclusion

Our data suggests some lipid oxidation products such as 27‐ hydroxycholesterol may increase with age. However, further analysis is needed to conclude how lipophilic carotenoids may associate with lipid oxidation and cognitive impairment.
Detection of Lamin A in mesenteric neurons: Accurate diagnostic method in patients with sporadic Alzheimer's Disease
Authors: Alberdi Laura Gil , Guerrero Carmen , Rebolledo Ana Belen
Published: January 2025

Background

Lamin A is barely expressed in human brain neurons or in murine models such as mice and rats. However, in Alheimer´s disease (AD) brains, neurons in the hippocampus and entorhinal cortex abnormally express lamina A from the initial stages of the disease, being a biomarker together with phosphorylated Tau of the nuclear pathology of AD.

Constipation and mesenteric neuronal loss are related to aging and neurodegenerative diseases such as AD. It has been suggested that tau could be involved in enteric dysfunction, since it is expressed in enteric neurons and its presence has been reported in colon samples from AD patients. There is a bidirectional communication mechanism between the brain and the gastrointestinal system in which both organs influence the function of the other, suggesting that disease in either organ can affect the function of the other.

The SPAM mouse model (expresses human tau with aggregating mutations S320F and P301S) in addition to presenting the neuronal cytoskeletal pathology of tau that manifests in AD (Braak V‐VI), expresses mutant phosphorylated tau in the cytoplasm of neurons of the myenteric plexus causing enteric neuronal death and functional impairment. SPAM tau mice also exhibit accumulation of phosphorylated tau in enteric neurons leading to significant neuronal loss and an early lethal intestinal phenotype.

Method

Paraffin sections obtained from colon biopsies from AD patients diagnosed post‐mortem as well as from healthy controls were processed for immunohistochemistry. The presence of the Lamin A in the nucleus of mesenteric neurons was analysed.

Result

The analysis by Immunohistochemistry showed the low nuclear expression of the biomarker Lamin A in the mesenteric neurons of the healthy samples and the overexpression of the biomarker in the colon samples of those diagnosed with AD.

Conclusion

The results presented in this study show that Lamin A is clearly overexpressed in enteric neurons of patients with AD, unlike what happens in the enteric neurons of controls, which would indicate that neuronal nuclear pathology manifests in both systems, brain and colon, of patients with AD. This associated neurological implication suggests the possibility of using lamin A for therapeutic detection of AD.
Contrast‐agnostic deep‐learning‐based detection of perivascular spaces in magnetic resonance imaging
Authors: Díaz Mario , Fuchs Erelle , Mattern Hendrik , Behme Daniel , Duarte Roberto , Hernandez Maria del C. Valdes , Wardlaw Joanna M , Schreiber Stefanie , Trujillo Maria , Moyano Jose Bernal
Published: January 2025

Background

To date, all computerised perivascular spaces (PVS) quantification methods require case‐wise, imaging modality, or study‐specific parameter adjustments, and suffer from generalisability problems in clinical settings, and misdetection of other cerebral small vessel disease (CSVD) markers. We propose a deep learning‐based PVS detection method to overcome these issues. We compare our proposal on magnetic resonance imaging data of CSVD participants against the performance of the Frangi filter.

Method

T1‐weighted (T1w) and T2‐weighted (T2w) neuroimaging data from 16 patients with severe CSVD were collected at the Hospital of the Otto‐von‐Guericke University Magdeburg. PVS across the entire brain tissue were manually segmented in T2w images by a medical student.

We extended SynthSeg (https://surfer.nmr.mgh.harvard.edu/fswiki/SynthSeg) for PVS detection (Figure 1). PVS‐SynthSeg, our proposal, is based on a convolutional neural network and trained using synthetic data sampled from a generative model that relies on brain atlases as a conditioning factor, as well as domain randomisation. We incorporated tubular structures into such brain atlases to expand the model’s capabilities for the identification of PVS. This provides PVS‐SynthSeg with the ability to detect PVS in scans from diverse scanners and protocols without requiring additional fine‐tuning or parameter adjustments.

We compared the precision and recall of PVS‐SynthSeg against that from the Frangi filter on both imaging modalities.

Result

The Frangi filter detected the majority of PVS in both T1w and T2w scans, albeit with high false positive rates–recall of approximately 80% and precision below 30% (Figure 2). PVS‐SynthSeg had more variability in recall but near‐one precision across both modalities, despite the presence of white matter hyperintensities (WMH).

Conclusion

We propose a deep learning‐based PVS detection algorithm. In a small sample, PVS‐SynthSeg detected PVS in T1w and T2w scans better than the Frangi filter without additional adjustments, even in scans affected by motion artefacts or with WMH. These findings highlight the promise of PVS‐SynthSeg as a modular and effective PVS detection method, however larger cohort testing needs to be conducted. Better PVS quantification can help us shed light into the role of PVS in CSVD and Alzheimer’s disease.
Characterizing dementia risk in individuals with mild cognitive impairment using manifold learning, blood biomarkers, cognitive and imaging data
Authors: Casanova Ramon , Gaussoin Sarah A. , Lu Lingyi , Barnard Ryan , Duran Tugce , Bateman James R. , Lockhart Samuel N. , Deep Gagan , Hughes Timothy M. , Hayden Kathleen M. , Espeland Mark A. , Craft Suzanne
Published: January 2025

Background

Uniform manifold approximation and projection (UMAP) is a technique for dimension reduction and visualization of high‐dimensional (HD) data. Here, we apply UMAP to represent in two dimensions, data from members of the Wake Forest School of Medicine Alzheimer’s Disease Research Center (WFUSM‐ADRC) clinical cohort.

Methods

We examined baseline data from 542 WFUSM‐ADRC participants with mean age 70.1 years (range 54‐95 years), including 66% women and 18% Black self‐reported participants. A total of 195 participants were adjudicated with mild cognitive impairment(MCI), 67 with dementia and 280 were normal controls(NC) at baseline. Participants were further classified according to the stability of their cognitive status during 6.7 years of follow‐up with respect to baseline. We created a vector of 36 variables including cognitive tests, blood‐based biomarkers, MRI measures and age for each participant using baseline data. Based on UMAP, a 2D view of the data was created. Next, we fitted a nonlinear support vector machine with a Gaussian‐kernel and generated the boundary decision using data from participants classified at baseline as NC and dementia who kept the same status during their follow‐up. Data from individuals with MCI who remained stable, converted to dementia, or reverted to NC was provided to the classifier. The distance of each sample to the boundary was estimated. We evaluated this distance as a multimodal measure of AD dementia risk using a Wilcoxon test.

Results

The classifier discriminated NC from dementia cases with an area under the curve of 96.3. The blue area in Figure 1 surrounded by the classifier’s boundary decision, we refer to as the “high‐risk zone”. Overall individuals with MCI falling inside the risk zone at baseline had significantly worse values of cognitive parameters (Verbal Fluency, AVLT, Digit Span, MoCA, Trails A &B), blood (GFAP, ptau181, NFL) and imaging biomarkers (AD Pattern Similarity scores, hippocampal and a temporal‐metaROI volume),(p < 0.001) than those individuals with MCI outside the high‐risk zone. Positive distances indicate the samples to be inside the zone. Differences in distances between the three MCIs groups were significant (p < 0.001).

Conclusions

UMAP 2D projections have explanatory value to evaluate dementia risk in MCI.
Navigating Cultural Nuances: Understanding and Addressing Formal Care Utilization among Latino Family Caregivers of Older Adults with Dementia
Authors: Manzo Alma A , Britton Maggie , Segundo Joahana , Baker Zachary G
Published: January 2025

Background

In the United States, Latino older adults are 1.5x more likely to develop Alzheimer’s disease than non‐Latino White older adults. Latino Family Caregivers (LFC) maintain home care for longer periods of time but use formal care less. Latino cultural values such as familismo influence how LFC provide care, but many LFC report a lack of family assistance that might otherwise compensate for lower formal care usage.

Methods

Phenomenological methodology was employed to understand LFC of people with dementia (n = 14). Participants were both female (n = 6) and male (n = 8) and interviews were conducted in both English (n = 8) and Spanish (n = 6). These semi‐structured interviews were analyzed via content analysis using NVivo 14 software. A primarily inductive approach was used to code the interviews; however, concepts were influenced by the Ottawa Decision Support Framework.

Results

Two main categories were identified, (1) Reasons LFC might refrain from using formal care and (2) How/when LFC choose formal care. (1) Many LFC conceptualized formal care as untrustworthy (n = 10), unsafe (n = 8), expensive (n = 13), and found financial support elusive (n = 12). (2) However, LFC are likely to use at home formal care as disease severity progresses (n = 8). Discussing formal care decisions with family was common (n = 6), but consulting a doctor for advice was a majority preference (n = 11). LFC prized prior experience (n = 9) and “genuineness” in formal caregivers (n = 5). Lastly, although formal caregivers speaking Spanish was important (n = 8), embracing Latino culture was equally valuable (n = 8).

Conclusion

Health care professionals (especially doctors) should consider cultural nuances when suggesting formal care to LFC’s. There are preconceived notions that LFC’s do not consider formal care, however if the formal caregiver is trustworthy, professional, and embraces Latino culture, LFC’s are likely to use formal care when the time is right. Future interventions should assist LFC’s in identifying professional and culturally competent formal caregivers and locating financial resources.
Association of sphingomyelin with Alzheimer’s pathology and cognition in non‐demented adults
Authors: Guo Fan , Sheng Ze‐Hu , Ma Lingzhi , Ou Ya‐nan , Zhao Qing‐Fei , Shan Tan Meng , Tan Lan
Published: January 2025

Background

Plasma sphingolipids were discovered to identify memory impairment and Alzheimer’s disease (AD) risk. It has been reported to play a role in the pathological processes of neurodegeneration and neuroinflammation; however, its exact mechanism in AD has not yet been completely found.

Method

A total of 476 non‐demented participants from Alzheimer’s Disease Neuroimaging Initiative were included. Multivariate cox regression was used to detect AD risk. Multiple linear regression and mixed effects modles were used to examine the sphingomyelins relationship with cerebrospinal fluid (CSF) AD biomarkers, white matter hyperintensities and cognitive. Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of AD pathology on cognitive.

Result

Multivariable Cox models showed that higher plasma sphingomyelin levels had lower risk of AD (HR = 0.9992; 95% CI, 0.9991 ‐ 0.9994; p < 0.004). Plasma sphingomyelin was positive correlated with RAVLT‐immediate scores, CSF Aβ42 levels, FDG‐PET, whole brain‐V, hippocampal‐V, fusiform‐V and EC‐THK. Meanwhile higher sphingomyelin is associated with lower CSF P‐tau and T‐tau levels, WMH and ventricular‐V. Higher plasma sphingomyelin can predict slower decrease of RAVLT‐immediate scores, FDG‐PET, whole brain‐V, fusiform‐V, MTL‐V, EC‐THK and increase of ventricular‐V. We found the association between sphingomyelin and verbal memory was partially mediated by levels of baseline CSF Aβ42, P‐tau and T‐tau; by FDG‐PET; and by hippocampal‐V. We found sphingomyelin interacted with cognitive diagnosis and APOEε4 status. The above results can be repeated and more pronounced in MCI, APOEε4 (+) groups.

Conclusion

This study demonstrates higher plasma sphingomyelin was associated with lower AD risk and better verbal memory. Additionally, AD core pathology, along with brain metabolization and hippocampal atrophy, may mediate the association between plasma sphingomyelin and cognition. How sphingomyelin integrated within memory and AD pathways, suggests a novel possibility for identifying markers for early detection and potential avenues for effective therapeutic intervention in AD.
Associations of Circulating Platelet Endothelial Cell Adhesion Molecule‐1 Levels with Progression of Cerebral Small Vessel Disease, Cognitive Performance and Incident Dementia
Authors: Sim Ming Ann , Tan Eugene , Chan Siew‐Pang , Chai Yuek Ling , Chong Joyce R , Venketasubramanian Narayanaswamy , Tan Boon Yeow , Lai Mitchell Kim Peng , Hilal Saima , Chen Christopher
Published: January 2025

Background

The association between platelet endothelial cell adhesion molecule‐1 (PECAM‐1) with cerebral small vessel disease (CSVD) and cognition in non‐demented subjects remains un‐investigated.

Method

A longitudinal, prospective cohort of subjects recruited from memory clinics was followed‐up for 5 years. Non‐demented subjects were included and classified as no cognitive impairment (NCI) or mild cognitive impairment (MCI). Annual neuropsychological assessments and 2‐yearly magnetic resonance imaging (MRI) scans were performed. The associations of baseline circulating plasma PECAM‐1 levels with neuroimaging markers of CSVD, cognitive decline (Montreal Cognitive Assessment [MoCA] scores and executive function Z‐scores), and conversion to dementia were evaluated.

Result

Of 213 subjects (age 70.2±7.7 years, 51.2% male, 122 (57.3%) NCI, and 91 (42.7%) MCI), median PECAM‐1 levels were 0.790 [IQR 0.645‐0.955] ng/ml). Compared with the highest tertile, subjects within the lowest PECAM‐1 tertile had higher age‐related white matter changes scores (first tertile: β 1.50, 95% C.I. 0.23‐2.77, p=0.02) and cerebral microbleeds (first tertile: Adjusted risk ratio [ARR] 2.59, 95% C.I. 1.81‐3.72, p<0.0001). PECAM‐1 levels were not associated with baseline MOCA and executive function.

Of the 204 participants with follow‐up data (median 60.0 [IQR 60.0‐60.0] months), 24 (11.8) had incident dementia. Compared with the highest tertile, subjects within the lower tertiles of PECAM‐1 were independently associated with higher risk of incident dementia (first tertile: Adjusted Hazard Ratio [AHR] 4.18, 95% C.I. 1.26‐13.93, p=0.020; second tertile: AHR 3.45, 95% C.I. 1.07‐11.14, p=0.038, Figure 1). The lowest PECAM‐1 tertile was associated with greater 4‐year progression of cerebral microbleeds (Incident Relative Risk [IRR] 2.44, 95% C.I. 1.20‐4.98, p=0.014), and decline in executive function (β ‐0.43, 95% C.I. ‐0.73, ‐0.14, p=0.004), and MoCA (β ‐1.32, 95% C.I. ‐2.30, ‐0.35, p=0.008) scores.

Conclusion

In non‐demented subjects, lower circulating PECAM‐1 levels are associated with greater CSVD progression, cognitive decline, and incident dementia. PECAM‐1 may be a potential therapeutic target for CSVD and cognitive decline.