bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subjects treated with expanded non‐genetically modified autologous Natural Killer cells (SNK01) show improved changes in CSF α‐synuclein and in cognitive function
Authors: Gil Clemente Humberto Zúñiga , Gallo Blanca Isaura Acosta , Díaz Rufino Menchaca , Amescua Cesar Alejandro , Hong Sean , Hui Lucia , Lee Hank , Chang Paul , Betito Katia , Song Paul Y 
Published: January 2025

AbstractBackgroundAccumulating evidence suggests that the presynaptic protein α‐synuclein (α‐syn), is involved in the pathophysiology of AD and elevated in the cerebrospinal fluid (CSF). The role of Natural Killer (NK) cells of the innate immune system in AD has largely been overlooked. In a murine model, depletion of NK cells augmented the accumulation of pathological α‐syn. Human NK cells have been shown to efficiently internalize and degrade α‐syn aggregates via the endosomal/lysosomal pathway. This has been proposed as a protective mechanism of NK cells against α‐synucleinopathy by removing harmful α‐syn aggregates from the patient’s brain. Our in vitro studies have shown that SNK01, an enhanced autologous non‐genetically modified NK cell product, is able to effectively internalize and degrade α‐syn aggregates.MethodIn this Phase 1 study, SNK01 was administered IV every three weeks for a total of 4 treatments using a 3+3 dose escalation design (1, 2 and 4×109 cells) in subjects with either mild, moderate, or severe AD (Median MMSE of 14). Cognitive assessments and CSF α‐syn analyses were performed at baseline and at 1 and 12 weeks after the final dose. The primary endpoint was safety and secondary endpoints included changes in cognitive assessments and biomarker levels.ResultEleven subjects (5 males and 6 females) were enrolled and 10 were evaluable. Median age was 79 years (56 to 85 years). No treatment related adverse events were observed. Despite 70% of subjects being treated at relatively low doses of SNK01, 90% of all evaluable subjects had either stable or improved (±0.1) composite ADCOMS scores at week 11 (one‐week after the final dose), and 60% of subjects (6/10) had a decrease in CSF α‐syn compared to baseline values. In the 5/6 subjects where data was available, these levels continued through week 22 for α‐syn. One additional subject had a decrease in CSF α‐syn compared to baseline values at week 22. At week 11, the decreases in α‐syn corresponded to stable/decrease in ADCOMS in 5/6 subjects.ConclusionSNK01 was safe and well tolerated. SNK01 appears to have clinical activity in AD while also reducing α‐syn protein levels in the CSF.
Incidence and Prevalence of Early Onset Dementia in Finland
Authors: Solje Eino , Aaltonen Mikko , Aho Kalle , Heikkinen Sami , Kivisild Ave , Lehtonen Adolfina , Leppänen Laura , Rinnankoski Iina , Soppela Helmi , Tervonen Laura , Haapasalo Annakaisa , Remes Anne , Hartikainen Päivi , Katisko Kasper , Krüger Johanna 
Published: January 2025

AbstractBackgroundEarly onset dementia (EOD) forms distinct economic, societal, and human burdens on patients, their families, the healthcare system, and society, differing from those associated with late onset dementia. However, epidemiological data on EOD, characterized by onset before the age of 65, is notably scarce.MethodOur objective was to assess the incidence of all‐cause progressive Early Onset Dementia (EOD) and its subtypes from January 2010 to December 31, 2021 in two specified regions in Finland (Northern Ostrobothnia and Northern Savonia). All visits at the dementia outpatient clinics were manually reviewed during that period. In addition, prevalence of EOD and its subtypes were calculated on December 31, 2021 with 335,376 inhabitants in Northern Ostrobothnia and 186,592 in Northern Savonia.ResultIn the population aged 30‐64 years, crude incidence was 20.5/100 000 persons at risk/year based on 711 new cases from January 2010 to December 31, 2021. The prevalence of EOD was 128.9/100 000 in the age group of 30‐64 years. Amnestic Alzheimer’s disease (48.1%) and behavioural variant frontotemporal dementia (13.1%) were the most frequent subtypes.ConclusionEOD represents a significant group of neurological disorders leading to early loss of work capacity, dependence of external assistance, and eventually to premature death. The outcomes of this study aim to assist authorities and healthcare professionals in organizing effective diagnostics and improved care tailored to the specific needs of EOD patients.
Cardiopulmonary coupling measures of sleep stability and risk of cognitive impairment in community‐based older men
Authors: Milton Sasha , Sun Haoqi , Stone Katie L , Yaffe Kristine , Westover Brandon , Thomas Robert J , Leng Yue 
Published: January 2025

AbstractBackgroundPoor sleep health is associated with cognitive impairment (CI) in older adults. The cardiopulmonary coupling (CPC) sleep spectrogram, which estimates the sleep state modulated synchronization between heart rate variability and respiration, is an increasingly recognized measure of sleep stability. However, little is known about the longitudinal association between CPC measures of sleep stability and risk of incident CI.MethodOur sample comprised 2628 men (mean [SD] age = 76.0 [5.3] years, all aged ≥65 years) without CI who had their sleep assessed using polysomnography at baseline (2003‐05) and were followed until 2016 for incident CI as part of the Osteoporotic Fractures in Men (MrOS) study. Electrocardiogram (ECG)‐derived CPC metrics included the percentage of sleep time spent with high frequency coupling (HFC%, 0.1‐0.4Hz, stable sleep), low frequency coupling (LFC%, 0.01‐0.1Hz, unstable sleep), and very low frequency coupling (VLFC%, <0.01Hz, an estimation of rapid eye movement sleep and wakefulness). Incident CI (encoded as a binary variable) was defined as self‐reported dementia diagnosis, dementia medication use, Modified Mini‐Mental State Examination (3MS) score <80, or a decline in 3MS score from baseline to any visit of ≥1.5 standard deviations below the mean. Multivariable logistic regression was used to assess the associations between tertiles of CPC metrics and incident CI.ResultA total of 419 men developed CI during a mean follow‐up of 10.8 years. After adjustment for covariates including demographics, lifestyle, comorbidities, medication use, and cognition at baseline, men in the middle tertile of HFC% were less likely to develop CI than men in the lowest tertile [OR (95% CI) = 0.73 (0.56,0.96)], while those in the highest tertile of HFC% had similar odds of incident CI [OR (95% CI) = 1.12 (0.87,1.45)] compared with the lowest tertile. Further adjustment for apnea‐hypopnea index (AHI) and use of continuous positive airway pressure (CPAP) did not appreciably alter these results. Neither LFC% nor VLFC% was associated with incident CI.ConclusionOlder men with intermediate levels of stable sleep had the lowest risk of developing CI over 11 years. Further research is needed to understand the mechanisms linking CPC measures of sleep stability to cognitive aging.
Gendered association between life‐course social mobility and cognitive function among middle‐aged and older adults in India
Authors: Ko Soohyeon , Kim Rockli 
Published: January 2025

AbstractBackgroundIn rapidly developing countries like India, individuals undergo fluctuations in social status throughout their lives. However, there have been few investigations of the link between life course socioeconomic status and cognitive function in late middle age, particularly regarding whether upward and downward mobility exert symmetric effects. Furthermore, limited attention has been directed toward understanding gender heterogeneity within this association.MethodThis study utilized data from the Longitudinal Aging Study in India 2017‐2018, including 61,257 individuals aged 45 years or above. Based on financial status of family during childhood and monthly per capita expenditure in later life, life course social mobility was classified as “consistently high,” “upward mobility,” downward mobility,” and “consistently low.” Cognitive function was evaluated using the composite cognitive index across five domains (memory, orientation, arithmetic function, executive function, and object naming). Multivariable regression and interaction analysis were employed for estimating associations, with a focus on gender differences.ResultParticipants, with a mean age of 60.13 years, consisted of 45.93% men and 54.07% women. Overall, compared to those who maintained consistently high status, individuals remaining consistently low were associated with the lowest cognitive function (b = ‐1.48, 95% CI = ‐1.60, ‐1.35), followed by those undergoing downward mobility (b = ‐0.86, 95% CI = ‐0.98, ‐0.74) and upward mobility (b = ‐0.76, 95% CI = ‐0.87, ‐0.64). Significantly, the difference between upward and downward mobility varied by gender (p = 0.016). Among men, upward and downward mobility had asymmetric associations, with upward mobility being associated with a higher cognitive function than downward mobility (b = 0.30, 95% CI = 0.11, 0.49), whereas no significant difference was found for women (b = ‐0.03, 95% CI = ‐0.21, 0.16).ConclusionThis study revealed notable disparities in cognitive function based on life course socioeconomic status. Furthermore, the association of upward and downward mobility on cognitive function exhibited gender‐specific differences. While for men, childhood disadvantage in cognitive function could be offset by upward mobility in adulthood, women experiencing low status at either temporal point in childhood or adulthood displayed lower cognitive function. These findings underscore the importance of tailored interventions, considering life trajectories of social status and gender, to address cognitive health disparities in rapidly evolving economies like India.
The role of imaging in outcomes and safety monitoring for preclinical intervention studies
Authors: Rafii Michael , Vemuri Prashanthi 
Published: January 2025

AbstractRecent breakthrough findings in clinical trials on amyloid‐lowering therapies have led to the approval of these drugs for the treatment of amyloid‐ positive elderly individuals who show symptoms of mild cognitive impairment and mild dementia. The next frontier is the testing the efficacy of treatments for secondary prevention of AD dementia. Phase III trials in asymptomatic AD are already under way, raising a host of novel questions on the sequelae of trial participation such as the emotional and social repercussions of biomarker disclosure, understanding the risk of side effects and eventually weighing the risk‐benefit ratio of amyloid‐lowering treatment. In this session jointly organized by the Neuroimaging and Partnering with Research Participants PIAs, I will focus on the participants’ perspective on the role of imaging in outcomes and safety monitoring of preclinical interventional studies. I will outline the importance of a partnership between the study team and participants in the design and conduct of study procedures to ensure that they are both efficient and ethical.
Supporting Participants in Preclinical Alzheimer’s Trials: Experience from a Research Participant Advisory Board and the A4 Study
Authors: Walter Sarah , Morales Guadalupe , Shaffer‐Bacareza Elizabeth , Karlawish Jason , Grill Joshua D , Donohue Michael C. , Cohen Paula , Aisen Paul S. S , Sperling Reisa A ,   The A4 Study Team
Published: January 2025

AbstractPreclinical Alzheimer’s disease (AD) trials can involve multiple years of follow‐up and burdensome procedures for older individuals. Optimizing the design and conduct of these trials requires input from participants and their families. Since 2020, the Alzheimer’s Clinical Trials Consortium (ACTC) Research Participant Advisory Board has provided input on study attributes including: participant and study partner compensation, consent language, and result communication tools. A key recommendation from the advisory board is to design studies with the option to learn individual research results. Participants find results personally meaningful, even when the clinical relevance of results has not been established. After release of topline study results, A4 research sites were provided reports that included treatment arm assignment and individual research results (cognitive scores, amyloid PET tertile, and Clinical Dementia Rating scale results). Research sites were provided guidance on communicating research results in a training webinar. A survey was subsequently sent to all A4 sites to understand what methods were used to communicate results and support participants. The 42 sites that completed the survey reported sharing results with 445 participants, or 65% of participants active at the end of the study. Participants expressed interest in taking part in other studies and, where eligible, were referred. Those with worsening cognition and function were referred for clinical evaluation and care. Some A4 participants told sites that they expected “something tangible” and “more than a one‐hour meeting” after the many years of participation. The A4 sites that hosted ‘thank you’ events to discuss study‐level results, with separate one‐on‐one sessions to discuss individual results shared these were appreciated by participants. The active involvement of the diverse ACTC Participant Advisory Board has benefited the design of preclinical AD studies. The A4 experience demonstrates that it is feasible to share individual research results, and that a majority of participants will opt to learn. Greater involvement of the Advisory Board at the earliest stages of study design and planning will maximize impact of their feedback, and help researchers move toward the goal of optimized, inclusive trials.
Pharmacological Evaluation of Withanolide A for Anti‐Alzheimer’s Effects: Inhibition of Mitochondrial Permeability Transition Pore (mPTP)
Authors: Sharma Lalit , Gupta Yogesh 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline, neuroinflammation, and mitochondrial dysfunction. In Alzheimer’s, abnormal Mitochondrial Permeability Transition Pore (mPTP) activity may contribute to mitochondrial dysfunction and neuronal damage. Withanolide A, a naturally occurring compound derived from Withania somnifera, have shown potential neuroprotective effects in various neurological disorders. This study aimed to investigate the anti‐Alzheimer’s effects of Withanolide A and explore their mechanism of action through the inhibition of mPTP.MethodIn our study, we employed both in vitro and in vivo AD models to assess the impact of Withanolide A on cognitive function, amyloid‐beta (Aβ) pathology, and mitochondrial function. The in‐vivo study was carried out on Swiss albino mice. The intracerebroventricular injection of the Aß (1‐42) peptide into the ventricular system of the mouse brain was employed for the induction of the AD. Cognitive function was evaluated through a battery of behavioural tests like Morris water maze, Y maze, and open field test while amyloid‐beta (Aβ) pathology was quantified using immunohistochemical analyses. Mitochondrial function was meticulously characterized through measurements of membrane potential, reactive oxygen species (ROS) production, and adenosine triphosphate (ATP) levels.ResultOur results demonstrated that Withanolide A significantly improved cognitive performance in AD behavioural mouse models, accompanied by a reduction in Aβ deposition. Importantly, Withanolide A exhibited a potent inhibitory effect on mPTP opening, thereby preserving mitochondrial membrane potential and attenuating ROS production. Further, ATP levels were sustained, indicative of improved mitochondrial bioenergetics. Subsequent exploration of molecular mechanisms elucidated the downregulation of pro‐inflammatory cytokines and upregulation of neurotrophic factors following Withanolide A treatment. These findings suggest a direct link between the anti‐Alzheimer’s effects of Withanolide A and their modulation of mitochondrial function through mPTP inhibition. These results highlight the multifaceted neuroprotective mechanisms employed by Withanolide A in mitigating AD pathology.ConclusionOur study provides compelling evidence for the potential of Withanolide A as a therapeutic intervention for AD. The observed inhibition of mPTP, coupled with improvements in cognitive function and mitigation of Aβ pathology, positions Withanolide A as a promising candidates for further research in the pursuit of effective treatments for AD.
Gait speed as a surrogate marker of change in cognitive function derived from multimodal lifestyle intervention: J‐MINT study
Authors: Fujita Kosuke , Sugimoto Taiki , Matsumoto Nanae , Uchida Kazuaki , Kuroda Yujiro , Arai Hidenori , Sakurai Takashi ,   J‐MINT study group
Published: January 2025

AbstractBackgroundThe effectiveness of multimodal lifestyle interventions to prevent dementia is being validated. Since a relatively long period (∼2 years) is required for manifesting an impact on cognitive function, the exploration of an alternative marker that exhibits changes within a comparatively brief duration, thereby prognosticating future alterations in cognitive function, is needed. The decline in gait function is associated with cognitive impairment and is also a predictor of future cognitive decline. This study examined whether gait speed can be used as a surrogate marker for change in cognitive function derived from multimodal lifestyle interventions.MethodData from a multi‐center, open‐label, randomized controlled trial in Japan (J‐MINT study) are utilized. Community‐dwelling older adults with mild cognitive impairment, aged 65 to 85 years, were enrolled in the J‐MINT study. The intervention group received 18 months of a multimodal lifestyle intervention (exercise, nutrition, cognitive stimulation, and vascular risk management), while the control group received only health information. Cognitive function was measured with a global composite score using eight neuropsychological tests. All variables were measured at baseline, 6, 12, and 18 months. Multiple regression analysis was performed for each of the allocation groups to investigate the association between the change in 18‐month cognitive function and the change in gait speed at 6 or 12 months from baseline.ResultAmong 378 participants analyzed (baseline age, 74.2±4.8 years; 50% of male; gait speed of 1.25±0.24 m/s), 194 were the intervention group. Significant gait speed improvement was observed in the intervention group at 12 months when comparing the control groups (least square mean = 0.033). Multiple regression analysis revealed a significant association between changes in gait speed and cognitive function only in the intervention group (gait speed change in baseline to 6M, β = 0.452, p = 0.016; baseline to 12M, β = 0.387, p = 0.042).ConclusionShort‐term changes in gait speed following multimodal interventions may serve as valuable surrogate markers, predicting of subsequent long‐term (approximately 18 months later) alterations in cognitive function. This suggests the potential of gait speed as an early indicator of intervention efficacy in preventing cognitive decline.
Proteomic markers of Alzheimer's disease and related dementia risk in individuals with a history of depression
Authors: Diniz Breno S , Chen Zhiduo , Kuchel George A , Fortinski Richard , Kuo Chia‐Ling 
Published: January 2025

AbstractBackgroundHistory of depression is one of the most significant, and potentially modifiable risk factors for Alzheimer’s disease and related dementia (ADRD). However, there is limited evidence on the underlying biological mechanisms that link the history of depression to the higher risk of ADRD. This study aimed to evaluate the proteomic markers associated with the higher risk of ADRD.MethodWe used the UK Biobank (UKB study) to address the study aim. Our sample consisted of 42,807 individuals (3,615 with a history of depression in the baseline assessment) who had plasma proteomic data available. We evaluate the proteomic predictors of the risk of ADRD among individuals with a history of depression using Cox Proportional regression and random forest analysis. The total follow‐up time was 13 years from the baseline analysis. We used the Benjamin‐Hochberg method to control for a false discovery rate.ResultA small panel of 6 proteins was significantly associated with an increased risk of progressing to ADRD upon follow‐up after controlling for age, educational level, medical comorbidity, and APOE genotype (GFAP, NFL, PSG1, GET3, HPGDS, and VGF; FDR adjusted p‐value <0.05). The predictive power of this proteomic panel was moderate, with C‐statistics = 0.79. Random forest machine learning analysis yielded similar results as the Cox regression analysis.ConclusionThis study indicates that the risk of ADRD among individuals with a history of depression is partially mediated by abnormal astroglial activation, axonal dysfunction, and neurodegeneration. Other biological mediators of risk also involve abnormalities in synaptic plastic, cell growth, peroxisomal lipid metabolism, and oxidative stress control. Our results point to novel putative mechanisms to develop interventions to mitigate the risk of ADRD among individuals with a history of depression.
Time spent in an impaired glucose state across the midlife and early late adulthood cognitive function: Study of Women’s Health Across the Nation
Authors: Leis Aleda M. , Karvonen‐Gutierrez Carrie A. , Thurston Rebecca C , Khoudary Samar R. El , Derby Carol A. 
Published: January 2025

AbstractBackgroundOver 30 million Americans have diabetes, with 9 million likely undiagnosed. Diabetes is associated with cognitive decline and risk for Alzheimer’s disease and related dementia (ADRD). The lifetime impact of diabetes and prediabetes on cognition may be cumulative. We examined whether time spent in an impaired glucose state during midlife was associated with worse cognitive function in early older adulthood.MethodThe Study of Women’s Health Across the Nation (SWAN) is a longitudinal multi‐center cohort of women followed from 42‐52 years. This cross‐sectional analysis includes 1336 women with cognitive testing at Visit 15, baseline fasting blood glucose measures, cognitive testing at Visit 7, and no history of myocardial infarction or stroke. Percentage of visits with an impaired glucose state (IGS; fasting glucose >100µg/mL), or diabetic state (DS; fasting glucose >126µg/mL), were considered, categorized as <25%, 25%‐<50%, 50%‐<75%, and ≥75%. Visit 15 outcomes included working memory (Digit Span Backwards (DSB) test), immediate and delayed memory recall (East Boston Memory Test (EBMT‐I and EBMT‐D)) and processing speed (Symbol Digit Modalities (SDMT) test). Separate linear regression models were constructed examining cumulative time in IGS or DS with each outcome at Visit 15, adjusting for Visit 15 covariates: race/ethnicity, education, BMI, age, physical activity, history of antidiabetic medication, number of visits with glucose, prior cognitive function score at Visit 7, and hormone therapy. SDMT models were adjusted for self‐reported overall quality of vision.ResultWomen were mean age 65 years (SD:2.7) (Table 1) and 50% were non‐Hispanic White. The majority spent <25% of their visits in IGS or DS, and few spent ≥75% time in IGS or DS (6.7% and 0.9%, respectively). IGS was not associated with cognitive outcomes (Table 2). However, those with ≥75% time in DS had a 4.5 unit (95%CI:‐8.8,‐0.2;p = 0.040) lower SDMT score compared to those with <25% time in DS.ConclusionWhile mild glucose impairment over midlife was not related to cognitive function in early older adulthood, prolonged diabetic‐level glucose was associated with worse processing speed in early older adulthood, suggesting the importance of diabetes screening and optimizing glucose control during midlife to preserve cognitive function at older ages.