bluuebunny/crossref_metadata_2025_split huggingface dataset:
Class 1 HDACs Modulate Synapse‐Related Genes in Mouse Models of Aging and Alzheimer’s Disease
Authors: McClarty Bryan , Rodriguez Guadalupe , Dong Hongxin 
Published: December 2023

AbstractBackgroundStudies have demonstrated that epigenetics plays an important role in both aging and Alzheimer’s disease (AD) pathogenesis, however, whether epigenetic dysregulation during aging can initiate AD development and/or exacerbate AD progression remains unclear. Given aging is the major risk factor of AD, it is critical to determine the epigenetic alterations occurring during aging and how these changes influence AD pathogenesis.MethodsIn this study, 3, 12, and 18‐month‐old APP/PS1 mice and WT littermates were used for a series of behavioral tests to evaluate and compare different memory domains, including recognition, short‐term working, and long‐term spatial reference memory in aging and AD progression. After behavioral testing, the hippocampus and prefrontal cortex (PFC) were collected for biochemical assessment to determine the dynamic changes of class 1 HDACs globally and at gene promoters that are associated with synaptic structure and function, namely Nr2a, GluR1 Glur2, and Psd95. Additionally, synaptic gene expression and H3K9ac levels at the gene promoters were evaluated during aging and AD progression.ResultsOur results showed that recognition and short‐term working memory declined in WT mice only at 18 months of age, but significantly declined in the three memory domains of APP/PS1 mice at both 12 and 18 months of age. Moreover, 18 months of age APP/PS1 mice showed exacerbated recognition and spatial working memory deficits. We also found HDACs modulate the synaptic‐related genes in a genotype and regional manner. More specifically, HDAC 2 modulated synaptic gene expression through dysregulations of H3K9ac levels at the gene promoters in the hippocampus during aging and AD progression. While HDAC 3 modulated synaptic gene expression through dysregulations of H3K9ac levels at gene promoters in the prefrontal cortex during AD progression. The dynamic changes of HDACs and H3K9ac levels during aging and AD progression are associated with specific declines in memory.ConclusionOur findings suggest a potential differential HDAC modulation of synaptic gene expression in aging and AD progression, which impacts the decline of different memory domains. Future work will confirm our findings and will begin using genetic manipulation approaches to dissect individual class 1 HDAC contributions to aging and/or AD progression in the hippocampus and PFC.
Effectiveness of the Interdisciplinary Home‐bAsed Reablement Program (I‐HARP) on improving functional independence of people living with dementia and process outcomes
Authors: Jeon Yun‐Hee , Simpson Judy , Norman Richard , Fethney Judith , Krein Luisa , Shim Mirim , Low Lee‐Fay , Woods Bob , Mowszowski Loren , Hilmer Sarah , Clemson Lindy , Naismith Sharon L , Brodaty Henry , Naganathan Vasi , Amberber Amanda Miller , Gitlin Laura N. , Szanton Sarah L 
Published: December 2023

AbstractBackgroundThis project evaluated a model of care integrating evidence‐based dementia rehabilitation strategies into a time‐limited, home‐based, interdisciplinary rehabilitation package: Interdisciplinary Home‐bAsed Reablement Program (I‐HARP). The aims were: to determine I‐HARP effectiveness on functional independence, mobility, quality of life and depression among people with dementia, their home environmental safety, carer burden and quality of life, and I‐HARP cost‐effectiveness; and to evaluate processes, outcomes and influencing factors of the I‐HARP implementation.MethodThe project was mixed‐methods action research combining a multi‐centre pragmatic RCT and realist evaluation. I‐HARP was a 4‐month model of care for community‐dwelling people with mild‐moderate dementia and family carers, incorporated into community aged care services and hospital‐based geriatric services in Sydney, Australia (2018‐22) and compared with usual care. Outcome assessments were conducted at baseline, 4‐ and 12‐month. Semi‐structured interviews with participants and focus groups with I‐HARP interventionists and participating site managers occurred post intervention. (ACTRN12618000600246)ResultOf 130 dyads of clients and their carers recruited, 116 dyads (58 per group) completed the trial (89% retention). The I‐HARP group had somewhat better mean results for most outcome measures than usual care at both 4 and 12 months, but the only statistically significant difference was a reduction in home environment hazards at 4 months. Post‐hoc sub‐group analysis of 66 clients with mild‐dementia found significantly better functional independence in the intervention group: 11.2 on Disability Assessment for Dementia (95% CI: 3.4,19.1; p = .005; ES 0.69) at 4 months and 13.7 (95% CI: 3.7,23.7; p = .007; ES 0.69) at 12 months. Preliminary results of economic evaluation pointed to potential benefits of I‐HARP over usual care. Interviews and focus group findings highlighted system and research design barriers (e.g., workforce, hospital system, communication, blinding and recruitment) and program facilitators (focus on enablement, interdisciplinary and teamwork).ConclusionThe I‐HARP model enhanced functional independence of participants with mild‐dementia but not in those with moderate‐dementia, so did not result in better outcomes in the group overall. A different type of rehabilitation model or strategies may be required as dementia becomes more severe. Key facilitators and barriers to I‐HARP implementation provide further insights to developing dementia rehabilitation model of care.
Maintain Your Brain: outcomes of an online program to prevent cognitive decline with aging.
Authors: Brodaty Henry , Valenzuela Michael , Singh Maria A. Fiatarone , Sachdev Perminder S. , McNeil John , Lautenschlager Nicola T , Maeder Anthony , Jorm Louisa , Millard Michael , Heffernan Megan , Anstey Kaarin J. , Ginige Jeewani Anupama , Chau Tiffany , Jose Juan Carlo San , Welberry Heidi , Briggs Nancy , Popovic Gordana 
Published: December 2023

AbstractBackgroundEfforts to prevent cognitive decline with aging have had mixed results with successful interventions delivered in person. While online approaches are more scalable and feasible to deliver at a population level, no multimodal online intervention has yet been demonstrated efficacy. We aimed to reduce cognitive decline with ageing using an online package of interventions delivered intensively for 12 months followed by monthly boosters for 24 months.MethodInvitations were sent to people aged 55‐77 years from the 45 and Up study, a population‐based cohort study of one in ten people aged 45 years and older in New South Wales, Australia (n = 267,000). Participants were required to be eligible for at least two of four modules addressing physical inactivity and associated health risks (Physical Activity), adherence to a Mediterranean‐type diet and health risks associated with poor nutrition (Nutrition), cognitive activity (Brain Training) and mental well‐being (Peace of Mind). Participants received modules based on their risks, with 1:1 randomized allocation to active personalised coaching modules (intervention) or static information‐based modules (control). The primary outcome was change in an online combined multi‐domain cognitive score measured using COGSTATE and Cambridge Brain Sciences tests. Secondary outcomes included specific cognitive domain and ANU‐ADRI risk scores.ResultOf 96,418 invitations issued, 14,064 (14%) consented, 11,026 (11%) were eligible and 6,104 (6%) completed all baseline assessments. Over three years, using intention to treat analysis, the intervention group improved significantly more in the global composite cognition (p<0.001). Significant benefits were also found in complex attention, executive function and learning and memory (all p<0.001), as well as on a validated dementia risk instrument (p = 0.007). Results were similar when adjusted for baseline age, gender, dementia risk and number of modules eligible and when analysis was based on those completing follow‐up.ConclusionAn online platform tailored to individuals’ risk factor profiles over three years significantly delayed cognitive decline in older adults. This platform is scalable; if delivered at a population level with may help reduce the prevalence of dementia globally.
Associations of anemia and cardiovascular disease with longitudinal changes in brain MRI markers and cognitive decline in older adults: A cohort study
Authors: Imahori Yume , Li Yuanjing , Laukka Erika J , Kalpouzos Gregoria , Vetrano Davide Liborio , Qiu Chengxuan 
Published: December 2023

AbstractBackgroundAnemia and cardiovascular disease (CVD) are two prevalent chronic conditions causing cerebral hypoxia in older adults. Although anemia and CVD often coexist in older people and potentially share underlying mechanisms, the independent effects of these two diseases with cognitive decline are largely unknown. The objective of this cohort study is to investigate the independent associations of anemia and CVD with cognitive decline in older adults, and further explore their associations with changes in MRI markers of brain aging using longitudinal MRI data.MethodThis cohort study used data from 2244 dementia‐ and stroke‐free participants in the population‐based Swedish National study on Aging and Care in Kungsholmen (age ≥60 years, female 62%). Participants were regularly followed from 2001‐2004 (baseline) through 2013‐2016. Anemia (WHO criteria) and CVD were determined at baseline. Cognitive function was assessed using a neuropsychological test battery across 12 years. A subset of participants (N = 503) underwent brain MRI examinations at baseline, and 327undertook follow‐up MRI scans after 3 and/or 6 years. Brain volumetric measures and markers of cerebral small vessel disease (cSVD) were assessed following standard methods. The associations of anemia or/and CVD with cognitive decline and changes in brain volume and cSVD markers were investigated using linear mixed‐effects models, while controlling for age, sex, lifestyle, vascular risk factors, chronic kidney disease, cancer, serum c‐reactive protein, and APOE genotype.ResultOf the 2244 participants, 5% had only anemia and 17% had only CVD. Both anemia and CVD were independently associated with a steeper decline in global cognitive composite score (anemia ‐0.01/year; 95%CI ‐0.03 to ‐0.00, CVD ‐0.02/year; 95%CI ‐0.03 to ‐0.02). Anemia was associated with faster decline in category fluency and perceptual speed, while CVD was significantly associated with an accelerated decline in all examined cognitive domains. Both anemia and CVD at baseline were associated with a steeper decline in total brain tissue volume, while CVD was additionally associated with steeper decline in volumes of hippocampus (P<0.05). Neither was significantly associated with changes in cSVD markers (i.e., white‐matter hyperintensities, lacunes).ConclusionBoth anemia and CVD are risk factors for accelerated cognitive decline and brain atrophy in older adults.
Design of ADEPT‐2, a phase 3, parallel group study to evaluate KarXT [xanomeline‐trospium] as a treatment for psychosis associated with Alzheimer’s disease
Authors: Kang Minsu , Watson Carolyn , Cummings Jeffrey L. , Grossberg George T , Marcus Ronald , Yeung Paul 
Published: December 2023

AbstractBackgroundPsychosis represents a major unmet medical need in patients with Alzheimer’s disease (AD) dementia. With no approved medications for AD dementia psychosis (ADP), current treatment relies on off‐label uses of antipsychotics with limited efficacy and significant safety concerns. Xanomeline is an M1/M4 preferring muscarinic receptor agonist that has previously been shown to have antipsychotic effects in subjects with AD (Bodick et al., 1997). While xanomeline had promising efficacy for potentially treating psychosis in AD, cholinergic adverse events limited further clinical development of xanomeline. KarXT is an investigational treatment that combines xanomeline with trospium, an FDA‐approved non‐specific muscarinic receptor antagonist. Unlike xanomeline, trospium does not measurably cross the blood‐brain barrier, providing a mechanism to mitigate peripheral cholinergic effects of xanomeline while maintaining its muscarinic receptor agonist activities in the brain.MethodsADEPT‐2 trial is a phase 3, randomized, double‐blind, placebo‐controlled, parallel group study to evaluate the safety and efficacy of KarXT for the treatment of ADP. Subjects aged 55‐90 years with moderate to severe psychosis associated with mild to severe AD dementia will be enrolled into the study. Eligible subjects will be randomized to receive either KarXT or placebo in a double‐blinded manner for 14 weeks and subjects who complete the study will be eligible to participate in a one‐year, open‐label safety extension study.ResultsThe primary efficacy endpoint of the study is change from Randomization to End of Treatment in the Neuropsychiatric Inventory‐Clinical (NPI‐C): Hallucinations and Delusions (H+D) score and the key secondary efficacy endpoint is change from Randomization to End of Treatment in the Cohen‐Mansfield Agitation Inventory (CMAI). The safety endpoints include the evaluation of safety and tolerability of KarXT compared with placebo in subjects with ADP. The study is planned to start in 2023 and will enroll approximately 360 subjects with psychosis associated with AD dementia.ConclusionADEPT‐2 is designed to assess the safety and efficacy of KarXT for the treatment of psychosis in patients with AD dementia. If ADEPT‐2 is successful, KarXT has the potential to be the first in a new class of pharmacologic treatment for AD psychosis based on muscarinic receptor agonism.
5‐LOX: blood based biomarker for Alzheimer’s disease (AD) and effect of peptide inhibitor on neurotoxicity developed in AD.
Authors: Yadav Yudhishthir , Nayal Abhilasha , Ashar Suhail , Dey Aparajit Ballav , Dey Sharmistha 
Published: December 2023

AbstractBackgroundThe inflammatory process plays a key role in neurodegenerative disorder. Pro‐inflammatory molecule, 5‐Lipooxygenase (5‐LOX), protein is involved in pathologic phenotype of AD. It includes Aβ amyloid deposition and tau hyper phosphorylation both but the detail mechanism is still illusive. This study determined the level of 5‐LOX in serum of Alzheimer’s disease (AD) patient, Mild cognitive impairment (MCI), normal elderly and rescue effect by YWCS, a peptide inhibitor of 5‐LOX on neurotoxicity by Aβ amyloid (Aβ25‐35) in neuroblastoma cells SH‐SY5Y.MethodThe level of serum 5‐LOX was estimated by surface plasmon resonance and presence of 5‐LOX in serum was confirmed by western blot. The peptide inhibitor YWCS was synthesized by solid‐phase peptide synthesis (SPPS) using F‐moc and Wang resin chemistry, and the purity of the peptide was verified by analytical RP‐HPLC. The neuroprotective effect of 5‐LOX peptide inhibitor YWCS in Aβ25‐35 induced neurotoxicity was analyzed by MTT assay and western blotting.ResultThe level of serum 5‐LOX was estimated by surface plasmon resonance and presence of 5‐LOX in serum was confirmed by western blot. The peptide inhibitor YWCS was synthesized by solid‐phase peptide synthesis (SPPS) using F‐moc and Wang resin chemistry, and the purity of the peptide was verified by analytical RP‐HPLC. The neuroprotective effect of 5‐LOX peptide inhibitor YWCS in Aβ25‐35 induced neurotoxicity was analyzed by MTT assay and western blotting.ConclusionThe differential expression of serum 5‐LOX among the study groups suggests, it can be one of potential serum protein marker and therapeutic regimen for AD and MCI. Peptide YWCS, can serve as new platform as 5‐LOX inhibitor which can prevent neurotoxicity developed in AD.
Association of Objective Sleep Duration with Cognition and Brain Aging Biomarkers in Older Adults
Authors: Tang Shi , Liu Rui , Song Lin , Ren Juan , Zhao Mingqing , Wang Yongxiang , Dong Yi , Liu Cuicui , Hou Tingting , Cong Lin , Du Yifeng , Qiu Chengxuan 
Published: December 2023

AbstractBackgroundThe neuropathological mechanisms linking sleep duration with mild cognitive impairment (MCI) are poorly understood.MethodThis population‐based study included 2032 dementia‐free participants (age ≥60 years; 55.1% women) derived from the baseline survey of the Multimodal Interventions to Delay Dementia and Disability in Rural China; of these, data were available from 841 participants for Alzheimer’s plasma biomarkers (e.g., amyloid‐β [Aβ], total tau, and neurofilament light chain [NfL] protein), 1044 for serum microvascular biomarkers (e.g., soluble adhesion molecules), and 834 for brain MRI biomarkers (e.g., total brain tissue, whiter matter, grey matter, hippocampus, lacunes, enlarged perivascular spaces [EPVS], and white matter hyperintensity [WMH]). We assessed sleep duration using the electrocardiogram‐based cardiopulmonary coupling analysis, global and domain‐specific cognitive function using a neuropsychological test battery, and MCI following the Petersen’s criteria. Data were analyzed with multivariable logistic and general linear models.ResultIn the total sample (n = 2032), 510 participants were diagnosed with MCI, including 438 with amnestic MCI and 72 with non‐amnestic MCI. Objectively‐measured long sleep duration (>8 vs. 6‐8 hours) was significantly associated with an increased likelihood of MCI and lower scores in global cognition, verbal fluency, attention, and executive function (P<.05). In the subsamples, long sleep duration was associated with higher plasma concentrations of Aβ40, total tau, and NfL, a lower Aβ42/Aβ40 ratio, and smaller volumes of total brain tissue, grey matter, and hippocampus (P<.05). There were no significant associations of sleep duration with serum soluble adhesion molecules concentrations, white matter volumes, WMH volumes, global EPVS, and lacunes (P >.05).ConclusionAlzheimer’s and neurodegenerative pathologies represent common pathways linking long sleep duration with poor cognition in older adults.
Association of liver dysfunction with incident dementia, cognition, and brain structure
Authors: Gao Pei‐Yang , Ou Ya‐Nan , Wang Hui‐Fu , Ma Ya‐Hui , Wang Zhi‐Bo , Tan Lan , Yu Jin‐Tai 
Published: December 2023

AbstractBackgroundAn association between liver dysfunction and cognitive impairment has been previously identified; however, further clarification is required due to the lack of comprehensive evidence. This study aimed to investigate the association between liver dysfunction and the risk of different types of incident dementia, cognitive function, and brain structural abnormalities.MethodA total of 431,754 UK Biobank participants without dementia at baseline were included between 2006 and 2010. The longitudinal associations between liver dysfunction and incident dementia were assessed using the Cox proportional hazards model, and the relationship between cognitive performance and brain structure was investigated using a linger regression model.ResultAfter 9.04 (Standard Deviation 2.61) years of follow‐up, 5,627 participants were diagnosed with all‐cause dementia, including 2,438 Alzheimer’s disease and 1,312 vascular dementia cases. We found that decreased alanine transaminase (Hazard Ratio 0.992, 95% Confidential Interval 0.989‐0.995, P<0.001) and increased aspartate aminotransferase (HR 1.006, 95% CI 1.002‐1.011, P = 0.002), increased aspartate aminotransferase to alanine transaminase ratio (HR 1.593, 95% CI 1.471‐1.724, P<0.001), increased direct bilirubin (HR 1.052, 95% CI 1.005‐1.101, P = 0.028), increased gamma‐glutamyl transpeptidase (HR 1.002, 95% CI 1.001‐1.006, P<0.001), alcoholic liver disease (HR 2.870, 95% CI 1.863‐4.420, P<0.001), fibrosis and cirrhosis of liver (HR 2.284, 95% CI 1.454‐3.588, P<0.001), and other liver disease (HR 1.433, 95% CI 1.040‐1.973, P = 0.028) were significantly associated with all‐cause dementia risk. Similar outcomes were obtained for Alzheimer’s disease and vascular dementia. Additionally, liver dysfunction was associated with poor cognition in four different cognitive tests and altered cortical and subcortical brain regions.ConclusionOur findings provide amplified evidence to suggest that liver dysfunction is associated with the risk of different types of incident dementia, and a close relationship has been identified between poor cognitive performance and altered brain structure.
Diagnostic performance and clinical applicability of plasma pTau181 to predict dementia risk in a large real‐world cohort of a memory clinic
Authors: Cano Amanda , Puerta Raquel , Núñez‐Llaves Raúl , de Rojas Itziar , García‐González Pablo , Olivé Clàudia , Montrreal Laura , Orellana Adelina , Rosende‐Roca Maitee , onio Ester , Pytel Vanesa Verónica , Alegret Montserrat , Valero Sergi , Tárraga Lluís , Marquié Marta , Boada Mercè , Ruiz Agustin 
Published: December 2023

AbstractBackgroundThe Alzheimer Association has recently remarked the diagnostic and prognostic revolution that plasma biomarkers will mean for AD diagnosis, and highlighting the need of further research to translate them as a realistic option in the clinical practice. However, many studies to date have assessed them in research cohorts. Here we evaluated the diagnostic performance and clinical applicability of plasma pTau181 as a predictive marker of dementia risk in a real‐world memory clinic cohort.MethodThe ACE cohort encompass 1649 patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia and other dementias, with a complete battery of neurological tests, biochemistry data, and paired CSF and plasma samples of the Ace Alzheimer Center Barcelona memory clinic. CSF AB42, AB40, pTau181 and tTau, and plasma pTau181 were measured using the Lumipulse G1200 automatic platform (Fujirebio Inc.). Complete cohort were divided in the Testing cohort (n = 1000) and Validation cohort (n = 649).ResultPlasma pTau181 significantly correlated (P<0.0001) with CSF pTau181 in MCI, AD dementia and other dementias, but not in SCD. Sex appeared not significant in plasma pTau181 levels, whereas age significantly influenced in the biomarker’s performance. ROC curve of A+T+ patients vs rest showed an AUC = 0.8250 and P<0.0001. Specifically for MCI patients, ROC curve of MCI A+T+ vs MCI A‐T‐ showed and AUC = 0.8874 and P<0.0001. A cut off value of 1.300 pg/ml of plasma pTau181 exhibited a 93.6% sensibility, 72.4% specificity, 77.8% precision and only 8.3% of false negatives in MCI patients. Hazard ratio of survival of conversion analysis showed that MCI patients above this cut off value exhibited a 4.570 higher risk to convert to dementia than MCI under the cut off value. Validation cohort confirmed these findings.ConclusionPlasma pTau181 could be useful as a pre‐screening biomarker of MCI patients with high risk to progress to dementia. However, positive patients will also require a CSF/PET confirmatory test. Plasma pTau181 by itself does not present a suitable performance in SCD patients. Another biomarker or a combination of biomarkers would be needed to this population. Further studies are need to obtain more clinical data and improve the biomarker performance to finally substitute CSF/PET biomarkers.