bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau pathology in P301S PS19 mice alters peripheral and cerebral metabolism, sleep, and excitability
Authors: Irmen Riley E , Carroll Caitlin M , Snipes James A , Sink Sandy A , Macauley Shannon L 
Published: December 2023

AbstractBackgroundTwo biomarkers for Alzheimer’s disease (AD) are amyloid‐beta (Aβ) and tau aggregation. AD patients often experience comorbidities like metabolic dysfunction and/or sleep‐wake cycle disruption, but it is unclear whether this can be directly linked to Aβ or tau aggregation. Previous research shows mouse models overexpressing Aβ also experience metabolic and sleep dysfunction, independent of comorbidities like type‐2‐diabetes. Our lab previously demonstrated that central and peripheral metabolic changes are linked. This bidirectional relationship is well described in mouse models of Aβ overexpression; however, this relationship is relatively unexplored in mouse models of tauopathy. Therefore, our lab is investigating how central and peripheral metabolism relate to sleep‐wake disruption in the P301S PS19 mouse.MethodTo investigate changes in peripheral metabolism, body weights are measured, and glucose tolerance tests are conducted on P301S PS19 and wild type female mice. Blood glucose levels are taken after fasting for four hours. Next, the mice are given an ip dose of 2g/kg glucose followed by blood glucose measurements in 15‐minute increments for two hours. Paired glucose and lactate biosensors placed within the mouse hippocampus track second by second metabolic fluctuations over three circadian days. Along with biosensors, EEG and EMG electrodes are positioned to record sleep‐wake cycles during this period. All methods completed on 3‐, 6‐, and 9‐month‐old P301S and wild type female mice.ResultWhile current experiments are ongoing, P301S mice become glucose sensitive where WT mice become glucose intolerant with age. Early analysis suggests pathology and age‐related differences in metabolism and sleep also develop over the circadian day. Our data suggests that tau aggregation increases peripheral glucose metabolism, in a manner different than Aβ pathology. Tau pathology disrupts normal sleep patterns where it decreases time spent in NREM and REM and alters EEG frequencies like delta, beta, and gamma. As age and pathology progress, cerebral metabolism of glucose and lactate is increased compared to age‐matched WT mice.ConclusionWe hypothesize tau pathology induced hyperexcitability alters sleep/wake cycles, peripheral and cerebral metabolism, and exacerbates pathology. Our current research is valuable in expanding knowledge of the relationship between metabolism, sleep, and tau in Alzheimer’s disease.
The Maintain Your Brain online multidomain intervention for dementia risk reduction: end‐user evaluations of what did and did not work and why
Authors: Casey Anne‐Nicole S. , Chau Tiffany , Heffernan Megan , Brodaty Henry 
Published: December 2023

AbstractBackgroundDementia prevalence is increasing, and risk reduction is a priority. Online interventions that are useable and acceptable to people seeking to reduce their dementia risk are needed. We aimed to assess and explore end‐user perceptions of a large‐scale multidomain online intervention targeting modifiable lifestyle risk factors for dementia.MethodMixed methods evaluation involving Maintain Your Brain (MYB) randomised controlled trial participants 55‐77 years of age at baseline who engaged in assessments, brain training, nutrition and physical activity, and mental health modules across three years. Of 5,260 participants invited, 2,386 completed online surveys at trial conclusion of whom 1,589 offered free‐text comments. Of survey respondents, 248 agreed to be contacted for interviews, 70 were invited and 40 were interviewed. Survey respondents rated ease of use and overall experience with MYB, endorsed whether they would recommend MYB, and provided comments. Interview completers further rated satisfaction with support, expressed online or face‐to‐face setting preference, answered open‐ended questions about participation, activities and modules, and provided further comments. Data were summarised using descriptive statistics and explored using multiple qualitative methods.ResultRespondents found computer‐based activities easy to use (92.2%), were satisfied with their overall experience (87.4%) and would recommend MYB (82.7%). Survey free‐text and interview comments addressed topics including computer literacy, health literacy, resource access, motivations, expectations, social relationships, and significant events. Perspectives on activities and information varied. Many enjoyed and/or appreciated the challenge of completing activities and assessments and the potential for health benefits from these activities. Others were disappointed by their own performance in activities and assessments, found testing and reporting repetitious, stressful and/or time‐consuming, and found educational information unhelpful. Many respondents would have preferred to access applications on phones or tablet devices and suggested that interventions should be available across platforms. Respondents wanted researchers to know that flexible and adaptive individually tailored goals and activities and timely feedback are important.ConclusionThe MYB online multidomain dementia risk reduction program was useable and acceptable. Similar programs should be accessible, well‐supported, cross‐IT platforms, and incorporate adaptive, individually tailored activities and feedback that is responsive to the varied and changing needs of older adults.
Pathogenic characteristics of genetically modified cells with TREM2 T44A mutation
Authors: Kim Danyeong , Shim Kyu Hwan , Yang Hyewon , Bae Heewon , Kang Min Ju , Shin Seunghwan , Kim Jongsung , Yun Kyusik , Jang Chang‐Hyun , An Seong Soo 
Published: December 2023

AbstractBackgroundTriggering Receptor Expressed on Myeloid Cells‐2 (TREM2) is known as a risk gene for Alzheimer’s disease (AD). and affect AD pathogenesis through beta‐amyloid (Aβ)‐related neuroinflammations and phagocytosis. TREM2 R47H mutation was the first reported from an AD patient in 2013. Although the TREM2 R47H variant was revealed to increase the risk of AD by three times, further mutations still need to study. Here, we found TREM2 T44A mutation from a patient of a 65‐year‐old AD patient. In order to confirm the pathogenicity of TREM2 T44A, the genetically modified cells were produced and investigated the association of the TREM2 gene with Aβ‐related pathology.MethodTREM2 Wild type (WT) and T44A were transfected onto the HEK 293, SHSY5Y, U87 cells by using a plasmid transfection system and selected using geneticin (G418). Gene expression and TREM2 protein was measured. For measuring Aβ uptakes, Aβ was measured after incubation with cells. Cell phagocytosis was conducted with treating pHrodo labeled with Aβ and obtained cell images and video.ResultTREM2 gene was overexpressed in transfected cells and TREM2 protein was elevated, but TREM2 T44A lowered compared to WT. TREM2 T44A showed higher Aβ42/40 ratio, with increasing extracellular Aβ42. The Aβ42 uptake were relatively lowered than TREM2 WT. Through images and video, TREM2 T44A showed lower red fluorescence than WT, but similar to MOCK.ConclusionIn this study, we transfected TREM2 WT and T44A in a variety of cell lines (HEK 293, SHSY5Y, U87) to investigate the pathogenicity of TREM2 T44A. TREM2 T44A was shown to increase extracellular Aβ42 and decrease Aβ42 uptake. This suggests that the Aβ uptake and elimination function of TREM2 was loosed by the mutation, and therefore Aβ was not completely removed, resulting in a slight increase in extracellular Aβ in the mutant cell. The loss of the Aβ uptake correlated with confocal and video results, the red fluorescence signals were decreased in TREM2 T44A, suggesting relatively lower Aβ phagocytosis. Thus, Aβ phagocytosis was inhibited by TREM2 mutation, and the lowered Aβ uptake could not clear it, suggesting that Aβ growth and accumulation may influence the pathogenicity of AD.
The relationship between sleep duration and cortical sulcal width in midlife and older adults
Authors: Faucher Caroline , Borne Léonie , Paton Bryan , Giorgio Joseph , Fripp Jurgen , Thienel Renate , Lupton Michelle K , Breakspear Michael 
Published: December 2023

AbstractBackgroundEmerging evidence suggests that poor sleep is associated with worse cognitive and structural brain health, and an increased risk of developing dementia (Bubu et al., 2016; Fjell et al., 2022; Tai et al., 2022). The present study investigated the influence of sleep duration on the cognition‐brain relationship in older adults using sulcal width (SW), a reliable measure of changes in the ageing brain (Bertoux et al., 2019). The influence of napping, depression likelihood, and genetic risk for dementia (APOE ε4 status) was also explored.MethodParticipants were 137 cognitively normal adults, aged 46‐72 from the Prospective Imaging Study of Ageing (PISA). Demographic information, sleep duration, and depressive symptoms were collected via online questionnaires. Cognition was assessed using the Cambridge Brain Systems battery. APOE genotype was determined from blood‐extracted DNA. Imaging data was acquired using a 3T Siemens PRISMA scanner. SW was extracted using the Morphologist pipeline (Borne et al., 2020).Canonical Partial Least Squares (PLS) were used to obtain latent variables of cognition and SW. ANCOVAs measured the effect of sleep duration categories (7‐7.5 hours versus {<7 or ≥8 hours}) on the cognitive and SW components, with sex and age as covariates. Status of depression likelihood was added as a covariate of interest. The effect of napping, and APOE ɛ4 allele on these same components were measured by ANCOVAs, with sex and age as covariates.ResultWe observed a significant effect of sleep duration on SW (F(1, 133) = 4.17, p = 0.043, Fig. 1). This effect remained significant (F(1,132) = 4.89, p = 0.029) after including depression likelihood as a covariate, which was also significant in the model (F(1,132) = 4.62, p = 0.034). A significant interaction between APOE ε4 status and age (p = 0.050) on SW was also observed.ConclusionResults add weight to studies suggesting that not too much or too little sleep is needed to maintain brain health in later life (Li et al., 2022; Liang et al., 2019). Depression, a risk factor for dementia (Livingston et al., 2020), was also associated with poorer brain health. Results suggest that at approximately 60 years of age, the influence of a positive APOE ε4 status is associated with increasing age‐related brain atrophy.
Diagnosis of Severity of Alzheimer’s Disease from Clinical notes in the Veterans Affairs Healthcare System
Authors: Aguilar Byron J. , Shishova Ekaterina , Li Xuyang , Nguyen Andrew H. , Morin Peter J , Berlowitz Dan , O'Connor Maureen K. , Miller Donald R , Jasuja Guneet , Zhang Raymond , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) typically progresses in three stages: mild, moderate, and severe. Early detection improves patient care related to identification of suitable interventions and end‐of‐life planning. However, AD severity diagnosis is uncommon. The aim of this study is to identify Veterans in various stages of AD using clinical notes in the Veterans Affairs Healthcare System.MethodNotes containing “Alz*” from fiscal year 2019 were identified then screened for information indicating a clinical diagnosis of probable AD. Screened notes with AD severity keywords (mild, moderate, severe, early, late, advanced) within four words of “Alz*” were considered as a severity diagnosis. Notes containing a single AD severity diagnosis were included in the study.Result141,816 Veterans with 547,318 notes containing “Alz*” were identified as probable AD cases. Roughly 9% of notes contained at least one severity keyword and 6% of notes contained a single severity keyword. 34,181 notes with a single severity keyword from 14,148 Veterans were included in this study. The cohort comprised of 96% males and 78% identified as White with a mean age of 79. Ten percent of Veterans with an AD note included severity diagnosis. Approximately 19%, 12%, 18%, 20%, 3%, and 28% of severity notes contained mild, moderate, severe, early, late, and advanced, respectively. The mean age for Veterans with a mild, moderate, or severe AD diagnosis increased from 78 to 81. The mean age for early, late, and advanced AD patients increased from 74, 79, and 81, respectively. AD severity diagnosis was found in notes related to primary care (11%), internal medicine (10%), psychiatry (8%), mental health (7%), neurology (6%), geriatric (5%), neuropsychology (1%), and psychology (1%).ConclusionAD severity diagnosis is uncommon. Identification of patients in various stages of AD will lead to a better understanding of transition from one severity to another and facilitate the coordination of services to improve patient care. Specifically, identification of AD patients in the early stage may identify candidates for novel therapeutics focused on delaying AD progression.
Selective vulnerability of the suprachiasmatic nucleus in progressive Alzheimer’s Disease: A human postmortem study using spatial in‐situ proteomics
Authors: Son Gowoon , Mladinov Mihovil , Pereira Felipe Luiz , Tu Chia‐Ling , Li Song Hua , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Pasquallucci Carlos Augusto , Jacob‐Filho Wilson , Spina Salvatore , Seeley William W. , Chang Wenhan , Neylan Thomas C. , Grinberg Lea T. 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) patients commonly experience sleep/wake (S/W) disturbances, such as sleep fragmentation and excessive daytime sleepiness. The S/W cycle is controlled by a complex system regulated by a master regulator, the suprachiasmatic nucleus (SCN) that controls wake‐ and sleep‐promoting nuclei. Despite its importance in orchestrating sleep architecture, little is known about the molecular changes that occur in the SCN during the progression of AD and how these changes contribute to S/W disturbances.MethodWe used postmortem brain tissue of 10 controls without AD pathology and 32 subjects with progressive AD stages. Our approach included quantitative neuropathological assessments of AVP and VIP‐expressing neurons in SCN and its adjacent hypothalamic region, the supraoptic nucleus (SON). We also used an in‐situ cell‐specific spatial proteomics platform [GeoMx Digital Spatial Profiling (DSP)] to probe levels of different pathological tau species and proteins commonly dysregulated in AD.ResultPreliminary findings reveal a significant decrease in SCN volume (∼75%) (Fig.1) and a loss of ∼58% AVP neurons and ∼41% VIP neurons in Braak stage (Braak) VI compared to Braak 0. The DSP results indicate that both neurons in the SCN have twice the burden of p‐tau levels as the SON (Fig.2‐right), and neurofibrillary tanglesAdditionally, SCN shows an increase in proteins associated with glia and immune responses (Fig.2‐left). Furthermore, an increase in microglial proteins is observed in the SCN in Braak I (Fig.3‐left). In contrast, the SON displays a milder pattern of protein dysregulation in Braak I (Fig.3‐right), consistent with its lower tau expression observed in histology and DSP.ConclusionSCN is vulnerable to AD pathology even in Braak I, which is characterized by volume loss, increased immune response protein dysregulation, and later neuronal loss, as well as p‐tau pathology. This pattern supports the idea that the SCN plays a role in S/W disturbances observed from early AD stages. Interestingly, its neighboring nucleus, SON, which also has AVP neurons, remained spared, providing opportunities for studies investigating factors related to selective vulnerability. Ongoing studies are addressing changes in the SCN and SON in intermediate AD stages.
The association of childhood socio‐economic position with later life brain structure in individuals of Hispanic/Latino background. Preliminary results from the INCA‐MRI study
Authors: Isasi Carmen R , Filigrana Paola , Moon Jee‐Young , Lipton Richard B. , Gallo Linda C , Kaplan Robert , Daviglus Martha L , Testai Fenando D , Marquine Maria J. , Cai Jianwen , Schneiderman Neil , Perreira Krista M , Stickel Ariana M , González Hector M , Decarli Charles 
Published: December 2023

AbstractBackgroundChildhood is a period of brain plasticity when environmental influences may have long‐lasting effects. Early socio‐economic position (SEP) may influence brain development at vulnerable stages and set the stage for increased vulnerability to Alzheimer’s Disease and related dementias (ADRD). In this study, we evaluated whether childhood SEP was related to brain structure in adulthood.MethodsThis analysis included the first 1320 individuals (61% women, age range 50‐85) of diverse Hispanic/Latino background with brain magnetic resonance imaging (MRI) assessments from the HCHS/SOL INCA‐MRI study, conducted at four major urban areas (Bronx, NY; Chicago, IL; Miami, FL, and San Diego, CA). Childhood SEP was assessed by self‐reported maternal educational achievement. We also calculated the difference between attained height and genetically predicted height using height‐associated SNPs, sex, and genetic ancestry as a biomarker of early environmental exposures. Positive values indicate taller attained stature than the expected based on SNPs, suggesting favorable early environmental influence on height; negative values suggest environmental conditions limiting growth. Measures of brain structure [total intracranial volume (TICV), total gray matter volume (TGMV) and hippocampus volume (HV)] were obtained using MRI with standardized procedures. Survey linear regression models were conducted adjusting for potential confounders.ResultsLow parental educational achievement was common, 55% of mothers completed less than a middle school education. In multivariable linear regression models, higher maternal educational achievement was associated with some measures of brain structure, such as greater TICV (b = 18.6, p<.001 for high school (HS) graduate; b = 26.2, p<.01 for > HS; reference <6 grade), higher TGMV (b = 5.8, p<.02 for HS graduate; b = 5.4, p<.10 for > HS), and higher HV (b = 0.14, p<.01 for HS graduate; b = 0.03, p = NS for greater than HS). Early life factors affecting height were associated with lower TICV (b = ‐18.9, p<.001), lower TGMV (b = ‐6.4, p<.001), and lower HV (b = ‐0.6, p<.01).ConclusionThis study showed associations of early childhood socio‐economic position with brain structure assessed in later adulthood. Findings suggest that height residual is a useful predictor of early life environment affecting later life brain volumes.
Association of gabapentin and neuropathological hallmarks in an autopsy cohort of older adults
Authors: Oh GYeon , Moga Daniela C , Fardo David W. , Harp Jordan P. , Abner Erin L 
Published: December 2023

AbstractBackgroundPrevious studies of the association between gabapentin use and neurocognitive change have shown conflicting results. We examined the association between end‐of‐life gabapentin use and neuropathological features in older adults using National Alzheimer’s Coordinating Center Uniform Data Set and Neuropathology Data Set (9/2005‐3/2022).MethodsWe conducted a cross‐sectional study including participants with at least one visit within two years before autopsy and age at visit 65+ years. Gabapentin use was determined based on the two‐year window. Outcomes of interest included burden of tau (Braak stage), amyloid (Thal stage, diffuse plaques, and neuritic plaques), α‐synuclein (Lewy bodies), cerebrovascular disease (infarcts, microinfarcts, and arteriosclerosis), hippocampal sclerosis, cerebral amyloid angiopathy, TDP‐43, and atrophy (cerebral cortex and hippocampus). Collection of Thal stage, TDP‐43, and atrophy information occurred after January 2014; these outcomes were assessed in the subset with data. For each dependent neuropathological hallmark, two models were constructed (M1: adjusted for age, sex, APOE, center, and cognitive status; M2: adjusted for M1 confounders, agitation, depression, antiseizure drug, and use of opioids). To mitigate bias, joint stabilized inverse probability of treatment and censoring weights were used.ResultsWe included 213 gabapentin‐users (mean age[SD]: 80.9[8.7]; male 53.5%) and 4107 non‐users (82.0[8.7]; 54.7%). Gabapentin use was associated with reduced odds of Braak stage IV‐VI vs. 0‐III, moderate/frequent vs. non/sparse diffuse plaques, presence of Lewy bodies, infarct, and cerebral amyloid angiopathy in M1 and M2, and hippocampal sclerosis in M1 (Figures 1A and 1B). For the subset outcomes, 116 gabapentin‐users (mean age [SD]: 81.0 [8.6]; male 50.9%) and 1919 non‐users (81.8 [8.9]; 54.3%) were included. Gabapentin use was associated with increased odds of Thal phase 3‐5 vs. 0‐2 in M1 and M2, and amygdala TDP‐43, hippocampus TDP‐43, and cerebral cortex atrophy in M2; whereas gabapentin use was associated with decreased odds of hippocampus atrophy in M1 and M2, and amygdala TDP‐43, hippocampus TDP‐43, and cerebral cortex atrophy in M1 (Figures 1C and 1D).ConclusionEnd‐of‐life gabapentin use was not significantly associated with burden of neuropathologic features and there were no clear patterns. Further studies with increased sample sizes and better measurement of gabapentin use are needed.
Types of social support and depressive symptoms in older adults: An IPD meta‐analysis of longitudinal ageing studies
Authors: Samtani Suraj , Mahalingam Gowsaly , Lam Ben C. P. , Lipnicki Darren M. , Costa Erico , Lima‐Costa Maria Fernanda , Xiao Shifu , Scarmeas Nikolaos , Kim Ki Woong , Numbers Katya T. , Ganguli Mary , Krishna Murali , Ng Tze Pin , Sachdev Perminder S. , Brodaty Henry , Skoog Ingmar , Riedel‐Heller Steffi G. , Shahar Suzana ,   COSMIC consortium and SHARED consortium
Published: December 2023

AbstractBackgroundDepression is a known risk factor for dementia, and social support may lower the risk of depression in older adults. There is, however, a lack of longitudinal analyses examining the association between emotional versus instrumental support and depressive symptoms in older adults. We analyzed the association of emotional and instrumental support with depression symptom scores using data from eight international longitudinal cohorts. This is an individual participant data meta‐analysis on harmonized social support and depression data.MethodWe obtained data from eleven COSMIC (Cohort Studies of Memory in an International Consortium) international longitudinal cognitive ageing studies, including data from Australia, Brazil, China, Germany, Greece, India, Indonesia, South Korea, Singapore, Sweden, and the United States. Randomly sampled 27,058 adults in later life (M = 71.7 years), of whom 59.5% were females. Social support was measured using individual items of emotional support (i.e., having a confidante) or instrumental support (i.e., help with daily living activities). Depression was measured using validated scales at baseline and follow‐up (M = 2.02 years). Covariates included age, sex, education, living situation, smoking history, diabetes mellitus, cardiovascular risk, global cognitive function and (where available) history of depression. Depression scores were standardized while other variables were harmonized before analysis.ResultIn the fully adjusted cross‐sectional models, having emotional support (B = ‐0.40, 95%CI: ‐0.60,‐0.21), but not instrument support (B = 0.15, 95%CI: ‐0.29,0.58) was associated with lower depressive symptoms. In the fully adjusted longitudinal models, having emotional support (B = ‐0.36, 95%CI: ‐0.53,‐0.19) but not having instrumental support (B = 0.07, 95%CI: ‐0.33,0.46) was associated with lower depressive symptoms at follow‐up.ConclusionEmotional, but not instrumental support, was associated with lower depressive symptoms cross‐sectionally and at follow‐up in harmonised data from 8 longitudinal ageing studies. Psychosocial interventions targeted at reducing the risk of depression (and therefore dementia) should focus on improving access to emotional support for older adults.