bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anterior hypothalamic pathology in Alzheimer’s disease: A human postmortem study using spatial in‐situ proteomics
Authors: Son Gowoon , Mladinov Mihovil , Pereira Felipe Luiz , Li Song Hua , Tu Chia‐Ling , Spina Salvatore , Seeley William W. , Chang Wenhan , Grinberg Lea T. 
Published: December 2022

AbstractBackgroundThe anterior hypothalamus contains several sleep‐promoting nuclei, including the suprachiasmatic nucleus (SCN), the key circadian clock in the brain. Sleep disturbances are a common in Alzheimer’s disease (AD), but little is known about the profile of AD‐related pathology in the anterior hypothalamic nuclei.MethodWe used the GeoMx Digital Spatial Profiling (DSP), an in‐situ spatial proteomics platform (Nanostring) to assess spatially resolved tauopathy and tau‐driven protein alteration in the SCN, supraoptic nucleus (SON), and periventricular nucleus (PV) in the anterior hypothalamus of four postmortem brains from three AD subjects and one control. The profiled regions‐of‐interest were confirmed by immunohistochemistry.ResultAll three nuclei showed significantly higher levels of p‐tau 404 and 396 in AD than control, and differential patterns of selective vulnerability for tau, with the SCN, expressing greater p‐tau 404 and 396 levels than the SON. In addition, the p‐tau immunoreactivity corresponds to the DSP data. Interestingly, the PV indicated upregulated β‐amyloid(1‐42) and β‐secretase 1 than others.ConclusionAD patients revealed increased p‐tau expression in the SCN located in the anterior hypothalamus. Given that tau pathology is one of the main features in AD, altered p‐tau level may lead the SCN and other hypothalamic protein alteration shown in this result, influencing the hierarchical clustering. We suggest tauopathy can be a preceding criterion for tau‐driven hypothalamic protein subpopulation, explaining AD‐driven neurodegeneration and dysfunction such as sleep dysregulation in AD.
Plasma Biomarkers of Neurodegeneration and Tau in Relation to Longitudinal Depressive Symptoms in Older Adults: Findings from the Harvard Aging Brain Study
Authors: Gatchel Jennifer R , Yang Hyun‐Sik , Mimmack Kayden J. , Arnold Steven E. , Blacker Deborah , Liu Lei , Selkoe Dennis J , Johnson Keith A. , Sperling Reisa A. , Marshall Gad A , Chhatwal Jasmeer P. 
Published: December 2022

AbstractBackgroundDepressive symptoms are common in late life and Alzheimer’s Disease (AD) but the underlying neurobiology of these symptoms and their relationships to AD biomarkers is unclear. Probing these relationships using biomarkers of neurodegeneration and tau that can be measured via plasma can importantly guide AD prognosis and treatment. The current study determined the relationships between baseline measures of neurofilament light (NfL) (a marker of neurodegeneration) and an N‐terminal fragment of tau (NT1, an early and specific marker of AD) and longitudinal depressive symptoms in a cohort of older adults.MethodLongitudinal data were analyzed from 342 participants from the Harvard Aging Brain Study, an observational cohort study of individuals who were cognitively unimpaired and with no/minimal depressive symptoms at baseline (age: 71.7 +/‐ 8.1; % female: 61%; average follow up: 3.94 years, range: 0–7.88). Depressive symptoms were assessed annually with the 30‐item Geriatric Depression Scale (GDS). At study baseline, all participants had plasma samples assayed for NfL and NT1 and underwent amyloid (PiB) PET imaging to derive a cortical amyloid composite. Linear mixed effects models were used to examine relationships between dependent variable longitudinal GDS (log‐transformed) and predictors of interest: (plasma NfL or NT1) x time, and covariates: age, sex, education. Secondary models were adjusted for cortical amyloid and examined the interactive effects of amyloid and plasma biomarkers on longitudinal GDS.ResultHigher baseline NfL predicted increasing GDS scores over time (β = 0.04 +/‐0.01, t = 3.8, p = 0.0001), while a trend was observed for NT1 (β = 0.02 +/‐0.01, t = 1.9, p = 0.06). Similar results were obtained when adjusting models for amyloid x time (NfL x time: β = 0.04 +/‐0.01, t = 3.8, p = 0.0002; NT1 x time: β = 0.02 +/‐0.01, t = 1.7, p = 0.09). Neither NfL nor NT1 interacted with amyloid to predict increasing GDS over time.ConclusionFindings support an association between depressive symptoms and plasma measures of neurodegeneration–whether cause or consequence. Moreover, for NfL, this relationship is independent of amyloid, suggesting that multiple pathways may underlie the emergence of depressive symptoms in older adults. Further longitudinal investigation in relation to cognition and across depressive symptom severity is needed to better understand the pathophysiology of depression in late life and AD.
Blood pressure postural changes variability is associated with cognitive decline: the S.AGES cohort
Authors: Strumia Mathilde , Vidal Jean‐Sebastien , Hanon Olivier , Rouch Laure 
Published: December 2022

AbstractBackgroundOver the past decade, higher blood pressure (BP) variability has been associated with cognitive decline (CD). To date, only one study investigated the specific impact of visit‐to‐visit BP postural changes variability on dementia but its association with cognition is still unknown. We aimed to investigate the association between BP postural changes variability and cognitive function in noninstitutionalized subjects aged ≥ 65 years.MethodThe S.AGES (Sujets Âgés) cohort followed for three years noninstitutionalized subjects aged ≥ 65 years without major neurocognitive impairment at inclusion. At each visit, an orthostatic systolic BP (SBP) ratio was calculated using the formula (sitting SBP/standing SBP) x 100. An orthostatic diastolic BP ratio was computed using the same method. Subjects with a SBP ratio > 100% had sitting SBP > standing SBP. We assessed the visit‐to‐visit BP postural changes variability according to several indicators: standard deviation, coefficient of variation (CV), variation independent of mean, residual standard deviation, average real variability, and successive variation. Cognitive performances were evaluated using the Mini‐Mental State Examination. Linear mixed models were used for the analyses.ResultWe included 2,974 subjects (mean age 78 years, women 56%). After adjustment for age, sex, education, baseline body mass index, smoking, alcohol intake, atrial fibrillation, congestive heart failure, transient ischemic attack or stroke, coronary artery disease, type 2 diabetes, dyslipidemia, seated SBP/DBP and antihypertensive treatment, greater visit‐to‐visit systolic BP postural changes variability was significantly associated with CD over time (adjusted β [95% CI] = ‐0.17 [‐0.29; ‐0.06], p = 0.004 for CV). Similar results were found for visit‐to‐visit diastolic BP postural changes variability (adjusted β [95% CI] = ‐0.14 [‐0.25; ‐0.03], p = 0.017 for CV).ConclusionGreater visit‐to‐visit BP postural changes variability was associated with CD. Further studies are needed to assess whether controlling orthostatic BP instability over time could be a promising interventional target to preserve cognition among older adults.
Polymorphisms in the WWOX gene are associated with brain glucose metabolism and influence cerebrospinal fluid p‐tau181 levels
Authors: Salles Giovanna Bortoluzzi , De Bastiani Marco Antônio , Povala Guilherme , Souza Diogo O. , Zimmer Eduardo R. , de Souza Débora Guerini 
Published: December 2022

AbstractBackgroundGenome‐wide association studies (GWAS) studies can be a powerful tool for identifying new single nucleotide polymorphisms (SNPs) associated with multifactorial diseases. Previous GWAS have identified more than 20 genes as potential factors of genetic susceptibility in Alzheimer’s disease (AD). One of them is the protein coding gene WW Domain Containing Oxidoreductase (WWOX), which is highly expressed in mature astrocytes and neurons. Here, we investigated the association between WWOX SNPs, 18F‐FDG PET neuroimaging and cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 181 (p‐tau181) in elderly individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).MethodsData was acquired from 537 participants (CU= 195; MCI= 314; AD= 28) of the ADNI database. The brain glucose metabolism was estimated using the standard uptake value ratio (SUVr, cerebellum as reference) of FDG‐PET. The presence of the SNPs were integrated to FDG PET images using voxel‐wise generalized linear regression models adjusted for age, gender, diagnostic status, and years of education (RMINC package). Through the Wilcoxon test we determined if the SNPs presence influenced p‐tau181 levels in CSF. All statistical analyzes were performed in the R statistical computing software (version 4.1.2) (significance level of p < 0.05).ResultsSixty‐seven WWOX SNPs were statistically associated with 18F‐FDG PET signal. Voxel‐wise analyses demonstrated that the top ten WWOX SNPs with the highest number of voxels altered in the FDG‐PET images were associated with cortical hypermetabolism (Figure 1, top three). Thirteen WWOX SNPs were significantly associated with lower p‐tau181 concentration in the CSF, including rs7193539 (p = 0.0004), rs7206890 (p = 0.0061), and rs11859281 (p = 0.0009), compared to the reference genotype.ConclusionSeveral SNPs of the WWOX gene were significantly correlated to brain metabolism. The presence of the SNPs can influence p‐tau181 levels, suggesting a role of WWOX in AD, as reported in other previous studies. Our findings suggest a protective effect of these WWOX gene variants. Additional studies are needed to better understand the biological implications of our findings.
Gait Correlates of Cognitive Function and Future Decline
Authors: Tipton Philip W , Ali Farwa , Syrjanen Jeremy A. , Graff‐Radford Neill R. , Machulda Mary M. , Fields Julie A. , Vemuri Prashanthi , Jack Clifford R. , Mielke Michelle M. , Boeve Bradley F. , Jones David T. , Graff‐Radford Jonathan , Knopman David S. , Petersen Ronald C. , Savica Rodolfo 
Published: December 2022

AbstractBackgroundSlow walking speed is associated with numerous negative health outcomes including global cognitive decline.1 More detailed gait analysis can differentiate among different dementia subtypes,10 but the predictive power of baseline gait metrics for domain‐specific cognitive decline needs further characterization.MethodWe conducted a follow up study on 534 participants of the Mayo Clinic Study of Aging who underwent evaluations every 15 months (median follow‐up = 5.4 years). We analyzed quantitative gait metrics, acquired with a pressure‐sensing walkway (GAITRite® instrument), and cognitive scores using a linear mixed effects model to identify correlations between z‐scored baseline gait metrics (cadence, swing time, stance time, velocity, double support time (DST), stride length, stride length standard deviation (SD), stride time SD, swing time SD, stance time SD, DST SD) and cognitive domain z‐scores (memory, attention, language, visuospatial, global) at baseline and over time. Models controlled for age, sex, and probable REM sleep behavior disorder at baseline.ResultThe table includes both baseline associations and difference in slopes (Δ), relative to the average person, in cognitive domains. These slopes ranged from about ‐0.05 for visuospatial to ‐0.12 for attention.ConclusionIncreased gait velocity and stride length are associated with less severe domain‐specific and global cognitive decline while increased swing time SD and DST are associated with more severe rates of decline in some domains. These findings suggest that baseline gait characteristics could be a helpful predictor of future cognitive changes.References:1. Savica R, Wennberg AMV, Hagen C, et al. Comparison of Gait Parameters for Predicting Cognitive Decline: The Mayo Clinic Study of Aging. Journal of Alzheimer's disease : JAD. 2017;55(2):559. doi:10.3233/JAD‐1606972. Mc Ardle R, del Din S, Galna B, Thomas A, Rochester L. Differentiating dementia disease subtypes with gait analysis: feasibility of wearable sensors? Gait & Posture. 2020;76:372–376. doi:10.1016/j.gaitpost.2019.12.028
Nurse Practitioner Follow‐Up Care Using Telehealth MMSE
Authors: Palumbo Mary Val , Greenough Victoria , Rambur Betty , Callas Peter W 
Published: December 2022

AbstractBackgroundDuring the COVID‐19 pandemic, many healthcare services moved to telehealth delivery for continuation of care. The Mini Mental Status Examination (MMSE) has been used for follow‐up assessment of disease progression and care planning after dementia diagnosis. Carotentuto et al. (2018) found no difference in MMSE scores when repeating a telehealth MMSE two weeks after a face‐to‐face visit. The purpose of this study was to determine if telehealth cognitive testing (MMSE) is a reliable alternative to traditional face‐to‐face testing when nurse practitioners are providing follow‐up care (every 6 months) for person with dementia and their families.MethodsTo evaluate MMSE testing administered via telehealth, a retrospective chart review of patients (N = 90) seen between April 2020 and December 2021 was conducted. Those fitting the inclusion criteria of at least two previous face‐to‐face MMSE assessments, and two MMSE telehealth assessments were analyzed (n = 45). Linear regression calculated the slope for each patient’s MMSE score per year to compare the face‐to‐face and telehealth rates of cognitive decline for each individual. A paired t‐test was used to compare MMSE slope for face‐to‐face and telehealth assessments.ResultsAlthough there was a larger decrease per year in MMSE score across telehealth assessments (during the pandemic) when compared to in‐person (‐2.7 vs ‐1.2, respectively), the difference in individual decline was not statistically significant (p = 0.10). There was also no significant difference between MMSE slope of decline in each of the two nurse practitioner providers for in‐person testing mean (p = 0.32), telehealth mean (p = 0.34) and difference in slopes (p = 0.27).ConclusionThese preliminary findings indicate that administering the MMSE via telehealth does not result in scores that are markedly different from in‐person testing. Therefore, it is reasonable to use telehealth for follow‐up dementia care visits when an objective measure of cognitive decline is helpful to guide family caregiving. Telehealth may be a good alternative for patients and family who are unwilling or unable to travel to the clinic due to health concerns, poor weather, long travel time or agitation in a clinic setting, even when the pandemic has ended.
Dyadic patterns of subjective cognitive reports as predictors of incident dementia
Authors: Numbers Katya T. , Lam Ben C. P. , Crawford John D. , Kochan Nicole A. , Sachdev Perminder S. , Brodaty Henry 
Published: December 2022

AbstractBackgroundSubjective cognitive decline (SCD), in the absence of impaired clinical testing, may be a clinical indicator of early Alzheimer’s disease (AD) and other dementias. However, not all individuals with SCD have cognitive decline. Corroboration of decline by an informant (i.e., close friend or family member) is one feature of SCD thought to increase the likelihood of preclinical AD. Few studies have examined whether different patterns of SCD in individuals and their informants are related to risk of dementia over time.MethodData from 628 dyads comprising participants (M = 78.65 years, 56.1% female) and their informants from the Sydney Memory and Ageing Study were analysed to determine whether different dyadic patterns of SCD recorded at baseline were associated with differential risk of incident dementia ten years later. Four groups were formed by categorizing participants’ and informants’ responses on a binary SCD measure at baseline: [1] both participant and informant NO (n = 180, 28.7%); [2] participant YES, informant NO (n = 232; 36.9%); [3] participant NO, informant YES (n = 41; 6.5%); [4] Both YES (n = 175; 27.9%). We compared incident dementia risk across these groups and conducted Cox regression adjusting for demographics, APOE4 status, mood, and personality.ResultFigure 1 shows the incidence dementia risk of the four groups. After controlling for covariates in the Cox regression, compared to Group 1, participants in Group 3 were at higher risk of incident dementia over 10 years (HR = 2.35, p = .020) as were participants in Group 4 (HR = 2.24, p = .004). Participants in Group 4 were at greater risk of incident dementia than participants in Group 2 (HR = 1.61 p = .034; see Table 1).ConclusionParticipants from dyads where both individuals endorsed SCD at baseline, and where the informant, but not the participant endorsed SCD, had a more than two‐fold increased risk of progressing to dementia over 10 years. Our results, though preliminary, highlight the value of collecting both self‐ and informant SCD ratings in research and clinical contexts and suggest that informant reports of SCD may be especially important for identifying pre‐clinical AD.
Sex and Race/Ethnic Differences in Risk Factors for Alzheimer’s Disease and Related Dementias: Implications for Prevention
Authors: Nianogo Roch A , Rosenwohl‐Mack Amy , Yaffe Kristine , Carrasco Anna , Hoffmann Coles M , Barnes Deborah E 
Published: December 2022

AbstractBackgroundWe previously estimated that 1 in 3 cases of Alzheimer’s disease and related dementias (ADRD) in the U.S. may be attributable to modifiable risk factors, the most important being physical inactivity, depression, and smoking. However, these estimates do not account for changes in risk factor prevalence over the past decade and do not consider potential differences based on sex or race/ethnicity. The objective of this study was to update and estimate the proportion of ADRD in the U.S. that are potentially attributable to modifiable risk factors and to assess for differences by sex and race/ethnicity.MethodWe estimated individual and combined population attributable risks (PARs) for ADRD for the following risk factors: physical inactivity, current smoking, depression, low education, diabetes, midlife obesity, midlife hypertension, and hearing loss. To account for non‐independence of the risk factors, we estimated their communality and uniqueness via principal component analysis. Risk factor prevalence and communality were determined using data from the nationally‐representative Behavioral Risk Factor Surveillance Survey (BRFSS) and relative risks for each risk factor were extracted from recent meta‐analyses. Respondents included 378,615 noninstitutionalized adults in the U.S., older than 18 years.ResultApproximately 1 in 3 (37%) cases of ADRD in the U.S. are potentially attributable to 8 modifiable risk factors, the most important of which are midlife obesity (17.7%, 95% CI: 17.5,18.0) physical inactivity (11.8%, 95% CI: 11.7, 11.9), and low educational attainment (11.7%, 95% CI: 11.5, 12.0). Combined PARs were higher for men (36%) than women (30%) and differed by race/ethnicity: Black (40%), Native Americans/Alaska Natives (39%), Hispanic (any race, 34%), White (29%), and Asian (16%). The most important modifiable risk factors, regardless of sex, were midlife obesity for Whites, Native Americans/Alaska Natives and Blacks; low education for Hispanics; and physical inactivity for Asians.ConclusionOur findings suggested that the major contributors to ADRD have changed over the past decade and differ based on sex and race/ethnicity. Therefore, Alzheimer’s disease risk reduction strategies may be more effective if they target higher‐risk groups and consider current risk factor profiles.
The Study of Neuronal Hyperactivity in the Early Stage of Alzheimer’s Disease
Authors: Yook Yeeun 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease, characterized by memory loss and cognitive impairment. The pathology of AD includes the accumulation of beta‐amyloid (Aβ) in the extracellular space and hyper‐phosphorylation of tau in neurons. Aβ pathology has been shown to begin approximately 20 years before tau pathology and mild cognitive impairment develop in AD patients. Aβ deposits cause alterations in brain function, leading to the loss of neurons in the cerebral cortex and hippocampus in the later stages of AD. However, the cellular mechanisms by which Aβ induces AD pathology remain largely elusive. Traditionally, lower neuronal activity has been thought to contribute to the synaptic failure and cognitive impairments observed in AD. However, recent studies suggest that Aβ triggers neuronal hyperactivity during the early stages of AD. Consistent with this observation, epileptic seizures have been detected in both mouse models of AD and human patients with Alzheimer’s. Uncontrolled or severe seizures can lead to further brain damage and exacerbate the cognitive decline seen in AD. Thus, neuronal hyperactivity could be one of the contributing factors to the neuronal loss induced by Aβ. However, it is unclear how Aβ can induce neuronal hyperactivity and seizures.MethodTo evaluate seizure susceptibility, we employed kainic acid‐induced seizures in a well‐established AD mouse model, the APP/PS1 mice. To measure neuronal activity, we employed primary cortical neuron cultures treated with a scrambled or Aβ 1‐42 peptide and recorded with a multi‐electrode array (MEA) recording system. Biochemistry and molecular biology assays were performed to study molecular players associated with Aβ‐induced neuronal hyperactivity.ResultOur data showed that acute Aβ treatment induces hyperexcitability in wild‐type (WT) cortical neurons. We also confirmed a higher susceptibility to seizures in APP/PS1 mice. Lastly, we identified a postsynaptic protein that is up‐regulated and potential involved in Aβ‐triggered neuronal hyperexcitability.ConclusionIn summary, our data are expected to provide insights into the etiology of AD‐associated brain hyperactivity and potentially suggest therapeutic targets for reducing seizures during early stage of AD.
Boosting Hippocampal Neurogenesis Rescues Cognitive Impairments in 3xTgAD Mouse Model of Alzheimer’s Disease
Authors: Lee Chi‐Chieh , Calegari Federico 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is an irreversible neurodegenerative disease with no treatment to date. Symptoms of AD include emotional disorders and memory impairments mainly resulting from dysfunction of the hippocampus, a brain area involved in learning, memory, navigation and regulation of mood. To attempt a rescue of hippocampal function in the disease, hippocampal neurogenesis was boosted in the Alzheimer’s mouse model.Method3xTgAD mice were injected with lentiviruses encoding for Cdk4/cyclinD1 (lenti‐4D) as a means developed by our group to enhance neurogenesis in the dentate gyrus. 3xTgAD mice with increased levels of adult‐born granule cells were then examined for behavioral and cognitive performance.ResultThe genetic manipulation by lenti‐4D system increased the number of neural stem cells and adult hippocampal neurogenesis (two‐fold) in dentate gyrus of 10‐month‐old 3xTgAD mice. The increased neurogenesis rescued some of the behavioral effects observed in 3xTgAD mice. In the open‐field test, the mice with new‐born neurons showed decrease of behavioural inhibition. In the Morris water maze, the same group of mice performed less anxiety behaviours and more perseverance, which indicates better memory.ConclusionIncreased neurogenesis by lenti‐4D system rescued some cognitive impairments in 3xTgAD mouse model of Alzheimer’s disease.