bluuebunny/crossref_metadata_2025_split huggingface dataset:
How do dementia risk differences between birth cohorts affect future incidence predictions: A microsimulation study
Authors: Brück Chiara C , Wolters Frank J , Ikram M. Arfan , de Kok Inge MCM 
Published: December 2021

AbstractBackgroundIn a recent coordinated analysis across population‐based cohorts, we have shown that the age‐specific dementia incidence has declined by 13% per decade since 1990. Here, we aim to incorporate these trends into the projection of the future dementia burden, using microsimulation models that can synthesise complex information, take time trends into account, and estimate long‐term and population wide intervention effects.MethodBased on the Microsimulation Screening Analysis (MISCAN) model from cancer research, we developed a dementia microsimulation model. It synthesises data from the population‐based Rotterdam Study with published disease stage durations from several mostly clinical cohorts. We incorporate changes in demographics by defining unique birth and life tables for every 10‐year birth cohort between 1910 and 1980. Three trend scenarios in age‐specific dementia incidence were calibrated to fit the observed incidence data from the Rotterdam Study: 1) no risk differences between birth cohorts; 2) a linear decline of 13% in incidence rate per birth cohort; and 3) two nonlinear declines that result in the same cumulative decline and average incidence rate as the linear trend. Projections of the dementia incidence in the Netherlands until 2050 were calculated for every trend scenario.ResultThe model simulated 10 million individuals, representative of the Dutch population in the 1910 to 1980 birth cohorts. The model was able to fit the observed incidence data well. Figure 1 shows the incidence projections for the Dutch population implementing the aforementioned trend assumptions. Assuming no trend results in the highest incidence projections, the linear trend results in the lowest, and the nonlinear trends lie in between. By 2050, compared to no decline, the linear and nonlinear trends result in 40% and 25‐35% fewer incidence cases.ConclusionAssumptions about the trend in incidence play a crucial role for the projections of the future dementia incidence, and subsequently prevalence and mortality. We developed a model that is well capable of projecting trends on future incidence. An application to the Dutch population projects 25‐40% lower incidence than currently assumed. Modelling the effect of interventions and risk changes on a population level provides essential information for policy makers and researchers.
Menopause and later‐life cognition: Findings from the longest‐running population‐based birth cohort
Authors: Needham Louisa , Lu Kirsty , Nicholas Jennifer M , Schott Jonathan M , Richards Marcus , James Sarah‐Naomi 
Published: December 2021

AbstractBackgroundAlzheimer’s Disease is more common in women than men. Menopause timing and type have been linked with cognition post‐menopause, but associations with dementia risk are unclear. Within the MRC National Survey of Health and Development (NSHD), childhood cognition predicts later‐life cognition and has largely explained menopause‐cognition associations post‐menopause. We now explore to what extent childhood cognition explains menopause‐cognition associations in later‐life and whether residual associations emerge.MethodProspective questionnaires at ages 43‐54 provided menopause age (years since birth until period cessation) and type (surgical/natural). Addenbrooke’s Cognitive Examination (ACE‐III) gave a measure of cognitive state at age 69 (maximum n=913). Cognitive domains were investigated using ACE‐III sub‐domains and cognitive tasks in a neuroimaging sub‐study (age 69‐71; maximum n=246) assessing memory, executive function, attention, visuospatial function, processing speed and non‐verbal reasoning. All cognitive outcomes were standardised. Multivariable regression analyses adjusted for relevant affective, early cognitive, sociodemographic, hormonal, health and genetic covariables, with multiple imputation of missing values using chained equations.ResultsMenopause associated with the following cognitive outcomes: total ACE‐III, ACE‐III verbal fluency, ACE‐III memory, ACE‐III visuospatial function, pre‐clinical Alzheimer’s cognitive composite, response inhibition, and intra‐individual variability in reaction times. Later menopause associated with better performance, while surgical menopause associated with worse performance. After accounting for childhood cognition, associations remained between menopause age and total ACE‐III (β=.012; 95% CI .001, .023), ACE‐III visuospatial function (β=.012; 95% CI .000, .023) and response inhibition (β=.034; 95% CI .008, .061), and between menopause type and response inhibition (β=‐.368; 95% CI ‐.665, ‐.070). With full adjustments, associations persisted between menopause age and ACE‐III memory (β=.011; 95% CI .000, .023). Intra‐individual variability in reaction times also remained associated with menopause age (β=‐.049; 95% CI ‐.079, ‐.019) and type (β=.413; 95% CI .076, .750).ConclusionIn later‐life, associations emerge between menopause and cognitive domains implicated in dementia (memory, processing speed, attention). Later menopause associates with better performance and surgical menopause with worse. Associations are not fully explained by known predictors of later‐life cognition including childhood cognition and other lifetime covariables accounted for. Further exploration of the link between menopause and dementia risk in women is warranted.
Regional abdominal adiposity is associated with BMI‐related brain regions in middle‐aged adults at high risk of Alzheimer’s dementia
Authors: Golan Sapir , Boccara Ethel , Ravona‐Springer Ramit , Inbar Yael , Yore Iscka , Heymann Anthony , Beeri Michal Schnaider 
Published: December 2021

AbstractBackgroundThere is evidence for the involvement of midlife obesity in mild cognitive impairment (MCI), dementia, and Alzheimer’s dementia (AD) risk in late life. Obesity is primarily measured by body mass index (BMI), which poorly reflects body fat distribution. Regional abdominal adiposity has been related to inflammation and metabolic syndrome, both consistently linked to the neuropathology of AD and related disorders (ADRD). We examined the relationship between regional abdominal adiposity and regional brain volume, among middle‐aged adults enriched for AD risk due to parental history of AD.MethodParticipants were from the Israel Registry for Alzheimer’s Prevention (IRAP), which follows middle‐aged offspring of AD patients (N=390). At this time, 44 participants (Table 1) were scanned, via magnetic resonance imaging (MRI), for regional abdominal adiposity, including hepatic, pancreatic, and abdominal adipose tissues (AAT, visceral (VAT), and subcutaneous (SAT)). T1‐weighted volumetric brain MRI focused on three regions implicated in obesity and cognitive impairment: para‐hippocampus, amygdala, and inferior frontal gyrus (IFG). Following logarithmic normalization, linear regression was used to examine the association of regional abdominal fat with brain volume adjusting for age, sex, education, and intracranial volume. An additional adjustment for BMI was done to examine whether the associations are above and beyond global adiposity.ResultSmaller amygdalar volume was associated with the percentage of VAT fat (r=‐0.324, p=0.044) and approached significance for pancreatic (r=‐0.283, p=0.08) and hepatic (r=‐0.307, p=0.057) fat. A smaller para‐hippocampal volume was associated with the percentage of pancreatic fat (r=‐0.317, p=0.05) and hepatic (r=‐0.447, p=0.004) fat, and approached significance for VAT fat (r=‐0.309, p=0.056). Fat percentage was not associated with IFG volume (Table 2; Figure 1).ConclusionGreater regional abdominal adiposity was associated with higher amygdalar and para‐hippocampal volumes, already in midlife, regardless of global body adiposity measured by BMI. Regional adiposity affects secreted factors relevant to brain function, suggesting an underlying mechanism. By AAIC 2021, we anticipate 100 IRAP participants will be assessed for regional abdominal adiposity, blood‐based related secreted factors, and brain MRI. These data may lead to the development of age‐specific interventions targeting specific adipose depots, which are expected to prevent or delay neuropathology, cognitive decline, and ultimately AD.
Cerebrospinal fluid and saliva lactoferrin as a diagnostic biomarker for Alzheimer’s disease in a mixed memory clinic population
Authors: Gleerup Helena Sophia , Jensen Camilla Steen , Høgh Peter , Hasselbalch Steen Gregers , Simonsen Anja Hviid 
Published: December 2021

AbstractBackgroundThe pathological changes in Alzheimer’s disease (AD) and other neurodegenerative disorders begin decades prior to their clinical expression. However, the clinical diagnosis of neurodegenerative dementias is not straightforward. Saliva is an easily obtained source of biomarkers, and previous studies have shown that biomarkers such as amyloid 1‐42 (Ab42), tau, lactoferrin and selected metabolites could be potential biomarkers for the diagnosis of AD and other neurodegenerative dementias. Lactoferrin is an iron‐binding, antimicrobial glycoprotein with a plethora of functions, including acting as an important immune modulator and by having a bacteriocidic effect, all factors which have been shown to be involved in the development and progression of AD. Two previous studies indicated that salivary lactoferrin could differentiate between neurodegenerative dementias. For the first time, lactoferrin levels were measured in the cerebrospinal fluid (CSF) in a consecutive cohort of patients from two memory clinics, and furthermore salivary lactoferrin was evaluated for its differentiation between AD and other neurodegenerative dementias.MethodFrom two mixed, memory clinic cohorts, 222 CSF and saliva samples from 71 patients diagnosed with AD, 56 patients diagnosed with mild cognitive impairment (MCI), 75 patients diagnosed with non‐AD dementia and 20 subjects classified as healthy controls (HC), were analysed for lactoferrin. In addition, the association between lactoferrin in CSF and saliva and the concentrations of tau, phosphorylated tau (p‐tau) and amyloid 1‐42 (Ab42) in CSF were addressed.ResultThere was no correlation between CSF and saliva lactoferrin. Furthermore, no statistically significant differences were found in the levels of CSF or saliva lactoferrin between the diagnostic groups. In addition, no significant relationships were found between lactoferrin levels and tau, p‐tau and Ab42, respectively.ConclusionFor the first time, CSF lactoferrin levels were assessed in mixed memory clinic cohorts. Although lactoferrin levels were quantifiable in CSF and saliva, neither CSF nor saliva lactoferrin could differentiate between neurodegenerative dementias in this study.
Fish intake and MRI burden of cerebrovascular disease in older adults
Authors: Thomas Aline , Crivello Fabrice , Mazoyer Bernard , Debette Stéphanie , Tzourio Christophe , Samieri Cécilia 
Published: December 2021

AbstractBackgroundCerebrovascular disease (CVD), a major contributor of cognitive aging, is characterized by subclinical damage visualized on brain MRI, including covert brain infarcts, white matter hyperintensities (WMH) and dilated perivascular spaces (dPVS). Few protective factors for brain vascular health, that may help prevent stroke and dementia, have been identified so far. Fish intake may prevent ischemic events and small vessel disease. When investigating factors with a pleiotropic effect such as fish, there is interest to capture pathophysiological burden globally, combining biomarkers into a single metric. Here, we investigated the association of fish intake with a global indicator of the MRI burden of CVD among older adults.MethodThis Three‐City Dijon study included 1,623 participants (≥65 years) without history of dementia, stroke or cardiovascular disease, who had completed a Food Frequency Questionnaire and underwent brain MRI with automated assessment of WMH, visual detection of covert infarcts, and grading of dPVS. A global indicator of CVD burden was estimated using a factorial analysis of mixed data; association of fish intake with the indicator was assessed by adjusted linear regression.ResultThe proportions of participants consuming fish less than once a week, once a week, 2 to 3 times and more than 4 times per week were 11%, 37%, 47% and 6%, respectively. The continuous CVD burden indicator, derived from the first dimension of the factorial analysis (32.4% of explained variance), was associated with a higher WMH load, more infarcts and higher dPVS severity. Higher fish intake was associated with a lower CVD burden indicator (P for trend <0.001). Compared to participants consuming fish less than once a week, the CVD indicator decreased by ‐0.19 units (95% CI, ‐0.37; ‐0.005) for those consuming fish 2‐3 times per week and by ‐0.31 units (‐0.59; ‐0.03) for ≥4 times per week. These effect estimates of eating fish at least twice a week were equivalent to having a 4 to 5 years younger brain in terms of vascular health (β = 0.05 units (0.03; 0.06) for each one year increase of age).ConclusionFish consumption may promote brain vascular health before manifestation of overt brain disease.
Objective home sleep profiles differentiate Alzheimer disease from α‐synucleinopathies
Authors: Levendowski Daniel J. , Boeve Bradley F. , Neylan Thomas , Walsh Christine M. , Tsuang Debby W. , Salat David H. , Hamilton Joanne M. , Ruoff Leslie , Payne Sarah , Shprecher David , Lee‐Iannotti Joyce , Westbrook Philip R. , Berka Chris , Mazeika Gandis , St. Louis Erik K. 
Published: December 2021

AbstractBackgroundNeurodegenerative disease (NDD) is associated with sleep disturbances, including decreased stage N3 and REM sleep and reduced spindle activity. Further, supine sleep position may impact NDD risk by altering glymphatic clearance. This study evaluated conventional and exploratory sleep metrics in the differentiation of subjects with normal cognition (NC) and patients with Alzheimer’s disease dementia (AD) and alpha‐synucleinopathies (α‐Syn).MethodHome sleep data were acquired across multiple study sites using the self‐applied Sleep ProfilerTM, including 44 NC subjects (age=69+5.0), 22 patients diagnosed with AD (age=75+7.1) and 25 with α‐Syn (Parkinson’s disease=14, Parkinson’s disease with Dementia or Dementia with Lewy Bodies=11; age=69+6.9). Recordings were auto‐staged and technically reviewed, with 86% of the records having two‐night averages. Logistic regression and Mann‐Whitney U tests were used to characterize group differences based on age, conventional sleep metrics (i.e., sleep efficiency, sleep onset (SO), awakenings, percent of sleep time (%) in REM,N1, N2 and N3, and sleep spindles) and exploratory sleep measures [i.e., % supine, % Light N2 (L2=N2 epochs absent of spindles with K‐complexes and/or alpha or EMG (>40 Hz) intrusion), % NREM sleep with hypertonia (NRSH=>4 consecutive epochs with persistently elevated EMG power relative to delta and theta power) and % atypical N3 (AN3=epochs staged N3 with low theta and sigma power relative to delta, alpha, beta and EMG)].ResultAD were older than both NC and α‐Syn patients (p<0.005). Both AD and α‐Syn had lower %REM and greater %supine than NC (p<0.005), and %NRSH was greater in α‐Syn than NC or AD (p<0.005). Based on logistic regression, AD was differentiated from NC based on age, %REM, %L2 (p<0.05) and %supine (p=0.06). α‐Syn was distinguished from NC using both conventional (%N3 and SO, p<0.05) and exploratory sleep metric (%AN3 and %NRSH, p<0.05; %supine, p=0.06). Age (p=0.05) and %NRSH (p<0.01) were the only metrics that differentiated α‐Syn from AD.ConclusionObjective home sleep profiles hold promise for differentiating NDD patients from NC. The sleep metrics that provided the greatest distinction between NDD and NC were %REM, %supine and NRSH, while only NRSH distinguished AD from α‐Syn patients. Further confirmatory studies are underway.
Supporting anti‐tau antibody trials using computer simulation of spatial tau propagation
Authors: Geerts Hugo , Rose Rachel , Walker Mike 
Published: December 2021

AbstractBackgroundAlthough tau pathology is a major driver of AD pathology, the mere complexity of tau biology significantly hampers the identification and validation of the most impactful target. Recent clinical trials using antibodies against various forms of tau have come up short in improving cognitive readout.MethodA Quantitative Systems Pharmacology computer platform of tau biology has been developed including tau species diversity, neuronal activity‐dependent tau secretion, tau binding to membrane surface receptors, subsequent internalization at the synaptic cleft and along the axonal membrane following a diffusion gradient, slow motor‐mediated axonal transport, intracellular degradation and templating of monomeric tau by seed‐competent tau to form higher‐order aggregates. Polysynaptic progression is implemented by modeling secretion from the first synapse and uptake in the second axon.ResultThe platform was calibrated to reproduce preclinical experiments from in‐vitro cellular assays and after injection of brain extract in Tg models. The model is humanized using published data on seed‐competent tau from postmortem AD brain at different Braak stages and spatio‐temporal progression over neuronal projections. By exploring the effect of target mediated drug disposal of antibodies, we show that depending upon the disease state only between 15 and 30% of misfolded tau protein can be captured by antibodies currently in clinical trials. Introducing PSP specific uptake parameters from preclinical experiments, the simulations suggest an even lower efficacy due to the higher affinity of PSP‐tau for membrane surface receptors. We further identify conditions under which specificity (i.e. monomeric vs misfolded tau) of antibodies outweigths sensitivity (affinity). Finally, the simulations suggest that reduced oligomerization and increased degradation have a greater impact on the accumulation of seed‐competent tau in distal regions, likely because they act during the long intracellular residence of misfolded tau protein.ConclusionAdvanced Quantitative Systems Pharmacology computer modeling combining drug exposure with mechanistic modeling allows to ‘humanize’ preclinical experiments and aims to support tauopathy R&D projects.
Sleep and hippocampal function during an associative memory task are influenced by surgical menopause at midlife
Authors: Brown Alana , Gervais Nicole J. , Gravelsins Laura , Nicoll Gina , Rieck Jenny , Almey Anne , Sun Dorothy Leqi , Ge Jennifer Xiangning , Laird Kaz , Reuben Rebekah , Karkaby Laurice , Perovic Mateja , Grady Cheryl , Einstein Gillian 
Published: December 2021

AbstractBackground17β‐estradiol loss is related to Alzheimer’s disease (AD) risk factors, including disordered sleep and associative memory decrements (Gervais et al., 2017; Rentz et al., 2017). Women have higher risk for AD than men, and those with mid‐life 17β‐estradiol loss due to surgical menopause, including bilateral salpingo‐oophorectomy (BSO) before age 48, have even higher risk (Rocca et al., 2007). Our learning objective was to investigate whether sleep and associative memory in women with BSO (mean age 44‐46) would be comparable to those with spontaneous/natural menopause (SM; mean age 57), and whether 17β‐estradiol‐based hormone therapy (ET) might mitigate these effects.MethodWe assessed sleep using the average of three nights of portable polysomnography (Temec) in women with BSO either taking ET (BSO+ET; n=16), or not (BSO; n=18), and in older spontaneously menopausal women (SM; n=14). Using EEG (Fp1‐Fp2), we obtained sleep staging automatically (Neurobit Technologies). Participants also completed a face‐name associative memory task during functional magnetic resonance imaging. Recognition accuracy and brain activation during encoding were measured.ResultBSO exhibited reduced sleep efficiency compared to BSO+ET. For BSO, there was no relationship between percent of total sleep time in N3 and hippocampal activation during associative encoding, even though percent of total sleep time in N3 was negatively associated with hippocampal activation during associative encoding in BSO+ET. For all groups, including BSO, lower latency to consolidated N3 correlated with better associative memory accuracy. There were no group differences in associative memory accuracy. In contrast to BSO, SM showed significantly longer latency to consolidated N3 than BSO+ET.ConclusionYounger women with BSO have comparable sleep to older women in SM. In younger women with BSO, ET improves sleep efficiency. Further, while associative memory may be disrupted by increased latency to consolidated N3 in all women, BSO and BSO+ET showed similar associative memory accuracy and latency to consolidated N3. Only BSO+ET exhibited a significant correlation between hippocampal activity during associative encoding and time spent in N3, indicating that ET may support the negative relationship between N3 and hippocampal function. Overall, ET in younger women with BSO potentially ameliorates poor sleep and associative memory decrements.
Multimodal evaluation of the melanopsin retinal ganglion cells system in relation to circadian rhythms in Alzheimer’s disease and aging
Authors: La Morgia Chiara , Mitolo Micaela , Santoro Aurelia , Romagnoli Martina , Maserati Michelangelo Stanzani , Evangelisti Stefania , De Matteis Maddalena , Palombo Flavia , Bacalini Maria Giulia , Capellari Sabina , Carbonelli Michele , Park Jason C. , Liguori Rocco , Tonon Caterina , Lodi Raffaele , Carelli Valerio 
Published: December 2021

AbstractBackgroundMelanopsin retinal ganglion cells (mRGCs) are deputed to circadian photoentrainment and pupillary light reflex (PLR) regulations. Circadian dysfunction is reported in Alzheimer’s disease (AD) and contributes to dementia. Single‐Nucleotide‐Polymorphisms (SNPs) in clock genes have been associated to AD.MethodWe included 29 mild‐moderate AD and 26 matched controls performing neuroophthalmological evaluation including optical coherence tomography (OCT), actigraphic recordings of rest‐activity rhythms, chromatic pupillometry and brain functional MRI (fMRI) with light stimulation. 84 clock genes were analyzed by NGS and relevant SNPs validated in a larger cohort of AD (n=449) and controls (n=326).ResultIn AD disease duration was 3.9±2.8 years and MMSEc score 20.2±4.2. OCT showed a significant reduction of the infero‐temporal GCL thickness (p=0.036) in AD. Actigraphy did not disclose significant differences for circadian parameters (IS, IV, RA). However, a subgroup of “circadian‐impaired” AD was evident, and most of circadian parameters declined with aging. Pupillometry revealed a significant reduction of PLR peak amplitude in the rod protocol (p=0.006) significantly correlating with aging in AD. Brain fMRI documented the absence of significant responses in AD with sustained blue light stimulation at difference with controls. Genetic analysis in extended AD and control cohorts showed a significant association of the rs30127178 SNP in PER1 gene with AD.ConclusionThese results demonstrate, by innovative multi‐modal approach, that mRGC system in AD is affected by neurodegeneration. This can be envisaged as a possible biomarker also for conversion from MCI to AD with potential implication for light therapy as a counteracting measure for dementia.