bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ischemia‐triggered, immune‐mediated neurodegeneration as a component of VCID
Authors: Buckwalter Marion S 
Published: December 2021

AbstractBackgroundPost‐stroke cognitive decline is an important component of vascular dementia. Ischemia and vascular disease is present in the brains of the majority of both Alzheimer’s Disease and VCID cases, and brain ischemia alone, in the form of a clinical stroke, doubles the risk of later cognitive impairment independently of known vascular dementia risk factors. In stroke survivors one of the most distressing complications is post‐stroke cognitive decline, which occurs in up to a third of individuals within five years and impacts significantly on quality of life.MethodsTo disentangle the effects of ischemia from other vascular mechanisms of dementia, we utilize mouse models of post‐stroke cognitive decline in adult and aged mice, mouse behavior, immunohistochemistry, and gene expression. In addition, we utilize prospective longitudinal cohort studies in human stroke survivors to examine how immune phenotyping of peripheral blood predicts cognitive decline at one year and chronically.ResultsWe found that normal wildtype mice develop delayed cognitive decline after stroke that is associated with a chronic neuroimmune response characterized by B and T lymphocyte infiltration of the stroke. Both genetic and drug studies demonstrate that B lymphocytes are necessary for post‐stroke cognitive decline. In humans with stroke and dementia, we find similar B and T cell infiltration. In a prospective longitudinal cohort of stroke survivors tested with a comprehensive cognitive test battery we see a high rate of cognitive impairment in at least one cognitive domain among the participants. In keeping with an autoimmune‐like mechanism, humans with immune alterations in the acute phase after stroke are more likely to have cognitive decline after stroke.ConclusionsTaken together we have demonstrated that normal mice exhibit ischemia‐triggered immune‐mediated neurodegeneration after stroke. Human studies demonstrate similar mechanisms, however more work remains to be done to identify immune mechanisms and biomarkers that predict cognitive decline in living humans after stroke. It will then be important to determine how much these post‐ischemia maladaptive immune responses contribute to VCID.
Small vessels in the brain and heart: How similar are they?
Authors: Hortobagyi Tibor 
Published: December 2021

AbstractBackgroundIn the brain and heart alike blood vessels are end arteries and their occlusion results in anaemic infarct with high mortality and severe morbidity in a high proportion of survivors. The role of collateral circulation and early recanalization is crucial in both contexts. Ischaemic preconditioning, reperfusion injury and haemorrhagic transformation are three key pathophysiological processes in both organs and the morphological and molecular processes at the level of microcirculation are fundamental to understand and therapeutically modulate the effects of ischaemia.MethodThe morphology of small vessels in brain and heart are compared based on published literature and pathologically assessed cases. The similarities and differences are related to the morphological and molecular consequences of hypoperfusion and vascular occlusion at the level of small vessels and microcirculation. In a case series, we retrospectively analysed the clinical data of 158 patients in a regional centre for acute stroke care. For clinico‐pathological analysis 98 cases (age 62±6.5y) were suitable.ResultAlthough small vessels and the microcirculation share morphological and molecular similarities in health and in response to ischaemic challenge, the specific and unique features of the blood‐brain barrier and the neurovascular unit in the brain are major differences, with implications for drug transfer to the ischaemic parenchyma. Haemorrhagic transformation accelerates the secondary progression of stroke and indicates higher risk of adverse outcome. Neurodegenerative changes impair the microcirculation and, vice versa, microcirculatory damage and dysfunction may trigger and accelerate the neurodegenerative cascade. Vascular and neurodegenerative mechanisms in dementia usually coexist. The morphological patterns of infarct evolution and healing are rather different in the brain and the heart, which also applies to the characteristics of the inflammatory cell composition.ConclusionOur findings underline the importance of post‐mortem pathological examination in the era of advanced imaging and laboratory diagnostic techniques. The fundamental differences in the histomorphology and in the sequence of cellular and molecular events during ischaemia and reperfusion in brain and heart indicate that adaptations of findings in cardiology and clinical neuroscience should be made with caution.
Clinical trial of neuroEPO in mild‐to‐moderate Alzheimer’s disease
Authors: Pérez Leslie , Sosa Saily , Valenzuela Carmen , Bringas Giosmany , Urrutia Nelky , Peñalver Ana Ibis , Dalmau Evelio , Fernández Ana , Obaya Teresita Rodriguez 
Published: December 2021

AbstractBackgroundNeuroEPO, a nasal pharmaceutical solution of recombinant human erythropoietin with low sialic acid, was in clinical development for the treatment of mild‐moderate Alzheimer’s disease.MethodA double‐blind, randomized, placebo‐controlled, multicenter, prospective, with adaptive design, phase II/III clinical trial involving 174 patients with mild‐to‐moderate Alzheimer’s, was conducted. NeuroEPO or placebo, with different doses, was administered by nasal route 3 times a weeks for 48 weeks. The primary outcome measure was score on the 11‐item cognitive subscale of the Alzheimer’s disease Assessment Scale (ADAS‐cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment). Secondary outcome measures included Clinician’s Interview‐Based Impression of Change Plus Caregiver Input (CIBIC‐plus), Global Dementia Scale (GDS), activities of daily living (ADL), hippocampal volume change over time (measured with MRI), neuropsychological scales, electroencephalography (EEG) and adverse events.ResultThere were statistically significant differences between neuroEPO and placebo in median change from baseline in the primary outcome at week 48. The change in ADAS‐cog11 scores final‐initial (PP population) for patients in the neuroEPO 0.5 mg (n= 50, median change: ‐ 4.0), neuroEPO 1.0 mg (n=49, median change: ‐ 5.0) and placebo (n=49, median change: 4.0) groups. A difference of 8.0 points CI 95% (6.0; 10.0) neuroEPO 0.5 mg vs. placebo and 9.0 points CI 95% (6.8; 11.2) neuroEPO 1.0 mg vs. placebo at week 48, (p=0.000), was observed. Patients receiving both doses of neuroEPO also showed a significant difference in global improvement (CIBIC‐Plus, p=0.000) and electroencephalography (EEG, p=0.003) compared with placebo group. About hippocampal volume change, 105 patients were analyzed. From them, 58% remained stable and 42% decline hippocampus volume. No serious adverse events related with neuroEPO were reported.ConclusionNeuroEPO improved clinical outcomes in patients with Alzheimer’s disease with good security profile. Therefore, it could be useful in the treatment of these kind of patients.
The longitudinal association of vision impairment with transitions to cognitive impairment and dementia
Authors: Ehrlich Joshua R , Swenor Bonnielin K , Zhou Yunshu , Langa Kenneth M 
Published: December 2021

AbstractBackgroundVision impairment (VI) has been identified as a potentially modifiable risk factor for dementia. However, it is not known at what stage of cognitive decline VI exerts an effect. The purpose of this study was to determine whether VI increases the risk of transitions from normal to cognitive impairment no dementia (CIND) and/or from CIND to dementia. These findings may inform understanding of mechanistic processes, as well as the development and implementation of future dementia prevention interventions.MethodWe used longitudinal data including visual acuity and cognitive status from the population‐based Aging, Demographics and Memory Study (ADAMS), a sample drawn from the U.S. Health and Retirement Study. The covariate‐adjusted associations between VI (binocular distance visual acuity <20/40) and odds of cognitive transitions (normal to CIND, CIND to dementia) were evaluated using a series of multivariable logistic regression models.ResultA total of 351 ADAMS participants without dementia at baseline were included (49.6% female, mean age 79.3 years, 21.7% with VI). Of these, 92 participants transitioned from normal to CIND and 76 transitioned from CIND to dementia during the course of the study. The odds of a transition from normal to CIND were 2.7 (95% CI 1.0‐7.5) times greater among those with VI, whereas the odds of a transition from CIND to dementia were not significantly associated with VI (OR= 0.8, 95% 0.4‐1.8).ConclusionThis study indicates that poor vision is associated with transitions from normal to CIND but not from CIND to dementia, suggesting that the impact of VI is greatest early in the process of cognitive decline.
Transcriptomic score: A biomarker index of Alzheimer’s risk and resilience
Authors: Hou Jiahui , Hess Jonathan , Glatt Stephen 
Published: December 2021

AbstractBackgroundOne definition of resilience is the absence of disease despite high levels of risk. And in most cases, risk itself is best quantified by a multivariate profile rather than a single risk factor. Thus, multivariate risk profiles may be most appropriate for defining risk and resilience. RNA expression may serve as a risk biomarker, but no method has been proposed to build a whole‐transcriptome risk index of Alzheimer’s disease (AD) that could identify resilient individuals at the highest transcriptomic risk. Here, we derived a novel method for transcriptome‐wide gene expression data called “transcriptomic risk score” (TRS). We also employed the algorithm to build a “transcriptomic resilience score” (TReS) that offsets that risk.MethodAnalogous to a polygenic risk score, TRS is a weighted rank‐sum statistic that represents a subject’s relative expression level across the transcriptome, where the standardized beta coefficients are used as weights. We leveraged the TRS approach on peripheral blood gene expression profiles of 364 normal controls and 188 AD cases from ADNI and AddNeuroMed batch 1. Using TRSas a means of risk quantification, we then identified resilient normal controls as those with the highest percentiles of risk. High‐risk AD cases with matched TRSs range were retained for comparison. Expression levels of individual transcripts not included in the best‐fit TRS were contrasted between the high‐risk normal controls and high‐risk AD cases using mixed‐effect linear models. A TReS was derived using the residual transcriptomic variation that buffers against the transcriptomic risk. The association between TReS and case status was evaluated using a logistic regression model.ResultThe derived TReS differentiated resilient subjects (high‐risk normal controls) and high‐risk AD cases in independent replication samples (216 normal controls and 223 AD cases), with significant differentiation seen at all evaluated p‐value bins and a maximum of 3% variance accounted for at a p‐value threshold of 0.1.ConclusionThis analysis indicated that TRS and TReS analysis of blood has the potential of facilitating the understanding of phenotypic variability and improving clinically useful biomarker profiles for AD.
Development and validation of the Yonsei Lifestyle Profile‐Satisfaction (YLP‐S) using the Rasch measurement model
Authors: Park Kang‐Hyun , Park Ji‐Hyuk , Hong Ickpyo 
Published: December 2021

AbstractBackgroundLifestyle also plays an important role in determining health and vitality among older adults. However, there is limited evidence about the lifestyle assessment. This study examined the psychometric properties of the Yonsei Lifestyle Profile‐Satisfaction (YLP‐S),MethodParticipants comprised community‐dwelling elderly from South. A confirmatory factor analysis (CFA) examined the unidimensionality assumption of the YLP‐S. Construct validity was tested by analyzing the item difficulty hierarchy, and item invariance was examined using differential item functioning (DIF) across sex and age. Participants comprised community‐dwelling elderly from South. A confirmatory factor analysis (CFA) examined the unidimensionality assumption of the YLP‐S. Construct validity was tested by analyzing the item difficulty hierarchy, and item invariance was examined using differential item functioning (DIF) across sex and age,ResultAmong 156 participants, 54 were males and 102 females. The CFA demonstrated that meaningful activity participation and nutrition subscales met the unidimensionality assumption. There was conceptual item difficulty hierarchy among the test items. The person strata values of the meaningful activity participation and nutrition were 5.37 and 1.33. Four items were showed showing DIF according to sex or age groups.ConclusionThe findings indicate that the YLP‐S demonstrated sound internal validity and it can be used for occupational therapists to measure multi‐faceted lifestyle of older adults.
Monitoring dementia and stroke comorbidity in Canada: Prevalence and mortality time trends among individuals aged 65+, from 2003–2004 to 2016–2017
Authors: Shaver Larry C , Toews Jennette , Plebon‐Huff Sieara , Pelletier Catherine , Robitaille Cynthia , Mcrae Louise 
Published: December 2021

AbstractBackgroundDementia and stroke are debilitating and interrelated conditions. This study describes the time trends in prevalence and mortality of comorbid stroke and dementia in Canada, among individuals aged 65+.MethodUsing data from the Canadian Chronic Disease Surveillance System (CCDSS) for Canadians aged 65+, Joinpoint analyses were conducted to estimate change over time (2003–2004 to 2016–2017) in the age‐standardized prevalence and all‐cause mortality of comorbid dementia and stroke. Validated case definitions were applied to longitudinal CCDSS linked administrative health data to identify comorbid cases (regardless of the sequence of disease identification). Diagnosed cases for both conditions were identified since 1996–1997, but a run‐in period was applied until 2003–2004 to allow a better capture of prevalent cases. Time trends were significant (unless otherwise noted), but differences between sexes were not significant.ResultFrom 2003–2004 to 2016–2017, the age‐standardized prevalence of the comorbidity increased from 1.4% (∼64,000 individuals) to 1.7% (∼110,000 individuals), representing an average annual percent change (AAPC) of 1.1% (females: 1.0%; males: 1.3%). The increase was more pronounced at the beginning of the period and among those aged 80‐84, 85‐89 and 90+. In contrast, during the same period, the age‐standardized prevalence rate among individuals with dementia/without stroke increased with an AAPC of 1.5% (females: 1.5%; males 1.7%), but only with an AAPC of 0.2% (not statistically significant) among those with stroke/without dementia.Following the general declining mortality pattern observed in the Canadian population, the age‐standardized all‐cause mortality rate for those with the comorbidity decreased (AAPC ‐1.4%; females: ‐1.2%; males: ‐1.7%), with a steeper reduction over the first portion of the period. However, Canadians without the comorbidity benefited from a greater decline in all‐cause mortality (AAPC ‐2.2%; females: ‐2.1%; males: ‐2.5%).ConclusionThis surveillance analysis explores the prevalence and all‐cause mortality of dementia and stroke comorbidity, by highlighting its evolution over time in older Canadians. Although further research is needed to explain the drivers of these trends, such public health surveillance data can inform health care policies and programs. Other countries could consider the CCDSS model for enhancing surveillance of dementia and its comorbidities.
Cardiometabolic multimorbidity accelerates cognitive decline and progression to dementia in older adults
Authors: Dove Abigail , Marseglia Anna , Shang Ying , Vetrano Davide Liborio , Grande Giulia , Laukka Erika J , Fratiglioni Laura , Xu Weili 
Published: December 2021

AbstractBackgroundThough cardiometabolic disorders (CMDs; including type 2 diabetes, heart disease, and stroke) have been individually associated with cognitive decline, their combined effect on the prodromal phase of dementia is unknown. We aimed to examine the extent to which CMD multimorbidity is associated with cognitive decline and the risk of cognitive impairment–no dementia (CIND) and its progression to dementia.MethodWithin the Swedish National Study on Aging and Care–Kungsholmen, 2934 dementia‐free adults aged ≥60—consisting of a cognitively intact (n=1821) and a CIND (n= 685) cohort—were followed over 12 years. At baseline and each follow‐up (every 3 or 6 years), participants were administered the Mini‐Mental State Examination (MMSE) and a neuropsychological test battery. CIND was defined as having no dementia and performance ≥1.5 SDs below age group‐specific means in at least one cognitive domain (episodic memory, processing speed, executive function, verbal fluency, or visuospatial ability). Dementia was diagnosed according to DSM‐IV criteria. CMDs were ascertained based on clinical examination, medication use, national patient registry data, and laboratory and instrumental tests. CMD multimorbidity was defined as the presence of ≥2 CMDs. Data were analyzed using multi‐adjusted linear mixed models, Cox regression, and Laplace regression, with adjustment for sociodemographic and vascular risk factors.ResultOf all participants, 813 (27.7%) had one, 221 had two (7.5%), and 23 (0.8%) had three CMDs at baseline. Compared to no CMDs, the presence of one (β= ‐0.22, 95% CI: ‐0.28 to ‐0.15), two (β= ‐0.28, 95% CI: ‐0.40 to ‐0.16), and three (β= ‐0.40, 95% CI: ‐0.77 to ‐0.03) CMDs was related to accelerated MMSE decline in a dose‐dependent fashion (p<0.001). In Cox models, CMD multimorbidity was associated with nearly double the risk of both CIND (hazard ratio [HR] 1.71, 95% CI 1.22‐2.41) and the progression of CIND to dementia (1.89, 95% CI 1.17‐3.04). Furthermore, CMD multimorbidity anticipated the onset of CIND by 2.5 years and its progression to dementia by 2.2 years.ConclusionCardiometabolic multimorbidity accelerates cognitive decline and increases the risk of CIND and dementia, anticipating the occurrence of both CIND and dementia by more than two years.
Retinal parameters, cortical microinfarcts and functional cognitive impairment
Authors: Hilal Saima , Cheung Carol Y. , Wong Tien Yin , Cheng Ching Yu , Schmetterer Leopold , Chen Christopher 
Published: December 2021

AbstractBackgroundQuantitative changes in retinal vessels and thinning of optic nerves have been associated with subclinical and clinical age‐related brain pathologies. However, data on the association between both retinal vascular and neuronal parameters with cortical cerebral microinfarcts and how these factors jointly contribute to functional cognitive impairment is lacking. We investigate the association of retinal vascular and neuronal changes with cortical CMIs on 3T MRI and to explore their interaction in relation to functional cognitive impairment in a memory‐clinic population.MethodA total of 538 participants (mean age:72.6±7.8 years) were included. Retinal vascular parameters (caliber, tortuosity, fractal dimension) were measured from retinal fundus photographs using a semi‐automated computer‐assisted program. Retinal nerve fiber layer (RNFL) and ganglion cell‐inner plexiform layer (GC‐IPL) thicknesses were obtained from spectral domain‐optical coherence tomography. Cortical CMIs were defined as hypointense lesions on T1‐weighted images, <5mm in diameter, restricted to the cortex, and perpendicular to the cortical surface. Functional cognitive impairment was assessed on Clinical Dementia Rating Sum‐of‐Boxes (CDR‐SoB) score.ResultLarger venular caliber (Rate ratios (RR):1.21, 95%CI:1.03‐1.42), increased venular fractal dimension (RR:1.25, 95%CI:1.07‐1.46), increased venular tortuosity (RR:1.08, 95%CI:1.02‐1.15) and thinner GC‐IPL (RR:1.22, 95%CI:1.12‐1.32) were associated with increasing CMI counts. A significant interaction term was found between venular fractals, venular tortuosity, thinner GC‐IPL and RNFL and cortical CMIs (p<0.05) on CDR‐SoB scores. Among individuals in highest tertile of retinal parameters, a significant interaction was observed between venular tortuosity (RR:1.14, 95%CI:1.09‐1.19, p‐interaction<0.001), GC‐IPL (RR:1.23, 95%CI:1.13‐1.34, p‐interaction<0.001) and RNFL (RR:1.48, 95%CI:1.31‐1.68, p‐interaction=0.002) with CMIs on CDR‐SoB scores.ConclusionWe showed that retinal vascular and neuronal parameters are associated with cortical CMIs independent of risk factors. Moreover, there was an interaction between retinal parameters and cortical CMIs on CDR‐SoB. Further studies may be warranted to evaluate the potential clinical utility of retinal parameters in risk prediction for CMIs.
Impairment of auditory integration in subjective cognitive decline, amnestic mild cognitive impairment, and Alzheimer’s disease
Authors: Wang Changming , Wang Zhibin , Liu Lei , Yang Pengcheng , Xie Beijia , Shi Xinrui , Jia Jianping , Li Liang , Tang Yi 
Published: December 2021

AbstractBackgroundLocalization of sound sources in a noisy environment or ‘auditory scene analysis’ depends on central auditory processing (CAP) that is vulnerable in cognitive impairment. Here, we investigated the behavioral and electrophysiological characteristics of auditory integration, as a particular function in CAP, in relation to neuropsychological functions in SCD, aMCI, and AD.MethodWe introduced a binaural integration paradigm to measure sound‐localization‐related features (identification and retention of acoustic signals) by detecting break in interaural correlation (BIC) and primitive auditory memory (PAM) in wideband noises. We used a 128‐channel EEG to record the event‐related‐potential (peak amplitude, peak latency, and inter‐trial phase coherence [ITPC]) for the paradigm.ResultA total of 121 participants (mean age 65.9 years) were included. Significant differences in BIC detection and PAM were revealed between groups adjusting for age and gender (BIC: F = 20.2, P < 0.001; PAM: F = 24.6, P < 0.001). Post‐hoc analysis showed that BIC detection and PAM were significantly higher in NC or SCD groups compared with aMCI or AD groups. Further adjusting for neuropsychological scores, the significances were not changed, suggesting that auditory integration impairment was partially independent from top‐down cognitive functions. In EEG experiment, the most prominent differences in EEG metrics among the four groups included the ITPC of N1 at left parietooccipital region (F = 3.85, P = 0.012) and of P2 at left parietooccipital (F = 3.89, P = 0.011) and frontocentral regions (F = 8.09, P < 0.001). Notably, there was a linear decrease for the ITPC of N1 and a U‐shape‐curve change for the ITPC of P2 among the four groups, indicating that EEG patterns are differentially modulated depending on disease severity. For the discrimination of AD vs NC and MCI vs NC, the AUC was 0.92 and 0.85 for BIC detection; 0.94 and 0.90 for PAM, respectively.ConclusionAuditory integration, as a partially independent phenotype, is impaired in aMCI and AD populations. A U‐shape‐curve change of P2 with the increasing disease severity was found, indicating a compensation on auditory scene analysis. Results support binaural integration paradigm as a biomarker for screening cognitive decline and identifying auditory integration deficit.