bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual decline in gait and cognition as a risk factor for dementia. The role of sex
Authors: Montero‐Odasso Manuel 
Published: December 2023

AbstractBackgroundMotor (slowing of gait) and cognitive declines are common in older adults. We reported that older adults with both motor and cognitive decline (dual‐decliners) had a higher risk of progressing to dementia than individuals with either decline alone. Our aim in this study is to examine the role of sex in these cognitive and motor trajectories before dementia.MethodsData was used from the Gait and Brain Study, a prospective cohort study in community‐dwelling older adults free of dementia at baseline. Participant’s motor and cognitive trajectories were assessed twice a year for 5 years, using gait speed and the MoCA test, respectively. We ascertained incident dementia using DSM‐IV‐RT criteria. The risk to progress to dementia was evaluated with Cox regression models, stratifying by sex and adjusting by age and comorbidities.ResultsFrom 207 older adults, 37 individuals (18%) progressed to dementia, from which 43% were males and 57% were females. Among dual‐decliners, males had a higher risk for progressing to dementia when compared with females (Males HR: 3.90, 95%CI: 1.02‐14.87, p = 0.046; Females: HR: 2.41, 95%CI: 0.72‐ 8.12, p = 0.155). In addition, in males, the association becomes stronger after adjusting for comorbidities (HR: 4.36, 95%CI: 1.08‐17.66, p = 0.039), whereas in females, the risk for progressing to dementia lowers when adjusting for comorbidities (HR: 1.44, 95%CI: 0.38‐ 5.41, p = 0.590), suggesting that number of comorbidities might be driving the association with dementia in females. Male dual‐decliners showed a stronger association with progression to dementia (HR = 4) when compared with females (HR = 1) in both adjusted and unadjusted models.ConclusionOlder adults that present both motor and cognitive decline (dual‐decliners) have the highest risk to progress to dementia, particularly if they are men. Sex differences in motor and cognitive trajectories before dementia may increase accuracy of dementia risk prediction. Future studies are needed to understand mechanisms underlying our findings.
Apathy as a Predictor of Motoric Cognitive Risk Syndrome
Authors: Ceide Mirnova E 
Published: December 2023

AbstractBackgroundApathy is a psychological syndrome, characterized by lack of motivation and interest, flattening of affect, and social withdrawal; that predicts cognitive decline including dementia. Current literature highlights apathy as a separate entity from depression, which is uniquely correlated to cognitive and functional decline in neurologic diseases like stroke and Parkinson’s Disease as well as in community dwelling‐older adults. Further, apathy may mediate the previously described association between depression and cognitive/functional decline. Our objectives were to 1) investigate the association between apathy at baseline and incident predementia syndromes including mild cognitive impairment (MCI) and motoric cognitive risk syndrome (MCR) and 2) explore the direct and indirect relationships of apathy and motoric cognitive outcomes.MethodWe prospectively studied the association between apathy (3‐item subscale of the Geriatric Depression Scale) and incident predementia syndromes in 542 community‐dwelling older adults enrolled in the Central Control of Mobility in Aging study, using Cox proportional hazard models. Associations were reported as hazard ratio (HR) with 95% confidence intervals (CIs), adjusting for age, education, baseline cognitive performance, and dysphoria. In a subset of 347 participants, we examined the mediating role of cytokines on the association between apathy and gait velocity in linear regression models at cross section. We also looked at the mediating role of apathy on the association between dysphoria and multimorbidity and gait velocity.ResultApathy was associated with incident MCR (HR 2.39, 95% CI: 1.10‐5.20), but not MCI. Linear regression models showed that Interleukin‐6 (Il‐6), but not C‐Reactive Protein was significantly associated with apathy adjusted for age, gender, and years of education (B = 0.037, 95% CI: 0.002–0.072, p = 0.04). Apathy was associated with a slower gait velocity (B = 14.45, 95% CI: 24.89–4.01, p = 0.01), cross sectionally. Mediation analyses demonstrated that IL‐6 modestly mediates the relationship between apathy and gait velocity. Additionally, apathy mediated the relationships between dysphoria and multimorbidity and gait velocity.ConclusionOverall, our findings indicate that apathy may be an early predictor of motoric cognitive decline, which precedes predementia syndromes. Inflammation plays a modest role, but the underlying biology of apathy warrants further investigation.
Trajectories of Motoric Cognitive Risk and Incident Dementia in Scotland
Authors: Mullin Donncha S 
Published: December 2023

AbstractBackgroundMotoric cognitive risk syndrome (MCR) ‐ objective slow gait and subjective cognitive complaints ‐ is quick and easy to measure, making it a potentially useful clinical tool for identifying those at high risk of developing dementia. This is the first exploration of MCR syndrome’s predictive ability for incident dementia in a Scottish cohort (Lothian Birth Cohort 1936) and the first examination of the various trajectories of MCR.MethodWe classified a total of 680 community‐dwelling participants (mean [SD] age 76.3 [0.8] years) free from dementia into non‐MCR or MCR groups. We used cox proportional hazard methods to evaluate the risk of developing all‐cause dementia in the years following MCR diagnosis. Our final model adjusted for age, sex, comorbidity index, apolipoprotein E status, physical activity level, and years of education. We analysed the trajectories for everyone with MCR by tracking their outcomes over 9 years. All analyses were performed in R version 4.0.2.ResultThe prevalence of MCR at baseline was 5.6% (n = 38/680). After 9 years of follow‐up, 11.6% (n = 79/680) of the total cohort developed dementia. The presence of MCR increased the risk of dementia (adjusted hazard ratio 2.37 [95%CI 1.06‐5.32; p = 0.0359]). The trajectories of those with MCR at baseline were: i) reverted to healthy (n = 6/38), ii) ongoing MCR (n = 13/38), iii) progressed to dementia (n = 9/38), or iv) died (n = 10/38).ConclusionMCR showed similar prognostic ability for dementia in a Scottish cohort as for other populations. MCR could identify a target group for early interventions of modifiable risk factors to prevent incident dementia. Individuals with MCR follow similar trajectories to the related predementia syndrome, Mild Cognitive Impairment.
A cross‐national comparison of the risk factors associated with the Motoric Cognitive Risk syndrome in high and middle‐income countries
Authors: Jayakody Oshadi , Verghese Joe , Blumen Helena M 
Published: December 2023

AbstractBackgroundThe Motoric Cognitive Risk (MCR) syndrome is associated with increased risk of Alzheimer’s disease and vascular dementia. MCR does not require cognitive or lab tests to diagnose, increasing its utility in resource‐poor settings. The specific risk factors associated with MCR in different high‐ and middle‐income countries are not established.MethodsWe examined the epidemiology of MCR in harmonized cross‐sectional data from 17,050 adults aged ≥ 65 years enrolled in the U.S. Health and Retirement Study (HRS; n = 3,748), English Longitudinal Study of Ageing (ELSA; n = 4,110), Mexican Health and Aging Study (MHAS; n = 738), the China Health and Retirement Study (CHARLES; n = 3,275), the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI‐DAD; n = 1,276) and the Survey of Health, Ageing and Retirement in Europe (SHARE; n = 3,973). MCR was defined as the presence of cognitive complaints and slow gait in the absence of mobility disability and dementia. Risk factors included demographics [age, sex, education], medical [hypertension, diabetes, Parkinson’s, heart disease, stroke, obesity], sensorimotor [grip strength, hearing], psychological [depression], behavioral factors [smoking, sedentariness, sleep quality] and falls (see Table 1 for definitions). Logistic regression was used to examine factors associated with prevalent MCR.ResultsParticipants’ mean age in different cohorts ranged between 71.3 and 80.2 years. Proportion of females ranged between 45.3% and 60.9%. MCR prevalence was 3.6%, 2.1%, 8.9% 6.1%, 5.8% and 6.8% in HRS, ELSA, MHAS, CHARLES, LASI‐DAD and SHARE, respectively. Tables 2 and 3 show risk factors associated with each cohort in univariate and multivariable models. Despite some overlaps, specific risk factors were associated with each cohort with relative risk ratios ranging as follows: 0.4‐2.8 for education and multiple falls in HRS, 2.3‐7.1 for poor hearing and sedentariness in ELSA, 2.3‐2.6 for weak grip strength and diabetes in MHAS, 1.9‐2.2 for depression and sedentariness in CHARLES, 0.5‐5.3 for education and stroke in LASI‐DAD and 0.3‐2.4 for education and depression in SHARE.ConclusionIn community‐dwelling older adults from twenty countries (high‐ and middle‐income), specific risk factors were associated with MCR in each cohort – laying the foundation for preventing MCR and subsequently dementia in ethnically, culturally, and socioeconomically diverse populations.
Predicting cognitive decline in short‐term as a viable method to improve recruitment in clinical trials of Alzheimer’s Disease
Authors: Nallapu Bhargav Teja , Petersen Kellen K. , Lipton Richard B. , Ezzati Ali 
Published: December 2023

AbstractBackgroundSuccess of Alzheimer’s disease (AD) trials is partially dependent on enrollment of participants who show cognitive decline (CD) during treatment with placebo. We investigated whether trials could be enriched for CD using machine‐learning based predictive models.MethodWe used data from the placebo arm of trial of Solanezumab for mild dementia due to AD (EXPEDITION‐3 trial; N = 894) as well as individuals at the same stage of disease from Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 86). Participants were classified as showing CD vs stable cognition (SC) based on their scores on the cognitive sub‐scale of the Alzheimer’s Disease Assessment Scale (ADAS‐Cog11; Range 0‐70). The CD group included individuals who showed a minimal clinically important difference (MCID of 3 or more points increase in their ADAS‐Cog11 scores from baseline to week 80) while the SC group had a change of less than 3 points. Participants were classified into CD and SC groups using different baseline feature‐sets including volumetric MRI and neuropsychological tests (Table 2). Models were trained using 70% of the EXPEDITION‐3 data and were validated using the remaining 30%. Models trained in EXPEDITION‐3 were then externally validated using the ADNI sample.ResultOnly 56% of EXPEDITION‐3 participants treated with placebo showed MCID at 80 weeks (Table 1). Performance of the different models is summarized in Table 2. Model 4 using the random forest algorithm, which included all features and data from 6‐month follow‐up, had the best overall performance in the internal validation sample (AUC: 0.75±0.03). Models 3 and 4 performed similarly when validated in the independent ADNI sample (AUCs: 0.70±0.05, 0.66±0.06, respectively). Both Models had positive predictive values approximately 15% higher than the base prevalence of cognitive decline in the ADNI subset (∼62%). The negative predictive value of Model 3 was 23% higher than the base prevalence of stable cognition in the participants, slightly higher than that of Model 4.ConclusionEnrichment of trials through predictive models may increase the chance of success. Using 6‐month follow‐up data improves accuracy of decliner identification and may provide a basis for early exclusion of a subset unlikely to discriminate active treatment from placebo.
Investigating the synaptic mechanisms of the spread of wild type and P301S 1N4R human tau in in vitro and in vivo models
Authors: Panzi Chiara , Restani Laura , Novelli Elena , Guarascio Rosellina , Cheetham Michael , Wray Selina , Caleo Matteo , Schiavo Giampietro 
Published: December 2023

AbstractBackgroundTau aggregates propagate across functionally connected neuronal networks in tauopathies as Alzheimer’s disease. However, the mechanisms underlying this process are poorly understood. Different studies showed that tau release is dependent on neuronal activity and that pathological tau can be found in the extracellular space confined in extracellular vesicles or in a free form. We recently showed that metabotropic glutamate receptors and SNAP25 modulate the release of pathologic tau from human and mouse synaptosomes. Here, with the use of blocking agents such as botulinum neurotoxins (BoNTs), we plan to test the effect on the synaptic release of tau in vitro and in vivo. BoNTs enter synapses and cleave specific synaptic SNARE proteins, impairing synaptic vesicle fusion and release. We aim at demonstrating the potential of BoNTs as tools to study neurodegenerative diseases.MethodsPrimary mouse hippocampal neurons were cultured in microfluidic chambers, transduced with lentiviruses expressing human tau (hTau) isoforms, and treated with BoNTs and stimulators. ELISA was used to quantify hTau in the culture media. AAVs expressing hTau were injected in the vitreous of wild‐type mice, and BoNT type A (BoNT/A) was injected in the superior colliculus (SC). Retina, SC and lateral geniculate nucleus (LGN) were analysed through immunohistochemistry.ResultsOverexpression of hTau in primary neurons increases the expression of synaptic markers as compared to non‐transduced cells, while any difference is detected between wild‐type and P301S hTau. Neuronal stimulation significantly increases the release of P301S hTau, whereas BoNT/A blocks it. Preliminary in vivo data show no difference in the expression and transfer of wild type and P301S hTau in the SC and LGN. The ongoing analysis of BoNT/A injected mice will reveal any effect on tau spread in the brain.ConclusionsThe release of hTau is modulated by specific SNARE proteins and differs depending on the isoform in vitro. The use of BoNT/A in vivo will help us to clarify the mechanisms modulating tau release in a complex system. Moreover, with the use of other BoNTs, we will provide novel insights into the mechanisms of synaptic tau release and identify novel molecular targets for the development of therapeutic interventions to treat tauopathies.
The impact of inflammation on plasma biomarkers of Alzheimer’s Disease
Authors: Hall James , Petersen Melissa , O'Bryant Sid E. 
Published: December 2023

AbstractBackgroundPlasma biomarkers of Alzheimer’s disease have been proposed as less expensive, less invasive and readily scalable biomarkers for use as diagnostic biomarkers, predictors of risk and progression and inclusion criteria for clinical trials. Our previous work has shown that medical comorbities such as dyslipidemia, diabetes, kidney disease and hypertension can impact the levels of these biomarkers and there are ethnic differences in this relationship. The current study extended this work by investigating the effect of inflammation on levels of plasma biomarkers of amyloid, tau and neurodegeneration in an ethnically diverse cohort.MethodData from 651 cognitively unimpaired non‐Hispanic White and 646 cognitively unimpaired Mexican American participants from the Health & Aging Brain Study‐ Health Disparities study were analyzed. Plasma markers of Aβ40, Aβ42, total tau and NfL were assayed using the ultrasensitive Simoa (single‐molecule array) technology. The relationship of peripheral inflammatory biomarkers (IL‐6, IL‐10, TNFα & CRP) to each of the AD plasma biomarkers was analyzed using partial correlation controlling for age, sex and APOE4 positivity.ResultHigher levels of Aβ40, Aβ42, total tau and NfL were associated with elevated IL‐6, IL‐10 and TNFα for both ethnic groups. CRP was not significantly associated with any of the AD biomarkers for either group. Although the Mexican American participants had significantly lower Aβ40 (p = .000) and higher total tau (p = .000) than non‐Hispanic White participants, the two groups did not differ significantly on the level of any of the inflammatory markers.ConclusionThe level of plasma AD biomarkers is influenced by the presence of peripheral inflammatory cytokines. CRP a non‐specific acute phase marker of inflammation is not related to plasma AD biomarkers in cognitively unimpaired older adults. Ethnicity in this bi‐ethnic study was not a factor in this relationship. Additional research investigating medical co‐morbidities as a factor in the inflammation‐AD plasma biomarker relationship is needed. As with medical co‐morbidities the level of inflammation may affect the interpretation and application of the plasma AD biomarkers in this study.
Osteopontin exhibits a bidirectional relationship with Alzheimer’s disease pathology in asymptomatic individuals with a parental history of sporadic Alzheimer’s disease
Authors: Quesnel Marc James , Labonté Anne , Picard Cynthia , Brinkmalm Ann , Blennow Kaj , Zetterberg Henrik , Breitner John C.S. , Villeneuve Sylvia , Poirier Judes ,   PREVENT‐AD Research Group
Published: December 2023

AbstractBackgroundOsteopontin (OPN) is a secreted protein that plays pivotal roles in the recruitment and activation of immune cells, cell survival, and tissue repair following injury. OPN has been demonstrated to be increased in the cerebrospinal fluid (CSF) and brains of individuals with Alzheimer’s disease (AD). However, in order to elucidate the role of OPN in the asymptomatic stage of sporadic AD, we analyzed data from the PREVENT‐AD cohort, which consists of asymptomatic individuals with a parental or multi‐sibling history of AD.MethodThe Olink Proximity Extension Assay was used to measure CSF levels of OPN. CSF levels of amyloid beta (Aβ1‐42), and total Tau (t‐Tau) were measured by enzyme‐linked immunosorbent assay (Fujirebio). Participants were staged as CSF Aβ1‐42 or t‐Tau positive according to specified thresholds of 989 pg/mL and 336 pg/mL, respectively. CSF levels of synaptic proteins, including GAP43, SYT1, SNAP25 and NRGN were measured by immunoprecipitation followed by mass spectrometry. Tau and Aβ positron emission tomography (PET) burdens were measured using 18F‐AV1451 and 18F‐NAV4694.ResultAβ(+)/Tau(‐) individuals displayed a reduction in CSF OPN levels, relative to Aβ(‐)/Tau(‐) individuals (p = 0.001). Furthermore, Aβ(+)/Tau(+) individuals exhibited a significant increase in CSF OPN levels relative to Aβ(+)/Tau(‐) individuals (p < 0.001), and at a trend level, to Aβ(‐)/Tau(‐) individuals (p = 0.069). In addition, CSF OPN levels were positively correlated with synaptic markers in the CSF, including GAP43 (p < 0.001), SYT1 (p = 0.001), SNAP25 (p < 0.001) and NRGN (p = 0.004). Finally, in PET imaging analyses, CSF OPN levels were positively correlated with pTau burden in the entorhinal cortex (p = 0.009), fusiform gyrus (p = 0.030) and lingual gyrus (p = 0.003). However, CSF OPN levels were not correlated with global cortical Aβ burden (p = 0.374).ConclusionOur results suggest that early Aβ pathology dampens OPN levels in asymptomatic individuals with a family history of AD. Furthermore, our data provide compelling evidence that OPN plays a critical role in the compensatory response to neurofibrillary tangle formation, neuronal loss and synaptic dysfunction. Finally, our findings reveal that OPN may be a valuable therapeutic target.
Unexpected and interesting distractors capture greater attentional gaze behavior in MCI in a naturalistic visual search task
Authors: Kleiman Michael J , Henriquez Adolfo M , Galvin James E 
Published: December 2023

AbstractBackgroundAlzheimer’s disease can influence gaze behavior, even in prodromal stages such as mild cognitive impairment (MCI). Alzheimer’s pathology impacts exploratory eye movements, and can be detected with eye tracking applied to novelty preference tasks that leverage visual short‐term memory. MCI due to Alzheimer’s disease is often associated with attentional deficits, with distracting stimuli capturing a greater amount of attention than seen in healthy controls (HC). In this pilot study, we examine the effects of distractors, including categorical, background, and “unexpected” distractors, in a novel naturalistic visual search task.MethodsUsing a novel visual search task, 45 participants (35 HC, 10 MCI) were asked to count the number of animals (either flying or land animals) in a natural scene while their eye movements were recorded. Scenes contained either no distractors (11 scenes), “expected” distractors of the opposite animal type (8 scenes), or “unexpected” distractors that appeared unusual, such as fish on land (2 scenes). Four of the scenes (1 with distractors) contained a vibrant or interesting background.ResultsNo difference was found between MCI and HC in gaze behavior towards expected distractors, however unexpected distractors captured significantly (p<.05) longer and more frequent visits in MCI participants (1.2 seconds and 7.0 visits) compared with HC participants (0.6 seconds and 4.5 visits). In contrast, duration and visits towards targets did not differ, however MCI participants took significantly longer to first attend targets (1.5 seconds) than HC participants (0.5 seconds) when unexpected distractors were present (p = .02). In MCI participants, interesting background stimuli captured significantly more gaze in the first 3 seconds of presentation (35.3% MCI vs 25.8% HC; p = .04).ConclusionsIn this preliminary study, we found that HC participants showed greater resilience to distractions compared to MCI participants, who showed less ability to maintain focus in the presence of unanticipated distractors. Attention was pulled from the counting task towards a distracting background as well as towards the unexpected distractors in MCI participants, but not when distractors appeared to fit naturally in the surrounding scene. Future research will examine effects of age‐related decline and biomarker status in unimpaired participants.
Anti‐inflammatory clearance of amyloid beta by a chimeric Gas6 fusion protein
Authors: Jung Hyuncheol , Lee Se Young , Kang Min Soo , Jung Hwa‐Jin , Shin Ah‐Young , Song Ji‐Yun , Chung Won‐Suk , Kim Chan Hyuk 
Published: December 2023

AbstractBackgroundAβ immunotherapy is the most promising approach in treating Alzheimer’s disease (AD). Although Aβ‐antibodies can substantially reduce Aβ burden in the brain, solutions for antibody‐induced inflammation and subsequent ARIA (Amyloid‐related imaging abnormalities) are still in demand. Here we developed a novel chimeric protein platform, GAIA (Gas6‐mediated anti‐inflammatory adaptor). GAIA platform utilizes TAM receptors, which are expressed on glial cells and mediate phagocytosis without associated inflammatory response.MethodWe developed a GAIA‐based novel chimeric protein (αAβ‐Gas6) which is composed of two distinct functional domains; a single‐chain variable fragment of Aducanumab, which selectively binds to Aβ, fused with Gas6, a TAM receptor‐binding domain. Aβ clearance and phagocytosis‐associated inflammatory responses of αAβ‐Gas6 were measured in comparison with Aducanumab.ResultαAβ‐Gas6 showed selective uptake of Aβ through phagocytosis in vitro. While Aducanumab induced phagocytosis only in primary microglia, αAβ‐Gas6 significantly induced phagocytosis in both cultured microglia and astrocyte. In comparison with Aducanumab, αAβ‐Gas6 secreted significantly lower amount of pro‐inflammatory cytokines, such as TNF, IL‐6, and IL‐1β. In vivo application of αAβ‐Gas6 reduced Aβ burden in an extent significantly lower in mice treated with Aducanumab. Finally, αAβ‐Gas6 groups showed significantly reduced excessive synapse elimination levels comparable to non‐AD wild type groups.ConclusionWe developed a novel chimeric fusion protein αAβ‐Gas6 by engineering TAM receptor‐binding domain Gas6. In comparison with antibody drug, αAβ‐Gas6 showed advanced amyloid clearance, significantly reduced neuroinflammation, and neurotoxicity. Thus, our results suggest a novel immunotherapeutic agent which can bifunctionally target Aβ and modulate gilal cells to reduce neuroinflammation.