bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visualization of brain targets with 89Zr‐immuno‐PET using a novel bispecific amyloid ß monoclonal antibody
Authors: Stergiou Natascha , Wünsche Thomas , Mes Iris , Schreurs Maxime , Verlaan Mariska , Kooijman Esther , Windhorst Albert D. , Dongen Guus AMS , Helboe Lone , Vergo Sandra , Christensen Søren , Asuni Ayodeji A , Jensen Allan , Bang‐Andersen Benny , Vugts Danielle , Beaino Wissam 
Published: December 2021

AbstractBackgroundRecent preclinical and clinical studies in the diagnosis and treatment of Alzheimer Disease (AD) focus on antibody based radioligands and therapeutics by targeting amyloid‐β (Aβ).1 So far, imaging brain targets with bispecific antibodies (using transferrin receptor protein1 as shuttling mechanism) has only been investigated using 124I.2 The disadvantages of 124I limit drastically its clinical potential.3 Therefore, 89Zr is suggested as more suitable positron emitter for labelling of antibodies4, especially in combination with DFO*, the next generation chelator candidate for clinical 89Zr‐immuno‐PET.5 In this study, we evaluated [89Zr]Zr‐DFO*‐NCS labeled bispecific Abeta‐mAb‐scFab8D3 and its mutated analogue Abeta‐mAb‐scFab8D3 T1/2 with faster pharmacokinetics for Aβ imaging and targeting in a preclinical Alzheimer mouse model.MethodAbeta‐mAb‐scFab8D3 ± T1/2 and the nonspecific isotype control B12‐mAb‐scFab8D3 ± T1/2 were modified with DFO*‐NCS, and subsequently radiolabeled with 89Zr.6 The radiolabeled biologicals (1 mg/kg) were intravenously injected in APP/PS1 transgenic mice as well as in littermates which served as controls (n=5 per group). Blood pharmacokinetics were determined up to 3 (T1/2) or 7 days post injection (p.i.). PET/CT and PET/MRI scans were acquired for 1h at different time points.ResultThe PET images showed a clear brain uptake for the bispecific Abeta‐mAb‐scFab8D3 ± T1/2 in APP/PS1 mice, while the corresponding B12‐mAb‐scFab8D3 ± T1/2 in APP/PS1 mice, as well as Abeta‐mAb‐scFab8D3 ± T1/2 in the littermates showed no specific uptake. Abeta‐mAb‐scFab8D3 demonstrated 2‐fold higher brain uptake (2% ID/g) than Abeta‐mAb‐scFab8D3 T1/2 (1% ID/g).Conclusion
89Zr‐DFO*‐immuno‐PET revealed high and specific uptake of the bispecific Abeta‐mAb‐scFab8D3 in the brain. In this context, we demonstrated that slow kinetics of the biologicals contribute to improve Aβ targeting. The new bispecific Abeta‐mAb‐scFab8D3 looks very promising and supports further development toward companion and complementary diagnostics for AD. References: 1. Selkoe, D. J. Nature Reviews Neurology 15, 365–366 (2019). 2. Sehlin, D. et al. Nat. Commun. 7, 10759 (2016). 3. Verel, I. et al. Cancer Biother. Radiopharm. 18, 655–661 (2003). 4. O’Brien, H. A. J. Radioimmunoimaging Radioimmunother. 17, (1983). 5. Chomet, M. et al. Eur. J. Nucl. Med. Mol. Imaging 1–14 (2020). doi:10.1007/s00259‐020‐05002‐7. 6. Vugts, D. J. et al. Eur. J. Nucl. Med. Mol. Imaging 44, 286–295 (2017).
Fluency in spontaneous speech predicts individual variance in executive function among seniors
Authors: Spencer Kiah A , Meltzer Jed A , Robin Jessica , Xu Mengdan , Rose Mira Kates , Bialystok Ellen 
Published: December 2021

AbstractBackgroundSeveral recent studies have used automated linguistic analysis of naturalistic speech in a picture‐description task (e.g. Cookie Theft) combined with machine learning approaches to distinguish the speech of those with dementia from healthy age‐matched controls. Extension of these techniques to predict continuous variables related to cognitive status offers a means to track the severity of dementia over time and evaluate the effectiveness of interventions. Here we examine the relationship of speech variability to executive function, the ability to manage conflicting information in speeded task performance. Higher executive function confers protection against the clinical manifestation of dementia despite underlying neurodegeneration.MethodIn a new sample of 76 healthy adults aged 65‐75, we measured executive function using an extensive test battery, and elicited spoken picture descriptions in the same individuals. The battery included N‐back, Simon task, verbal fluency, Color Word Interference (CWI or Stroop test), Trails A & B, the elevator subtests of the Test of Everyday Attention, and Logical Memory. Two picture description narratives were recorded and subjected to automated analysis generating over 400 linguistic features, grouped into 8 composite measures.ResultExploratory factor analysis revealed one factor accounting for most variance in the executive function battery. This factor exhibited significant correlations with four of the eight speech composite measures, from strongest to weakest: word finding difficulty, local coherence, lexical richness, and syntactic complexity, reflecting greater fluency in spontaneous descriptive speech. No significant correlations were found with repetitiveness, global coherence, information units, and sentiment. Ongoing analyses include factor characterization of the language measures with a larger normative sample.ConclusionOlder individuals with higher executive function, as captured by common laboratory tests, also exhibit more fluent speech as quantified by automated linguistic analysis. Word finding difficulties may reflect overall slowing of cognitive processes and access to long‐term memory. Automated speech analysis may ultimately serve as an inexpensive and repeatable measure to track cognitive status over time in older adults at risk of dementia.
Utility of Birmingham Cognitive Screen (BCoS) to differentiate vascular cognitive impairment and Alzheimer’s disease
Authors: Apostolopoulos Dimitrios , Bickerton Wai‐Ling , Brett Lucy , Laverick Rosanna , Rotshtein Pia , Hosseini Akram A. 
Published: December 2021

AbstractBackgroundClinical and cognitive assessments are widely used as screening tools for dementia. There is need to find cognitive tools that could differentiate dementia syndromes. This study explores the use of the Birmingham Cognitive Screen (BCoS), a one‐hour assessment of 5 cognitive domains, in revealing differential neurocognitive profiles for Alzheimer’s disease (AD), and vascular cognitive impairment with deep brain structure ischaemia (VCI‐DBSI).MethodAn observational study that received ethical approval by the UK National Research Ethics Committee was carried out with participants recruited from the Midlands in the UK. A total of 128 participants between the ages of 39 and 75 met the inclusion criteria and categorised into three groups. 43 AD (Alzheimer’s disease ), 38 VCI‐DBSI ( Vascular Cognitive Impairment‐Deep Brain Structure Ischaemia ), and 47 healthy controls. Fourteen BCoS tasks were entered into 3 binomial logistic regression models to differentiate AD and VCI‐DBSI groups from controls and each other.ResultGender proportion (p=0.002) and years of education (p=0.025) differed between groups and so were controlled for. 14 BCoS tasks differed significantly between groups (all p<0.002). The resulting three logistic regression models were statistically significant (all p <0.001) and explained 62‐87% of variances while correctly classifying 85.2‐94.4% of cases. Compared to controls, AD participants were more impaired in memory and VCI‐DBSI participants were more impaired in attention/executive function.ConclusionThe BCoS showed good discriminatory ability between AD, VCI‐DBSI, and control groups based on memory and attention/executive function, indicating potential as a differentiating biomarker for use in the office.
Unpacking cognitive composites: A longitudinal analysis
Authors: Cox Timothy , Shishegar Rosita , Lim Yen Ying , Robertson Joanne , Lamb Fiona , Laws Simon M , Porter Tenielle , Fripp Jurgen , Doecke James D , Maruff Paul T , Savage Greg , Rowe Christopher C , Masters Colin L , Villemagne Victor L , Burnham Samantha C ,   the Australian Imaging Biomarkers and Lifestyle (AIBL) Research Group
Published: December 2021

AbstractBackgroundThe development of cognitive endpoints that can accurately assess changes in cognition over short time frames is crucial for clinical trials and research of Alzheimer’s disease (AD). Understanding the changing influence of contributing test scores on composites throughout the disease course provides the opportunity to optimise cognitive composite scores for different stages of AD.MethodAIBL participants with declining cognitive performance were included in this study N=1275 [688 cognitively unimpaired (CU), 277 mild cognitively impaired (MCI), 310 AD; aged 73±9; 718 females]). Two cognitive composite scores (Episodic Memory (EM) and PACC) and their component test scores (California Verbal Learning Test‐II Delayed Recall (CVLT‐II DR), Logical Memory Delayed Recall (LMII), Rey Complex Figure Test 30 minute delayed recall (RCFT‐DR) and CVLT‐II DR, LMII, Digit Symbol Substitution Test (DS), MMSE, respectively) were evaluated. We first examined the relationship between each of component tests score for each composite. We then compared the extent to which longitudinal trajectories of each component test score and each cognitive composite score differed at each disease stage.ResultCVLT‐II DR contributed the most to the EM composite followed by RCFT‐DR and LMII with the influence remaining unchanged across each disease stage. For PACC, CVLT‐II DR contributed the most to the initial decline, with MMSE and LMII contributing similar amounts and DS contributing the least. CVLT‐II DR contributed substantially to changes in PACC earlier in the disease course but MMSE drove the PACC change in later stages of disease. Initially, both composites follow similar longitudinal trajectories. However, the EM composite reaches a floor not observed for the PACC.ConclusionUnderstanding the temporal contribution of component tests scores on cognitive composites could provide improved cognitive endpoints tailored to use. For instance, MMSE is sensitive to change later in the disease trajectory and therefore should be included in a composite endpoint for trials in prodromal or clinical AD, however is unlikely to have value for preclinical AD trials.
Does the prevalence of different clinical variants of early onset dementia increase with age in people younger than 65? Data from an epidemiology study in Modena province, Italy
Authors: Salemme Simone , Vinceti Giulia , Adani Giorgia , Tondelli Manuela , Galli Chiara , Carbone Chiara , Fiondella Luigi , Filippini Tommaso , Vinceti Marco , Chiari Annalisa , Zamboni Giovanna 
Published: December 2021

AbstractBackgroundEarly onset dementia (EOD) has significant impact on patients and families. In a recent epidemiological study conducted in the province of Modena, Italy, we reported that the most frequent EOD in persons aged 30‐64 years was the amnestic variant of Alzheimer’s Disease (AD), followed by the behavioral variant of frontotemporal dementia (FTD). Previous studies have shown that ageing increases prevalence of AD even in patients younger than 65. However, it is not known whether different variants of AD and other causes of EOD are equally affected by ageing. Here we studied prevalence of the different clinical variants of EOD by age group.MethodWe identified all EOD patients seen in the network of dementia services of the Modena province, from 2006 to 2019. We included all patients with a diagnosis of dementia with symptom onset before age 65 alive on census date. We stratified them according to their age group and computed crude and sex‐adjusted prevalence rates.ResultPrevalence of all AD showed a nearly exponential growth ranging from 1.8/100,000 in the 40‐44 age group to 141.4/100,000 in the 59‐64 group. Among AD variants, prevalence of the amnestic variant was the most influenced by the age, increasing from 17.5/100,000 in the 40‐44 group to 102.6/100,000 in the 59‐64 group, while prevalence of posterior cortical atrophy and logopenic variant of primary progressive aphasia (PPA) showed an almost flat growth curve. Prevalence of all FTD increased linearly from 1.8/100,000 in the 40‐44 group to 86.6/100,000 in the 59‐64 group, with such increase being all driven by the behavioral variant (bvFTD), which increased from 1.8/100,000 to 66.1/100,00. Non‐fluent and semantic variants of PPA did not increase with age, although an association with age may have been underestimated by their low frequency.ConclusionIn patients younger than 65, prevalence rates of amnestic AD and bvFTD increase with ageing, while other clinical variants of AD and FTD does not seem to show that pattern. These results contribute to a better understanding of the different clinical variants of EOD and their risk factors.
The association of vascular risk factors with cognitive impairment in ART‐treated HIV‐positive adults aged 50 years or older in Northern Tanzania
Authors: Flack Katherine , Rainey Emma , Urasa Sarah , Koipapi Sengua , Kalaria Rajesh , Mukaetova‐Ladinska Elizabeta , Howlett William , Dekker Marieke , Walker Richard , McNally Richard , Paddick Stella‐Maria 
Published: December 2021

AbstractBackgroundThe ageing of the global HIV‐positive population brings with it the novel challenges of geriatric medicine, such as management of comorbidities including cardiovascular disease and HIV‐associated neurocognitive disorder (HAND). Recent literature from high‐income countries suggests vascular risk factors, which are increasingly prevalent throughout sub‐Saharan Africa (SSA), are stronger predictors of HAND than HIV‐disease severity. There is a paucity of evidence surrounding the association between HAND, vascular risk factors and end‐organ damage (EOD) in older cohorts of people living with HIV (PLWH) in SSA. This study aimed to establish prevalence, and evaluate the relationship between vascular risk factors, EOD and HAND in individuals aged ≥50 receiving HIV treatment in TanzaniaMethodA systematic sample of outpatients with HIV on combined antiretroviral therapy (cART) were recruited in Kilimanjaro and assessed for vascular risk factors (hypertension, hypercholesterolaemia, diabetes, smoking etc) and markers of vascular EOD (prior myocardial infarction and LVH on ECG, stroke on neurological examination or MRI‐brain, estimated‐glomerular filtration rate and retinal arteriovenous ratio measurements). HAND were defined by AAN criteria following a detailed locally normed neurocognitive assessment battery, neurological and clinical examination and informant history, and will subsequently be confirmed by consensus panel.ResultComplete data were available for 145 individuals (mn age 56, 72.7% female). Provisional HAND prevalence was high (64.7%, 31.4% symptomatic) despite well‐managed HIV‐disease (70.5% suppressed viral load). 34.0% of the cohort were hypertensive, 10.5% obese, 33.3% had hypercholesterolaemia, 5.3% had diabetes and 4.6% smoked. Vascular EOD prevalence ranged from 1.3% (prior myocardial infarction) to 12.5% (LVH). No significant association was found between vascular factors and HAND. Conversely symptomatic HAND was significantly correlated with lower BMI (p=0.034) and lower total serum cholesterol (p=0.014).ConclusionHAND prevalence was high, however prevalence of vascular risk factors was lower than in recent Tanzanian community studies. The lack of association between vascular factors and HAND does not support the hypothesis that HAND is driven by vascular damage. However, the high prevalence of HAND observed suggests an alternative aetiology within this cohort. Further research is urgently required to explore factors contributing to the high burden of neurocognitive impairment among PLWH in SSA.
Developing an effective strategy to implement non‐pharmaceutical interventions amongst residents with dementia in residential care facilities: Caregivers’ perspectives
Authors: Gillis Katrin , Stifkens Kathleen , Lahaye Hilde , Van Bogaert Peter 
Published: December 2021

AbstractBackgroundNon‐pharmaceutical interventions based on unfulfilled needs amongst residents with dementia reduce symptoms of agitation, aggression and depression. However, to implement these interventions in daily practice in residential care facilities, caregivers need to (a) analyse resident’s behaviour, (b) recognize unfulfilled needs and (c) apply an individualized non‐pharmaceutical intervention.ObjectivesTo develop an effective strategy for the implementation of such complex approach, insights in caregivers’ perception of barriers and facilitating factors are needed.MethodsA total of thirteen focus group interviews with fifty‐six caregivers from twelve residential care facilities was conducted between October 2019 and February 2020.ResultsDespite a person‐centred vision and culture in residential care facilities, caregivers recognize that dealing with altered behaviour amongst residents with dementia is challenging and that non‐pharmaceutical interventions are seldom used. However caregivers are willing to invest in a team‐based person‐centred approach, different perspectives on priorities in care processes seem to influence the implementation. Participants refer to the importance of an open team culture where safety is guaranteed. An open culture stimulates an attitude of reflection, which is necessary to attune person‐centred care to different perspectives. Therefore the presence of clinical and facilitating leadership is crucial to ensure motivation, a sense of competency, communication, problem‐solving competences, practical organization of non‐pharmaceutical interventions and continuity in care processes. Ward managers and clinical leaders prefer to be supported by an implementation coach who provides education and training to the team members and who facilitates from a neutral perspective moments of intervision on a regular base.ConclusionsCaregivers recognize the presence of a person‐centred vision and culture, team willingness and different perspectives on priorities in care processes as influencing factors for the implementation of non‐pharmaceutical interventions. Strong clinical and facilitating leadership and the availability of an implementation coach may support caregivers in dealing with different perspectives on priorities in care. Implications for clinical practice: An educational package, intervision sessions and a leadership trajectory are recommended elements of strategy to implement non‐pharmaceutical interventions based on unfulfilled needs amongst residents with dementia.
Discordant low amyloid‐β PET and high neocortical tau PET retention
Authors: Krishnadas Natasha , Dore Vincent , Lamb Fiona , Tyrrell Regan , Bozinovski Svetlana , Villemagne Victor L.L. , Rowe Christopher C. 
Published: December 2021

AbstractBackgroundExtracellular amyloid‐β (Aβ) plaques and intracellular tau neurofibrillary tangles characterize Alzheimer’s disease (AD). Combined use of Aβ and tau PET biomarkers demonstrates that high neocortical tau is rarely observed in the absence of high Aβ. We describe the prevalence of participants with high neocortical tau PET retention (visually and quantitatively) with a correspondingly low Aβ PET result and characterize these participants.MethodAIBL participants who had both an Aβ and tau PET scan were included. Centiloid <25 defined a low (negative) Aβ result. Tau PET SUVR (standardized uptake value ratio) was estimated in three composite regions of interest (ROI): mesial temporal (Me), temporoparietal (Te) and rest of neocortex (R). The 99%ile of the Aβ‐ve cognitively unimpaired participants determined the threshold for each ROI.ResultFour hundred and sixty‐six participants were included. Of all Aβ‐ participants (n=287), 12 were above the threshold in Te and R ROIs. Four participants (1.4% of all Aβ‐) had high neocortical tau tracer retention, quantitatively and visually, in a pattern consistent with AD (Braak stage V‐VI) (Figure 1). Despite the low Aβ PET, one participant had high plasma Aβ, while another had low CSF Aβ1‐42, high CSF pTau and tTau and an 18F‐FDG PET pattern consistent with AD. High plasma pTau‐217‐plus was observed for three of these four participants (result unavailable for one participant).ConclusionWe have identified four participants with low Aβ PET and high neocortical tau PET retention. The alternative biomarker results in these cases are suggestive of a diagnosis of AD, despite the low Aβ PET result. We propose that in these instances, the Aβ PET ligand may not be detecting Aβ, maybe due to a different conformation of the aggregates. While infrequent, this finding has been reported using 11C‐PiB. Overall, the prevalence of this discordance was <2% in the sampled cohort, suggesting it is an uncommon occurrence. However, this study is limited by the lack of alternative Aβ biomarker results. Studies in larger cohorts are necessary to validate these findings, while genetic testing and postmortem correlation will enhance our understanding of the potential explanation for this finding.
Chronic habitual hypohydration that elevates serum sodium above 142 mmol/l is a risk factor for accelerated cognitive decline and dementia, suggesting lifelong optimal hydration as preventive measure
Authors: Dmitrieva Natalia I , Boehm Manfred 
Published: December 2021

AbstractBackgroundWith no known cure for dementia, finding preventive measures to delay onset of the disease represents an important goal for dementia research. Our previous studies demonstrated that chronic subclinical hypohydration accelerates degenerative changes and increases prevalence of many age‐dependent degenerative diseases including dementia (PMID:31484829). Worldwide surveys find wide differences in habitual water intake and substantial prevalence of hypohydration in general population (PMID:26066354). Hypohydration results in elevation of extracellular sodium triggering activation of water conservation mechanisms (PMID:18509340). Analysis presented here evaluates associations of serum sodium at middle age as a measure of hydration habits with cognitive decline and dementia diagnosis later in life.MethodsData from Atherosclerosis Risk in Communities (ARIC) study were obtained from the BioLINCC data repository. In ARIC study, 15,792 45‐65 year‐old participants were evaluated over 5 visits spanning 25 years (Fig. 1A). Here, association of serum sodium with dementia diagnosis by visit 5 (age:70‐90 years) was assessed by multiple logistic regression analysis. Multiple linear regression analysis was used to asses associations with cognition measures: Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT). The models were adjusted for age, sex, gender, education, BMI, eGFR, glucose, and cholesterol. For visit 5, the models were additionally adjusted for diagnosis of heart failure, stroke and high blood pressure.ResultMidlife serum sodium is associated with dementia diagnosis at visit 5 both with adjustment for age only (OR=1.13 95%CI 1.05‐1.21, P<0.001) and in fully adjusted model (OR=1.09 95%CI 1.01‐1.19, P=0.03). This association is reflected in increased prevalence of dementia from 4% to 6‐7% in 70‐90 year‐old participants whose middle age serum sodium exceeded 142mmol/l: an approximate threshold for activation of water conservation mechanisms triggered by hypohydration (Fig. 1B). Consistently, higher serum sodium is associated with reduced performance on DSST and WFT cognition tests with substantial decline in upper half of the normal sodium range. The trend is already present at middle age (Fig. 1C‐D).ConclusionHabitual life‐long hypohydration accelerates cognitive decline and increases risk of dementia. Keeping serum sodium below 142 mmol/l by drinking appropriate amount of liquids may delay cognitive decline and decrease prevalence of dementia.