bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of plasma Amyloid‐β 42/40 ratio in early and pre‐clinical AD
Authors: Vogelgsang Jonathan , Klafki Hans , Morgado Barbara , Jahn‐Brodmann Anke , Esselmann Hermann , Bauer Chris , Schuchhardt Johannes , Peters Oliver , Priller Josef , Schneider Anja , Fliessbach Klaus , Jessen Frank , Duzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Ramirez Alfredo , Wiltfang Jens 
Published: December 2022

AbstractBackgroundIn 2021 Adacanumab, the first antibody that might potentially treat causal neuropathology associated to Alzheimer’s disease (AD), was approved by the FDA. However, early, most likely pre‐cognitive treatment is required raising a high need for early and low‐invasive diagnostic biomarker. Here, we present plasma Amyoid‐beta (Aβ) measurements in a large longitudinal observational study from the German Center for Neurodegenerative Diseases (DZNE, DZNE‐Longitudinal Cognitive Impairment and Dementia (DELCODE) study).MethodPlasma Aβ40 and Aβ42 of 1049 baseline samples from the DELCODE cohort were measured in a semi‐automated fashion according to our recently published protocol. Aβ immunoprecipitation and Mesoscale immuno‐measurement were controlled for batch effects. All samples were well balanced and Mesoscale Aβ measurements were performed in two technical replicates on the same assay plate. 41 samples with a coefficient of variation > 10% between the two technical replicates were re‐measured. Corresponding CSF and plasma Aβ measurements were available for 377 samples for further downstream analysis.ResultInterassay variability from a QC sample using 6 replicates was 8.3%, 8.0%, and 6.9% for Aβ40, Aβ42, and the Aβ42/40 ratio, respectively.CSF and plasma Aβ42 and Aβ42/40 ratio correlated with r=0.169 (p<0.001) and r=0.466 (p<0.0001), respectively. No correlation was observed for Aβ40. Plasma Aβ42/40 was able to distinguish samples from donors with a CSF Aβ42/40 ratio classified as pathological or normal with an AUC of 0.82. ApoE inclusion increased the AUC for plasma Aβ42/40 to 0.87 with a specificity of 0.73 and a sensitivity of 0.87.Importantly, plasma Aβ42/40 was not only able to differentiate participants with high vs. low CSF Aβ42/40 in general, but also predicted Aβ status in patients with milder or no cognitive impairments: in controls, the AUC for the plasma Aβ42/40 ratio was 0.78, in SCI 0.76, and in MCI 0.71. There was only one dementia case with a normal CSF Aβ profile, thus no further comparison could be performed for donors in dementia stage.ConclusionPlasma Aβ can differentiate CSF pathological vs normal AD patients. Further analysis including follow‐up data to identify the early predictive value of plasma Ab will be performed including neurocognitive measurements to include all plasma Aβ measurements.
Evaluation of a functional assessment tool in patients with mild cognitive impairment or Alzheimer’s disease in Lima, Peru
Authors: Custodio Nilton , Montesinos Rosa , Chambergo‐Michilot Diego , Herrera‐Perez Eder , Caipa Maritza Pintado , Seminario G Wendy , Cuenca José , Mesia Laura , Failoc‐Rojas Virgilio E , Diaz Monica M 
Published: December 2022

AbstractBackgroundFunctional assessment screening tools are crucial for dementia evaluations. The Alzheimer’s Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL) scale is a versatile functional assessment screening tool that can be used to monitor functional decline of patients with Alzheimer’s disease (AD). We sought to evaluate the validity and reliability of the ADCS‐ADL scale in Peruvian patients with mild cognitive impairment (MCI) or AD.MethodThis was a cross‐sectional study of older adults from a multidisciplinary neurology institute in Lima, Peru in one of three groups: cognitively healthy controls, MCI or AD. ANOVA or chi‐square tests were used. Psychometric properties evaluated included reliability (intraclass correlation coefficient, ICC; internal consistency, Cronbach’s alpha) and validity (external and convergent).ResultWe included 276 patients in the analysis. Age, sex, educational level, and depressive symptoms did not vary significantly between the groups, but the Mini Mental State Examination and Addenbrooke’s Cognitive Examination scores were significantly different between groups. ICC was 0.996 and Cronbach’s alpha was 0.937 for the ADCS‐ADL. The ADCS‐ADL could not differentiate patients with MCI from cognitively healthy controls, but it accurately differentiated degrees of cognitive impairment within the AD group. The ADCS‐ADL correlated highly with all functional assessment and cognitive screening tools, except for the Alzheimer’s Disease Assessment Scale‐Cognitive subscale.ConclusionThe ADCS‐ADL scale is reliable in a population of patients with AD in Lima, Peru, and correlated with most functional assessment scales used to evaluate patients with AD.
Distinct Patterns of Brain Atrophy in MCR and amnestic MCI pre‐dementia syndromes
Authors: Nagamalla Vineela M , Verghese Joe , Ayers Emmeline , Barzilai Nir , Beauchet Olivier , Lipton Richard B. , Shimada Hiroyuki , Srikanth Velandai K , Blumen Helena M 
Published: December 2022

AbstractBackgroundBoth amnestic Mild Cognitive Impairment (aMCI) and the Motoric Cognitive Risk (MCR) syndrome are reliable predictors of Alzheimer’s Disease (AD). There is also some evidence for that MCR is a stronger predictor of vascular dementia (VaD) than AD. The current study directly compared cortical and hippocampal atrophy patterns in MCR and aMCI to inform the development of interventions targeted to these pre‐dementia syndromes. We hypothesized that MCR would be associated with a widespread pattern of cortical atrophy while aMCI would be associated with atrophy restricted to hippocampal and neighboring temporal regions.MethodCross‐sectional data from 733 older adults without dementia and functional disabilities from the MCR‐consortium were examined. MCR was operationalized as slow gait and subjective cognitive complaint, using previously established cohort‐specific criteria. aMCI was operationalized as 1.5 standard deviation or more below standardized performance on episodic memory measures. FreeSurfer v6.0 was applied to T‐1 weighted MRIs to examine cortical thickness and hippocampal atrophy patterns in MCR and aMCI relative to those without MCR and aMCI, respectively. Separate general linear models (GLMs) examined the associations between overall and regional cortical thickness, hippocampal volume, and MCR and aMCI. All GLMs were adjusted for age, sex, education, total intracranial volume, white matter lesion burden, and study site.ResultThe mean age of the sample was 74.4 years (45.4% women). The prevalence of MCR and aMCI was 7.6% and 2.6 %, respectively. Both MCR and aMCI was associated with overall cortical atrophy. Yet, while MCR was associated widespread cortical atrophy – that included prefrontal, insular, cingulate, motor, parietal and temporal regions – aMCI was associated with a restricted pattern of atrophy that primarily included temporal and hippocampal regions.ConclusionThis study revealed distinct patterns of atrophy in older adults with MCR and aMCI pre‐dementia syndromes. A widespread pattern of cortical atrophy – that is more consistent with VaD or mixed dementia than AD – was observed in MCR. A more restricted pattern of atrophy – that is more consistent with AD than VaD or mixed dementia – was observed in aMCI. Thus, the biological underpinnings of MCR and aMCI likely differ, and may require tailored interventions.
An introduction to GENFI and the development of novel behavioural and cognitive measures for genetic FTD
Authors: Rohrer Jonathan D. 
Published: December 2022

AbstractBackgroundThe Genetic FTD Initiative (GENFI) is the largest familial FTD cohort study worldwide and over its initial ten years has created a network of nearly 30 research centres across Europe and Canada, and a cohort of over 1000 participants.MethodGENFI was established to develop robust biomarkers that could be used in clinical trials. In terms of clinical and cognitive measures, the study has used a set of novel symptom scales as well as a detailed neuropsychological battery, all harmonized across the network, to identify new rating scales and composite measures.ResultThe study has characterized behavioural and neuropsychological changes across the different genetic forms of FTD, highlighting the earliest prodromal changes that occur in different domains, including emotion recognition, semantic knowledge and executive dysfunction. GENFI data has also been used to validate two core clinical/cognitive scales, highlighting their utility for clinical trials in genetic FTD: the CDR plus NACC FTLD and the FTD Rating Scale (FRS). An extension to the CDR plus NACC FTLD with motor and neuropsychiatric domains highlights the contribution of symptoms outside of classical behavioural and language domains to accurately measuring disease progression. The study has also combined neuropsychological measures to create a cognitive composite measure (GENFI‐Cog), individualized to each genetic group, which greatly reduces sample sizes required for clinical trials.ConclusionThe GENFI study has developed and validated a number of clinical and cognitive measures that are now being implemented in clinical trials for novel therapeutics in familial FTD. Future studies in GENFI will help to refine these even further.
Magnetic resonance imaging biomarkers in genetic FTD
Authors: Rowe James B 
Published: December 2022

AbstractBackgroundMRI provides a suite of tools for safe, non‐invasive, repeatable and scalable assessment of the changes in brain structure and function associated with neurodegenerative disease. MRI has been part of the principal assessment in the international Genetic Frontotemporal Dementia Initiative since 2012 (GENFI). This presentation reviews the goals and achievements of MRI in GENFI, and considers future directions to elucidate disease mechanisms, inform clinical trials design, and provide single subject prognosis.MethodGENFI established protocols for harmonisation and standardisation of MRI, and coordinated infrastructure for curation and quality control. 3T MRI sequences have been optimised and closely approximated across diverse vendors, for whole‐brain qualification of volume (T1w), diffusion (DWI), perfusion (ASL), macro‐molecular environment (T2) and function (BOLD fMRI), with >2500 assessments from>1000 participants: including symptomatic people with mutations in MAPT, C9orf72 and GRN; pre‐symptomatic mutation‐carriers; and asymptomatic non‐carriers from the same families. There are >20 peer‐reviewed open‐access MRI‐based publications to date.ResultsGENFI MRI revealed a long pre‐symptomatic phase in people with FTD‐associated mutations, with atrophy present and progressive in frontotemporal regions >10 years before estimated onset. For some mutations, differences in mutation carriers (vs non‐carriers) are evident in early adulthood. The pre‐symptomatic structural change is associated with subtle cognitive and behavioural change. It is prognostic and non‐linear, accelerating with aging towards symptom onset. Intriguingly, functional integration is maintained in macro‐scale brain networks of pre‐symptomatic carriers, suggesting a mechanism of functional resilience to progression of underlying neuropathology. The consequences of mutations are not confined to frontotemporal regions: GENFI has highlighted behaviourally‐relevant changes in volume and shape, white‐matter hyperintensity and diffusivity in parietal lobe, basal ganglia, thalamus and cerebellum. The MRI tools can be used to identify stages and subtypes of genetic‐FTD.ConclusionOver ten years, GENFI has shown how MRI can be delivered at scale in multi‐centre studies of genetic FTD, revealing the long pre‐symptomatic phase, with gene‐specific mechanisms and consequences. The sensitivity, reliability and progression of gene‐specific changes in diverse MRI modalities are ideal to support clinical trials of novel therapeutic agents.
International collaboration and the FTD Prevention Initiative
Authors: Russell Lucy L 
Published: December 2022

AbstractBackgroundThe Frontotemporal dementia Prevention Initiative (FPI) is a collaborative group made up of familial FTD (fFTD) research groups across the world. This includes the Genetic FTD Initiative (GENFI) in Europe and Canada, ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) in the USA, the Multi‐partner consortium to expand dementia research in Latin America (ReDLat), the Dominantly Inherited Non‐Alzheimer’s Dementias (DINAD) in Australia, and The New Zealand Genetic FTD Study (FTDGeNZ). Initial efforts have been focused on individuals from families who are known to carry mutations in the C9orf72, GRN and MAPT genes.MethodsTo advance therapeutic trials for fFTD, data has been shared within the FPI across the different cohort studies to understand the stratification and disease progression of mutation carriers. As well as the development of a large network of ‘trial‐ready’ participants for upcoming trials, with further extension of this network to Asia, the FPI also aims to develop a set of principles for fFTD trials that will guide data and sample sharing.ResultsAn initial FPI project has shown the range of ages at symptom onset (AAO), death and duration in fFTD, with relatively poor correlation of individual AAO with both parental and family AAO, particularly in those with C9orf72 and GRN mutations. Further work has shown the ability of blood neurofilament light chain protein levels to predict subsequent disease progression. Lastly, a combination of clinical, cognitive, imaging and fluid biomarker data has allowed the development of disease progression models that will be useful in future clinical trial design.ConclusionsThe FPI is the first initiative to bring together the academic fFTD community to contribute to a global effort to find therapeutics for this devastating disease. Future work aims to extend the network and continue to establish our partnerships with our families, patient advocacy groups, and industry partners.
Consumption of ultra‐processed foods and cognitive decline in the ELSA‐Brasil study: a prospective study
Authors: Gonçalves Natalia G , Ferreira Naomi Vidal , Khandpur Neha , Steele Euridice Martinez , Levy Renata Bertazzi , Lotufo Paulo A , Bensenor Isabela M , Marchioni Dirce Lobo , Suemoto Claudia Kimie 
Published: December 2022

AbstractBackgroundConsumption of ultra‐processed foods (UPF) has progressively increased worldwide in the last 30 years. High intake of UPF is associated with cardiovascular disease and cancer and hypothesized to induce systemic inflammation and oxidative stress. Although UPF may also be a risk factor for cognitive decline through these pathways, little is lnown about the effects of UPF on cognition. We aimed to investigate the longitudinal association between UPF consumption and cognitive decline in the ELSA‐Brasil study during 9 years of follow‐up.MethodParticipants were evaluated in three study waves (2008‐10, 2012‐14 and 2017‐19).Data on diet measured by food frequency questionnaire was categorized according to degree of food processing using NOVA. Cognitive performance was evaluated using a standardized battery of tests ‐ the immediate recall, late recall, recognition, semantic and phonemic verbal fluency and the trail‐making tests. A global composite z‐score was derived from these tests. Association of consumption of UPF (% of total daily gram intake) with cognitive performance over time was evaluated using linear mixed effects models, adjusted for sociodemographic, lifestyle, and clinical variables.ResultIn 8,160 participants (mean 50.6±8.7 y, 56% women, and 55% white) during a median follow‐up of 9 years, the mean baseline calorie intake was 2,842±982 kcal, 28% (493g) of which came from UPF (Table 1). During follow‐up time, consumption of UPF in the fourth and fifth versus the first quintile were related to a decline in the executive funtion (β = ‐0.007, 95% CI = ‐0.013; ‐0.002, p = 0.004) and memory performance (β = ‐0.004, 95% CI = ‐0.009; 0.000, p = 0.048), respectively (Table 2). No association of UPF consumption and verbal fluency was observed (Table 2).ConclusionDuring nine years of follow‐up, high consumption of UPF was associated with cognitive decline, particularly in the memory and executive funtion domains.
Chemical ablation of locus coeruleus terminals in mice dysregulates behavioral features reminiscent of prodromal Alzheimer’s disease
Authors: Korukonda Anuradha , Iannitelli Alexa F , Weinshenker David 
Published: December 2022

AbstractBackgroundThe prodromal stages of Alzheimer’s disease (AD), which precede cognitive impairment by decades, are characterized by neuropsychiatric symptoms such as anxiety, agitation, impulsivity, and sleep disturbances that significantly impair quality of life. The brainstem noradrenergic locus coeruleus (LC) modulates behaviors that are reminiscent of these prodromal symptoms. Furthermore, the loss of norepinephrine (NE) terminals in LC‐projecting regions is a prominent feature of early AD, implicating LC dysfunction as a possible contributor to prodromal symptoms. However, the behavioral and pathological consequences of LC terminal loss have not been fully investigated.MethodAdult male and female C57BL/6 mice aged 4‐6 months were administered either saline or the LC‐specific neurotoxin, N‐(2‐chloroethyl)‐N‐ethyl‐bromo‐benzylamine (DSP‐4) (50 mg/kg, i.p.) on day 1 and day 7 (12 animals/group). Performance in behavioral tests that assess arousal (sleep latency), locomotor activity (novelty‐induced and circadian), anxiety (novelty‐suppressed feeding), and associative memory (contextual fear conditioning) commenced one week following the last treatment. In addition, brain sections consisting of LC, hippocampus, and cortical areas were immunostained for tyrosine hydroxylase (TH) to evaluate LC integrity, NE transporter (NET) to determine fiber/terminal density to LC‐projecting regions, and glial fibrillary acidic protein (GFAP) to assess astrogliosis. Fluorescence immunoreactivity (IR) was analyzed with ImageJ.ResultAnimals treated with DSP‐4 displayed significantly increased latency to feed in a novel environment compared to saline‐treated animals, with no treatment differences in the home cage, suggesting elevated neophobic behavior. Furthermore, DSP‐4‐treated animals trended towards decreased locomotor activity in the center of the environment over 1 hour and 23 hours, indicating increased thigmotaxis. No behavioral treatment differences were observed for sleep latency and contextual fear conditioning paradigms. Immunofluorescence revealed no treatment differences in TH IR in the LC but reduced NET IR in LC‐projecting regions of DSP‐4‐treated animals, demonstrating preserved LC cell bodies and LC fiber loss. No significant treatment differences were found for GFAP.ConclusionThese data suggest that chemical ablation of LC terminals with DSP‐4 can contribute to neophobia and anxiogenic responses, implicating LC terminal loss in mediating prodromal symptoms relevant to AD. Further studies are warranted to identify the physiological and molecular mechanisms underlying LC dysfunction for alleviating prodromal AD symptoms.
Depletion of voltage‐gated potassium channel Kv1.1 contributes to behavioral deficits in transgenic mouse model of Alzheimer’s disease
Authors: Addo‐Osafo Kwaku , Choquette Jessica M , Peters Samuel T. , Fomenko Vira , Xu Jordan , Craft Ryan , Gimlin Kayleen , Vossel Keith 
Published: December 2022

AbstractBackgroundPatients with Alzheimer's disease (AD) are at risk for seizures and accelerated cognitive decline. Mechanisms of seizures and related synaptic dysfunction in AD are active areas of investigation. Alterations in ion channels have been identified in transgenic mouse models of AD, but levels of voltage‐gated potassium channels (VGKCs) have not been fully explored. In particular, little is known about Kv1.1 channels in AD. Mutations in Kv1.1 or autoantibodies against Kv1.1 cause neuronal overexcitation in several human diseases, including episodic ataxia type 1, epilepsy, myokymia, and limbic encephalitis, indicating that Kv1.1 is critical for regulating neuronal excitability.MethodTo explore VGKCs in AD, we used hAPP‐J20 mice ages 4‐6 months and determined mRNA and protein levels of four highly expressed VGKCs ‐ Kv1.1, Kv1.2, Kv1.4, and Kv4.2 ‐ in dentate gyrus, entorhinal cortex, motor cortex, and somatosensory cortex (SSC).ResultUsing RT‐qPCR, we identified reductions in Kv1.1 mRNA in the SSC of hAPP‐J20 mice. Western blotting revealed reductions in the Kv1.1 channel in the SSC of hAPP‐J20 mice and human parietal cortex in mild and moderate stages of AD. Immunolabeling revealed that the reductions in Kv1.1 channels in the SSC occurred in pyramidal cells and GABAergic interneurons. Kv1.1 levels in the SSC were lower in hAPP‐J20 mice, which overexpress mutant hAPP and have high Aβ(1‐42) levels, than in the wild‐type hAPP line I5, suggesting some dependence on Aβ(1‐42) levels. Levetiracetam treatment (75 mg/kg/day) administered for 28 days did not affect Kv1.1 levels in hAPP‐J20 mice. To assess Kv1.1 depletion in an AD model, we crossed Kv1.1 heterozygous mice (Kv1.1 +/‐) with hAPP‐J9 mice, which have lower expression of mutant hAPP than J20 mice. We performed behavioral tests on mice ages 4‐9 months. While Kv1.1 +/‐ mice and hAPP‐J9 mice had normal survival, the double mutant (Kv1.1 +/‐ hAPP‐J9) mice had premature mortality and impairments in elevated plus maze and light‐dark box tests (n=16‐25 mice/genotype) of anxiety.ConclusionThese data indicate that elevated Aβ(1‐42) levels may act synergistically with Kv1.1 depletion to exacerbate cognitive deterioration in AD. Ongoing investigation will further characterize the relationships between Kv1.1 loss and AD‐related hyperexcitability.