bluuebunny/crossref_metadata_2025 huggingface dataset:
Age determines the profile of cognitive impairment after COVID‐19. Results of an international, multi‐cohort, pooled analysis and meta‐analysis
Authors: Gonzalez‐Aleman Gabriela , Vavougios George D. , Tartaglia Carmela , Guekt Alla , Uvais Nalakath A. , Hosseini Akram A. , D'Avossa Giovanni , Ferreccio Catterina , Perez‐Lloret Santiago , Botero‐Rojas Camila , Insua Francisco Gonzalez , Figueredo‐Aguiar Mariana
Published: December 2023

Background

Evidence‐based data are still lacking to define de characteristics of cognitive impairment after COVI‐19. Previous findings suggest that Covid‐19 sequelae may resemble early Alzheimer’s disease (AD). In this abstract, our team present data from Argentina, Canada, Russia, Greece, and the UK including 1919 patients and 1031 controls.

Method

Participants were 18 to 97 years old. Neuropsychological evaluation included Montreal Cognitive Assessment – MoCA, Toronto Cognitive Assessment‐ TORCA, and/or batteries specially built for the evaluation of cognitive dimensions. Some cohorts included the anosmia. Participants were evaluated at a maximum of 6 months after discharge. A factorial analysis was performed on each country identifying 3 factors that could be compared between countries: one accounting for memory and language, the second is an attentional factor, and the last is a working memory factor. Between countries that have young population, there was a fourth factor accounting for executive functioning (planning and inhibition). We carried out meta‐analysis of common factors and co‐variates.

Result

Average duration of formal learning is 11.06 ± 5.11 years, and the mean age is 52.61 ± 15.87 years. Meta‐analysis revealed an impairment in language (verbal fluency) for all patients vs controls. Factorial scores revealed that all the participants were impaired in attentional tasks but those over 60 years old were impaired also in working memory and the youngest participants in executive functioning. Significant differences between cases and controls in attentional, memory, and language tasks identified 4 different groups: normal cognition (71%); one dimension impaired (20.5%); two dimensions impaired (6.5%); and three dimensions impaired (2%). In older adults, these proportions rise to 28% for the impairment in one dimension; 11.5% for two dimensions, and 3.5% for three dimensions and is significantly associated with the infection diagnoses (p = 0.013) and with presence and severity of anosmia (p = 0,000).

Conclusion

Older adults are at greater risk of suffering persistent cognitive impairment after recovery from SARS‐CoV‐2 infection and cognitive impairment is correlated with the presence and severity of anosmia.
Amygdala volume as neuroimaging marker of limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) in neurodegenerative disease: a post‐mortem MRI and pathology study
Authors: Wesseling Alex , Calandri Ismael Luis , Ossenkoppele Rik , van de Berg Wilma D.J. , Rozemuller Annemieke J.M. , Pijnenburg Yolande A.L. , Hoozemans Jeroen , Jonkman Laura E.
Published: December 2023

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is characterised by hyper‐phosphorylated TAR DNA‐binding protein 43 (TDP‐43) aggregates within the amygdala and (para)hippocampal regions. LATE neuropathological change can occur in patients with neurodegenerative disorders including Alzheimer’s (AD) and Parkinson’s disease (PD), as well as in healthy controls. LATE is associated with lower cognitive performance in AD patients. No neuroimaging marker for LATE is currently available, but identification would be of importance for accurate disease prognosis and as potential exclusion criteria for e.g. AD clinical trials. The current study aims to assess whether MRI‐measured amygdala and hippocampal volume can differentiate LATE status in neuropathological‐confirmed AD and PD brain donors.

Method

Post‐mortem in‐situ 3DT1 3T‐MRI data were collected for 15 cases (9 AD and 6 PD) with post‐mortem confirmed LATE neuropathological change, as well as 30 non‐LATE (18 AD and 12 PD) donors. Each donor with LATE was matched with two non‐LATE donors on age, sex and neuropathological (i.e. Thal and Braak) staging. Neuropathological assessment was done on tissue of the right hemisphere. Amygdala volume, including amygdala subfield volumes, as well as hippocampal volume, were calculated using Freesurfer (version 7.1.1) and corrected for total intracranial volume. Group differences were assessed with univariate analyses using post‐mortem delay as covariate, subfield analysis were Bonferroni corrected.

Result

Brain donors with LATE neuropathological change showed significantly lower right amygdala (p = .002) and right hippocampal (p = .007) volumes (figure 1). Amygdala subfield volumes were available for 13 LATE and 27 non‐LATE cases. When investigating the amygdala subfields, we found significant LATE compared to non‐LATE differences within the anterior amygdaloid area (p = 0.005) and the lateral nucleus (p = 0.002) (figure 2). In AD (n = 27), LATE cases showed significantly lower right amygdala (p = .023) and right hippocampal (p = .003) volumes compared to non‐LATE cases. In PD (n = 18), only the volume of the right amygdala was significantly lower in LATE cases compared to non‐LATE cases (p = .043) (figure 3).

Conclusion

MRI‐measured amygdala volume, especially of the anterior and lateral nucleus, can differentiate LATE neuropathological change, and may therefore serve as a promising neuroimaging biomarker in neurodegenerative disease.
Social relations, cognitive health disparities and COVID‐19 stress
Authors: Antonucci Toni C , Brauer Simon , Zahodne Laura B. , Ajrouch Kristine J
Published: December 2023

Background

The prevalence and incidence of COVID‐19 was higher among racial/ethnic minority groups in the U.S. (APM Research Lab, 2020), but stressor types, resilience, and impacts on cognitive health are unknown. Economic and socioemotional stress each affect health and contribute to racial/ethnic health disparities (Sternthal, et al., 2011). Further, changes in stress and social relations influence cognitive decline (Dickinson et al., 2011; VonDras et al., 2005). However, it is unclear if associations are similar across racial/ethnic groups.

Method

Participants in the recently completed U.S. based Detroit Area Wellness Network COVID‐19 Supplement (DAWN‐CS) project (N = 606) were recruited from a longitudinal cohort study (i.e., Social Relations Study; Antonucci & Akiyama, 1994), supplemented by address‐based and respondent‐driven sampling to obtain a racially/ethnically balanced sample of Middle Eastern/Arab (MENA), Black, and White older adults (aged 65+). Eligible persons (aged 65+) within screened households were selected with probability to allow appropriate inference to the target population. Inclusion criteria for DAWN‐CS were: age 65+, fluency in English or Arabic, and identifying as MENA, Black, or White. Participants were administered psychosocial questionnaires and cognitive measures via telephone. Global cognition was a latent variable indicated by episodic memory, language, attention, and working memory tests.

Result

Older adults who saw their network members more frequently during the COVID‐19 pandemic reported more economic stress and demonstrated worse cognitive health. Within‐group analyses showed unique patterns: only among Black older adults was there an association between more contact frequency and higher economic stress. Further, the association between economic stress and worse cognitive health was evident among MENA and White older adults, but not Black older adults. Pandemic‐related socioemotional stress (e.g., conflict with family and friends) did not vary by race/ethnicity and was not associated with contact frequency during the COVID‐19 pandemic. Further analyses examine whether social relations buffered the effects of pandemic‐related economic stress on cognitive health.

Conclusion

Including underrepresented populations in the study of social relations, stress and cognitive health advances science and addresses societal health in its entirety. Strengths of this study include its racially/ethnically balanced sample, which improved the power and validity of racial/ethnic group comparisons.
Are there baseline structural MRI differences between individuals who progress along the Alzheimer’s disease continuum and those who remain cognitively stable? A systematic review
Authors: Saadat Nazanin , Parker Ashleigh F. , Kwan Heather , Grewcock Riley , Gawryluk Jodie
Published: December 2023

Background

Early identification of individuals that will progress along the continuum from normal cognition to mild cognitive impairment (MCI) and to Alzheimer’s disease (AD) is imperative for timely prevention and intervention measures. Structural magnetic resonance imaging (MRI) is a non‐invasive technique commonly used to examine neurodegeneration. The current review summarizes the literature on structural brain differences between individuals who experience conversion to MCI from normal cognition or AD from MCI and those who remain stable.

Method

Medline and PsycINFO databases were searched for studies that compared baseline structural MRI of individuals who converted from normal cognition to MCI, or from MCI to AD, to those with normal cognition or MCI who remained cognitively stable. Inclusion criteria included studies with baseline structural MRI, cognitive follow‐up to assess conversion/stability, and comparison between converters and non‐converters. Two authors reviewed each abstract and a third review resolved any conflicts. The same process was used for full‐text articles. Information regarding sample size, acquisition and analysis and results were extracted and all studies were reviewed for quality using the AXIS tool.

Result

A total of 1670 studies were imported for screening in Covidence and 440 duplicates were removed. Following abstract screening, 293 studies were eligible for full‐text review. Many of the identified studies took a region of interest approach focused on hippocampal volume and found significant differences between converters and non‐converters. Many studies used multi‐site, multimodal databases (e.g., Alzheimer’s Disease Neuroimaging Initiative) to retrospectively examine converters and non‐converters. Many more studies looked at individuals who converted from MCI to AD than normal cognition to MCI. Further analyses of the full text review and findings will be presented.

Conclusion

Characterization of baseline differences in brain structure between those who progress on the AD continuum and those who remain stable is crucial for early diagnosis and treatment. The current review indicates that such differences are evident on structural MRI. The medial temporal lobes have been identified as a region of interest. However, it will be important for future research to use a whole brain approach and for further examination of individuals who convert from normal cognition to MCI.
Tau and lipid coalescence drives early lipid dysregulation in Alzheimer’s disease
Authors: Oliveras Anna
Published: December 2023

Background

In Alzheimer’s disease (AD), intraneuronal tau protein accumulation into neurofibrillary tangles correlates with clinical signs and neurodegeneration1. Besides neurotoxic protein aggregation, dysregulation of lipid metabolism is emerging as a common disease mechanism2. The main regulators of lipid metabolism in the brain are astrocytes and astrocyte‐neuron communication is key to provide metabolic support to neuron3. While tau has been suggested to bind to lipids4, little is known about the potential tau‐lipid interactions in the brain, it’s role in neuron‐astrocyte crosstalk and how this relates to AD pathology.

Methods

We employ a multiscale approach harnessing human 2D and 3D multicellular models combined with advanced imaging techniques, spanning from single molecule insights to ultrastructural features and functional imaging. We aim to unravel the structural and functional complexity of emerging protein‐lipid landscapes in AD and to elucidate how their misregulation triggers early lipid dyshomeostasis.

Results

Tau propagates in brain organoids in highly dynamic intracellular droplet‐like structures rich in lipids. Strikingly, the molecular identity of tau droplets is cell‐type specific; tau interact with lipids in neurons but not in astrocytes (fig.1‐2). The dynamics of neuronal tau‐lipid accumulations are driven by microtubule interactions and show liquid‐like behavior. Furthermore, highly dynamic tau‐lipid droplets transition to stillness overtime giving rise to a heterogenous spectrum of conformational ensembles of tau (fig.3).

Conclusion

Tau‐lipid interactions in vivo are neuron‐specific. Lipid colocalization correlates with dramatic changes in the structural properties of tau. In neurons, tau and lipids coalesce in highly dynamic intracellular liquid‐like droplets that undergo time‐dependent transition to potential pathological states. Our results highlight intriguing functional implications of cell‐type specific tau‐lipid interactions impacting on neuron‐astrocyte communication and overall brain lipid metabolism. Targeting tau‐lipid interactions in neurons promise exciting new avenues in AD therapeutic strategies.

1. Busche, et al. Synergy between amyloid‐β and tau in Alzheimer’s disease. Nat. Neurosci. (2020).

2. Yin. Lipid metabolism and Alzheimer’s disease: clinical evidence, mechanistic link and therapeutic promise. FEBS J. (2022).

3. Yang, et al. Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases. Cell Biosci. (2022).

4. Sallaberry, et al. Tau and Membranes: Interactions That Promote Folding and Condensation. Front. Cell Dev. Biol. (2021).
Precision Medicine in Alzheimer’s Disease: Phenotype Investigation, Medication Effects and Variant Analysis in Cell Type Specific Subgroups
Authors: Tost Eric Palanques , Grenn Francis , Hu Junming
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by cognitive decline and dementia and has few clinically approved treatments. The clinical and neuropathological heterogeneity of AD suggests the existence of AD subgroups with unique mechanisms and implies the need for cell‐type specific subtyping and treatments. The goal of this project was to investigate the differential effects of medications on cognitive tests in eight previously defined brain cell type‐based polygenic risk scores (PRS).

Method

Medication usage information, imputed genotypes, phenotypic data and cognitive test scores were collected for 487,409 participants from the UK Biobank to use in the analysis of the different PRS groups. We determined the characteristics of the PRS used by comparing 16 phenotypes in high and low risk subjects. Association between four cognitive test scores (fluid intelligence, reaction time, prospective memory, and pairs matching) and medication status (treated vs. untreated) was determined using logistic regression. Cognitive scores were rank‐transformed for the analysis, and the logistic regression was performed separately for high‐risk and low‐risk genetic groups. Genome‐wide association studies (GWAS) were used to detect genetic variants linked to medication usage. This analysis was repeated for all, high risk and low risk samples, using only medications that demonstrated a significant association with improved cognitive function during follow up examination.

Result

Phenotypic variation was wide among different PRS groups. Genetically different PRS groups shared phenotypic characteristics, suggesting that different underlying mechanisms lead to similar outcomes. Six medications were significantly associated (P<0.05) with improved cognitive function during follow‐up examination. Atenolol, a high blood pressure medication, was associated with the largest gain, with an improvement on the effect of cognitive function by 67% in the high‐risk compared to the low‐risk subjects from an astrocyte genetic subtype (Ast‐M9). The atenolol GWAS focused on the Ast‐M9 high risk group identified two genome wide significant variants at the same locus. These were previously shown to be associated with phenotypes related to blood pressure and were known eQTLs.

Conclusion

Our findings suggest potential novel implications for genetic subtype‐driven treatment options for AD. Further research is needed to validate these associations that may explain differential effects of medications in AD‐subtypes.
Investigating the endocytic mechanism of pathological tau at the synapse
Authors: Stuart Skye , Moretto Edoardo , Schiavo Giampietro
Published: December 2023

Background

The spatiotemporal spread of pathological tau observed across anatomically connected brain areas in Alzheimer’s disease suggests that tau pathology propagates trans‐synaptically. The underlying endocytic mechanisms of tau occurring at the post‐synapse remains poorly characterised. This study aims to investigate the mechanism/s controlling neuronal endocytosis of tau at the synapse, and understand how this mechanism is altered in tauopathies, with the goal of identifying targets to prevent pathological tau spread.

Method

To achieve this ambitious target, human tau undergoing synaptic endocytosis will be monitored in living neurons with confocal microscopy in specifically designed unidirectional microfluidic devices. Incorporating this novel model, targeted screening using pharmacological and genetic approaches will identify which endocytic mechanisms are exploited by pathological tau to enter neurons. Finally, targets of interest will be further investigated through co‐localisation studies to human tau and post‐synaptic markers using super‐resolution microscopy.

Result

Preliminary experiments showed that by infecting an isolated population of neurons with the P301S‐tau mutant, tau‐positive puncta and aggregates are detected in synaptically connected neurons, suggestive of trans‐synaptic tau propagation. In addition, we demonstrated that tau transfer is dependent on neuronal stimulation, supporting the notion that tau spreads across synapses in an activity‐dependent manner.

Conclusion

Further work is required to optimise this experimental set up for investigating the exact mechanisms underlying tau endocytosis at the post‐synaptic level. Elucidating the specific pathways involved in tau uptake at the synapse will aid the identification of novel targets to prevent pathogenic tau spread and tauopathy progression.
Description of the Gut Microbiome Composition in Puerto Ricans with Alzheimer’s Disease Compared to Healthy Controls
Authors: Sepulveda Vanessa , Soler‐Llompart Cecilia Michelle , Sala‐Morales Ana Cecilia , Godoy‐Vitorino Filipa , Santiago‐Berríos Michel , Ruiz‐Adames Javier A. , Olivieri‐Henry Gerianne , Pérez‐Luzunaris Fabián J. , Herrero‐Rivera Carlos
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common type of dementia, a debilitating disorder that could result in complete loss of mental functions and death. In Puerto Rico, AD is the fourth leading cause of death, while in the United States is the sixth. Evidence suggests that the gut microbiome plays a role in the pathophysiology of AD through neuroinflammation and amyloid deposition at brain. Our Objective: Study the gut microbiome composition and diversity of Puerto Ricans with AD compared to cognitive‐intact controls and associate the microbiome with cognitive impairment.

Method

We recruited 53 participants, 28 with AD and 25 controls, who underwent clinical and cognitive assessments(MoCA/CDR). Genomic DNA extractions performed on collected fecal samples. NextGen Illumina MiSeq was used to sequence 16S rRNA genes (V4 region) and analyzed with standard pipelines for microbiome species.

Result

Preliminary analyses showed no statistically significant differences between AD and controls in bacterial diversity and richness. However, AD participants showed an abundance of Euryachaeota, while controls had higher levels of Bacteroidetes. We found significant differences in alpha diversity with cognitive decline and a reduction of Roseburia ‐a known butyrate producer with protective and anti‐inflammatory properties‐ in participants with severe cognitive impairment.

Conclusion

First study in Puerto Rico comparing a neurodegenerative disease common in the aging population with the gut microbiome. The study of the Gut‐Brain‐Axis may open the possibility for preventive microbiota‐based therapies and strategies for a healthy microbiome resulting in better outcomes for our patients with and without AD.
Prediction of functional dependence with digital clock drawing, word recall, and assessment of lifestyle and health factors
Authors: Gomes‐Osman Joyce Rios , Jannati Ali , Banks Russel R , Ciesla Marissa R , Toro‐Serey Claudio R , Libon David R , Swenson Rodney , Tobyne Sean , Showalter John , Pascual‐Leone Alvaro
Published: December 2023

Background

Distinguishing mild cognitive impairment (MCI) and Alzheimer’s disease‐related dementia (ADRD) requires assessing the clinical impact of cognitive deficits on a patient’s activities of daily living. To accurately monitor cognitive decline, it is thus critical to combine early screening of cognitive deficits with the assessment of functional impairment. The Digital Clock and Recall (DCR™), consisting of DCTclock™ and a 3‐word delayed recall, employs AI‐enabled performance analyses to evaluate memory, executive function, visuospatial abilities, and motor functions. The Life and Health Questionnaire (LHQ) is a brief digital survey that captures key lifestyle and health factors for cognitive decline/dementia. We evaluated whether the combination of the DCR and LHQ can predict functional status, measured by the Functional Abilities Questionnaire (FAQ) reported by an informant, in older individuals with statuses ranging from cognitively unimpaired to MCI and ADRD.

Method

849 participants from a multisite study (age mean±SD = 72.1±6.7; 56.8% female; years of education mean±SD = 15.4±2.7), classified as cognitively unimpaired (n = 369), MCI (n = 262), or ADRD (n = 215). Mild (mFD) and moderate (modFD) levels of functional dependence were defined as FAQ score ≥ 6 and ≥ 9, respectively. We conducted 10‐fold cross‐validated regularized logistic regressions using LHQ responses and DCR metrics to predict mFD or modFD, controlling for age, sex, and education.

Result

LHQ significantly predicted mFD and modFD (p’s<0.001, R2 = 0.13, and R2 = 0.12). Adding DCR metrics to the model improved both models (p’s<0.001, R2’s = 0.18 and 0.13, respectively). Surviving LHQ questions for predicting mFD related to unintended weight loss, social engagement/volunteering, cognitively stimulating tasks, sleep, and life satisfaction/purpose. Surviving LHQ questions for predicting modFD related to unintended weight loss, social engagement/volunteering, cognitively stimulating tasks, and sleep.

Conclusion

A brief assessment that can be completed in primary care settings in <10 min consisting of an objective digital cognitive assessment and a survey of self‐reported lifestyle and health factors can not only identify early cognitive impairment but also reliably predict level of functional dependence in instrumental activities of daily living ‐ without need for an informant.
Thermodynamics of amyloid formation
Authors: Nagel‐Steger Luitgard , Fazelnia Nazanin , Willbold Dieter
Published: December 2023

Background

Is amyloid formation an exothermic process with the potential to damage brain tissue by local hyperthermia? In our study we aim to find answers to the above question. Several proteins, i.e. lysozyme and amyloid‐β peptide, known to form amyloid structures are investigated primarily by differential scanning calorimetry (DSC) in order to determine their thermodynamic properties.

Method

Experiments in DSC are complemented by a set of other biophysical methods in order to clarify molecular parameters for the evaluation of the heat capacity measurements.

Result

For this purpose a seeded amyloid formation assay has been designed. In this assay the structural conversion of a given amount of monomeric protein is accelerated and synchronized by the addition of preformed amyloid fibril fragments to result in reproducible heat bursts caused by amyloid formation.

Conclusion

First results are reported and the measured enthalpies are related to known enthalpies from protein structural conversion processes.
Acute response of astrocytes under rose bengal photoinduction‐mediated vascular injury
Authors: Norris Christopher M. , Gant John C , Rogers Colin B , Nelson Peter T , Sompol Pradoldej
Published: December 2023

Background

Cerebrovascular pathology, often found in autopsy confirmed Alzheimer’s disease (AD), is widely believed to exacerbate AD pathophysiology and complicate anti‐AD treatment strategies. Perivascular cells such as astrocytes maintain the microenvironment for proper brain cell function and vascular integrity. Early occurrence of cerebral small vessel disease and astrocyte reactivity could lower the threshold of neuronal disorders and AD. Studies of astrocyte and microvascular pathology and function in the brain have been limited and reaction of astrocytes to vascular damage has yet to be fully understood.

Method

AAV‐Gfa‐EGFP or AAV‐Gfa‐GCaMP6 was injected into the barrel cortex of wild type mice followed by glass window installation. After 3 weeks recovery, rhodamine dextran was IV‐injected and intravital brain imaging through two‐photon microscopy was performed at pre‐ and post‐photoinduction. Photoactivation of IV‐injected Rose Bengal dye (RB) technique was used to create vascular pathology. ImageJ was used for data analysis and GraphPad prism was used for statistical analysis.

Result

After photoinduction, green fluorescence intensity was increased in blood stream of both EGFP and GCaMP expressing brains. This result indicates a leakage of brain parenchyma component to blood stream. Astrocytic EGFP fluorescence intensity and astrocyte processes complexity were reduced after photoinduction in a time‐dependent manner. Interestingly, astrocyte calcium signaling was strikingly increased after photoinduction and returned back to the baseline at ∼1,000s post‐induction. The highest peak of astrocyte calcium signaling was located near a site of vascular damage, indicated by an increased in rhodamine fluorescence intensity in the brain parenchyma area. Astrocytic GCaMP intensity at the astrocyte endfeet surrounding small vasculature was increased, on the other hand, GCaMP intensity at the astrocyte processes are decreased in a time‐dependent manner. Consistently, we observed a reduction of vascular diameter after photoinduction in both EGFP and GCaMP expressing brains.

Conclusion

Acute vascular injury induced by rose bengal photoinduction altered astrocyte integrity and cellular signaling. This injury model resembles vascular constriction and hemorrhages found in human brain that could accelerate neurodegeneration and AD progression.
Lithium carbonate treatment decrease neuroinflammation and ameliorates long‐term memory in a Down syndrome animal model
Authors: de Souza Larissa Estessi , Spelta Lidia Emmanuela Wiazowski , Buchpiguel Carlos A , Real Caroline Cristiano , Faria Daniele de Paula
Published: December 2023

Background

Individuals with Down Syndrome (DS) have an increased genetic risk for developing Alzheimer’s Disease (AD), due to a higher expression of genes related to the pathophysiological development of the disease and to the inflammatory process. Brain damage is already substantial when the first clinical signs of AD appear, it is essential to study therapeutic alternatives that delay its development. As lithium carbonate has been identified as a neuroprotective and neuroplastic agent in neurodegeneration, the aim of this study is to evaluate the treatment effect of lithium carbonate in the neuroinflammation and long‐term memory of Ts65Dn animal model of DS.

Method

Ts65Dn mice (trisomy confirmed by genotyping) were treated with a lithium carbonate microdose (0.25 mg/kg dissolved in water) for 18 months and compared to non‐treated animals. To evaluate the treatment, [11C]PK11195 PET images were acquired at the ages of 5, 14, 20 and 24 months. Whole brain images were quantified in SUV (Standardized Uptake Value) and long‐term memory was assessed by the novel object recognition test (1).

Result

[11C]PK11195 uptake was increased at 14 months in the non‐treated animals when compared to the respective age of 5 months (+29%), although not statistically significant. However, when mice were treated with lithium, this increase was not detected. Compared to 14 months, at the ages of 20 and 24 months, there was a decreased uptake in the non‐treated animals (Ts65Dn: ‐52%, p = 0.01 at 20 months; Ts65Dn: ‐59%, p = 0.006; at 24 months) and whereas in Ts65Dn‐lithium, the uptake did not change significantly among the ages. There was a decrease in the long‐term memory index in the non‐treated animals, at the ages of 20 (p = 0.03) and 24 months (p = 0.009), compared to 14 months‐old whereas in the treated animals the memory was preserved.

Conclusion

The treatment with lithium carbonate prevented glial cells alterations during life‐span and preserved long‐term memory of a Down syndrome animal model indicating that this treatment can contribute to a healthy brain aging in this syndrome.
Defining and characterizing neocortical tau resistance in preclinical Alzheimer’s Disease
Authors: Properzi Michael J , Townsend Diana , Klinger Hannah M , Boyle Rory , Coughlan Gillian T , Hanseeuw Bernard J , Amariglio Rebecca E. , Rentz Dorene M. , Jacobs Heidi I.L. , Price Julie C , Chhatwal Jasmeer P. , Schultz Aaron P. , Hohman Timothy J. , Donohue Michael C. , Johnson Keith A. , Sperling Reisa A. , Buckley Rachel F.
Published: December 2023

Background

Topographical staging of tauopathy in preclinical Alzheimer’s disease (AD) posits early deposition in the entorhinal region (medial temporal lobe; MTL) followed by spread to adjacent neocortical (NEO) regions. Predictive models support a cascade of tau deposition as baseline MTL tau robustly predicts NEO tau accumulation. In clinically normal (CN) Ab+, elevated tau in MTL and NEO is associated with accelerated progression to dementia relative to those with only elevated MTL tau. The frequency and profile of neocortical tau resistance (defined as MTL+/NEO‐) remain unclear.

Method

We defined tau resistance using two longitudinal datasets. To compare directly across MTL (entorhinal/amygdala/parahippocampal) and NEO (inferior‐temporal/fusiform/middle‐temporal/inferior‐parietal) composites, we averaged regional SUVrs within each composite then normed them to independent samples of younger CNAb‐ adults. We selected CN participants from ADNI and HABS with ≥2 time‐points of Flortaucipir‐PET (nHABS = 200; nADNI = 149; cerebellar‐greyreference). We extracted slopes from a linear mixed model covarying for age, APOEe4 and Abstatus. We compared baseline MTLnormed values with slopes in a NEOnormed. We defined tau resistance as those with elevated baseline MTLnormed tau‐PET but no change in NEOnormed tau‐PET over time. We used non‐parametric group comparisons to determine differences in a range of variables (Table1).

Result

We found a poor to moderate correlation between baseline MTLnormed values and adjusted NEOnormed slopes (rHABS = 0.12; rADNI = 0.36; Fig.1), with a non‐linear association at higher levels of MTLnormed. In HABS, tau resistance was identified in 13% (n = 10) of those with elevated MTLnormed. There was a trend for Black/African American individuals to be less tau resistant (Table.1). In ADNI, 26% were identified (n = 11), there was a trend toward less APOEe4 carriers in the resistant group. Although the ranges of change were different across the two cohorts, adjusted MTLnormed and NEOnormed slopes were similarly strongly correlated (rHABS = 0.69; rADNI = 0.74; Fig.2).

Conclusion

Our preliminary findings suggest that resistance to neocortical tau in CN exists in up to a quarter of those with elevated MTL. Given the complexities with determining cross‐sectional and longitudinal tau‐PET thresholds, our approach to identifying MTL+ or NEO+ may be too conservative. Future work will validate tau resistance via cognitive decline and clinical progression.
The late onset Alzheimer’s disease‐associated TREM2 R47H regulates susceptibility to ferroptosis
Authors: Li Gang
Published: December 2023

Background

Genome‐wide association studies (GWAS) have identified TREM2 R47H as one of the genetic risk factors associated with late‐onset Alzheimer’s disease (LOAD). However, the mechanism underlying the contribution of this variant to the pathogenesis of, and/or the susceptibility to LOAD is still elusive.

Method

Disease‐associated functional SNPs were identified and characterized by coupling Reel‐seq (Regulatory element‐sequencing), a high‐throughput mapping technique, with SDCP‐MS (SNP‐specific DNA competition pulldown‐mass spectrometry), a proteomics analysis. Ferroptosis was validated by combining MTT assay, MDA assay as well as C11‐BODIPY staining in human microglial cells.

Result

rs75932628, an exonic SNP encoding for TREM2 R47H, is part of a cis‐regulatory element modulating TREM2 expression by recruiting a protein complex that contains two iron chaperons. Iron suppresses TREM2 expression by disrupting the binding of these proteins to rs75932628 and this disruption is further enhanced more by the risk allele A than the non‐risk allele G. Moreover, down‐regulation of TREM2 inhibits GPX4 expression via a TREM2‐mediated signaling pathway, resulting in ferroptosis due to accumulation of lipid peroxides.

Conclusion

Iron, as the most abundant heavy metal in nature, induces ferroptosis by down‐regulating GPX4 via the LOAD‐associated TREM2 R47H.
The Digital Clock Drawing Test and Delayed Recall Predict Informant‐Rated Functional Impairment in Individuals with Cognitive Impairment
Authors: Jannati Ali , Gomes‐Osman Joyce Rios , Banks Russel R , Toro‐Serey Claudio R , Ciesla Marissa R , Tobyne Sean , Showalter John , Pascual‐Leone Alvaro
Published: December 2023

Background

Nearly 6.7 million people aged 65 and older in the US are living with Alzheimer’s disease (AD). Early detection of dementia presents a difficult challenge, as the earliest signs of cognitive decline often go undetected. Thus, more sensitive and clinically meaningful cognitive screening tools are needed. Evaluating the patient’s dependence in activities of daily living is critical to detect progression toward dementia. The Linus Health DCTclock™ employs AI‐enabled analyses of the clock drawing process to evaluate cognitive and motor function. We evaluated the utility of four DCTclock composite scales including Spatial Reasoning, Drawing Efficiency, Information Processing, and Motor Skills, 22 DCTclock subscales, and the 3‐word Delayed Recall score from the Digital Clock and Recall (DCR™) to predict the informant‐rated functional activities questionnaire (FAQ) score in older adults ranging from cognitively unimpaired to individuals with mild cognitive impairment (MCI) and AD‐related dementia (ADRD).

Method

939 participants in a multisite study (age mean±SD = 72.1±6.7; 57.1% female; years of education mean±SD = 15.4±2.7; primary language English), classified as cognitively unimpaired (n = 406), MCI (n = 293), or ADRD (n = 238) were included. We conducted cross‐validated regularized logistic regressions with FAQ score ≥6 or ≥9 (mild or moderate functional impairment, respectively) as dependent variable and DCTclock composite scales, subscales, and Delayed Recall score as predictors, in addition to age, sex, and education.

Result

Combination of DCTclock subscales and Delayed Recall predicted FAQ≥6 and ≥9 with AUCs = 0.79 and 0.81, respectively. DCTclock composite scales predicted FAQ≥ 6 and ≥9 with AUCs = 0.75 and 0.77, respectively. Combination of DCTclock composite scales and Delayed Recall predicted FAQ≥6 and ≥9 with AUCs = 0.77 and 0.79, respectively. DCTclock subscales by themselves predicted FAQ≥6 and ≥9 with AUCs = 0.77 and 0.79, respectively.

Conclusion

The DCR, a brief digital cognitive assessment with automatic scoring that can be completed in primary‐care settings, can infer the effect of cognitive impairment on a patient’s functional activity with great accuracy and within a few minutes. This makes the DCR an empowering tool for primary‐care providers in practical evaluation of patients with cognitive impairment.
Diet Association with Intracranial Atherosclerosis in High Risk Individuals
Authors: Cherian Laurel J , Agarwal Puja , Agrawal Sonal , James Bryan D , Leurgans Sue E. , Bennett David A. A , Aggarwal Neelum T. , Schneider Julie A
Published: December 2023

Background

Healthy diet reduces cognitive decline and dementia. Vascular risk factors are associated with increased atherosclerosis, but associations between dietary pattern and atherosclerosis in older brains are unclear. This study investigates associations between diet pattern and risk of atherosclerosis in individuals with preexisting hypertension (HTN) or myocardial infarction (MI).

Method

Study includes 677 autopsied participants (mean age at death = 91.1±6.1, 71% women) of the Rush Memory and Aging Project, a longitudinal clinical neuropathological cohort study, with complete dietary and neuropathology data. The mean MIND and Mediterranean diet (MedDiet) scores (assessed annually using a 144‐item Food Frequency Questionnaire) were computed (mean interval to death = 5.85±3.92 years). HTN and MI history was self‐reported. Large vessel atherosclerosis was evaluated at the circle of Willis, and severity of intracranial atherosclerosis was assessed based on the number of atherosclerotic plaques, extent of involvement in each vessel, and the degree of vessel occlusion to create a 4 level grading system (0‐3). All regression models were adjusted for age, sex, education, caloric intake, and APOE4.

Result

Of the 677 subjects, 362 (53%) had mild, 142 (21%) had moderate, and 29 (5%) had severe atherosclerosis. There was no direct relationship between diet and atherosclerosis. Both MI (β = 3.031 (p = 0.003)) and HTN (β = 2.063(p = 0.015)) were associated with intracranial atherosclerosis. The interaction models indicated significant interaction of hypertension with MedDiet (β = ‐0.077, p = 0.029) and a qualitatively similar interaction with MIND diet (β = ‐0.212, p = 0.055) for intracranial atherosclerosis. Interaction of MI with MIND (p = 0.007) and MedDiet(p = 0.006) was also significant for intracranial atherosclerosis. In stratified analysis, among individuals with preexisting MI (N = 130), those with better diet have lesser odds of intracranial atherosclerosis (MedDiet: OR(95% CI) = 0.88 (0.81, 0.97)); (MIND: OR(95% CI) = 0.77 (0.59, 1.01)).

Conclusion

In older adults with a history of hypertension or myocardial infarction, a healthy dietary pattern is associated with less severe intracranial large vessel atherosclerosis. These data suggest that healthy diets may be more effective in maintaining brain vascular health in persons with a history of vascular risk or disease. In‐vivo studies of dietary habits and brain health, specifically in those at high vascular risk are needed.
Associations between blood‐based biomarkers and other outcomes related to Alzheimer’s disease
Authors: Göschel Laura , Dell'Orco Andrea , Hoede Patty , Koertvelyessy Peter , Fillmer Ariane , Aydin Semiha , Cano Stefan , Melin Jeanette , Pendrill Leslie , Lehmann Sylvain , Ittermann Bernd , Teunissen Charlotte E. , Flöel Agnes
Published: December 2023

Background

Blood‐based biomarkers (BBM) have shown promising potential in diagnosis and prognosis of patients affected by Alzheimer’s disease (AD) pathology. This observational study analyzed the cross‐sectional relation between BBMs and disease relevant outcomes (e.g., cognition, imaging modalities).

Method

The study sample comprised individuals with subjective cognitive decline (N = 35), mild cognitive impairment (N = 30), dementia due to suspected AD (N = 27) and healthy controls (N = 35). Data for the following measures were assessed: 1) AD‐related BBMs measured in plasma on Simoa: amyloid beta ratio 42/40 (Ab42/40), tau phosphorylated at threonine‐181 (p‐Tau 181), glial fibrilic acid protein (GFAP), and neurofilament light chain (NfL), 2) several cognitive parameters, 3) structural volumes, functional connectivity and brain metabolite concentrations measured by 7T magnetic resonance imaging (MRI) and spectroscopy (MRS), and 4) concentrations of general blood count. Linear mixed models were used to assess associations between the AD‐related BBMs (1) and the other measures (2 to 4).

Result

While none of the associations between Ab42/40 and the AD‐related outcome measures reached significance (p > 0.05), higher concentrations of p‐Tau 181, GFAP and NfL were associated with lower values for MMSE, memory and executive function and parietal cortical thickness, as well as higher concentrations of MRS Myo‐inositol and blood creatinine (figure 1). Additionally, GFAP and NfL were associated with lower MRS N‐Acetylaspartic acid (NAA), and GFAP was associated with smaller hippocampus volume. Beta‐coefficients and p‐values for all associations are provided in table 1.

Conclusion

Unlike Ab42/40, abnormal concentrations of p‐Tau 181, GFAP and NfL showed strong and robust associations to other AD‐related outcome measures making them a better target for screening, diagnosis and possibly prognosis for individuals with AD.
An exploratory analysis of the relationship between cerebral flood flow, mood, and fluid cognition in older adults
Authors: Farris Kristen M , Ashford Nathanial K , Miglani Jasroop K , Parsey Carolyn M , Levendovszky Swati Rane , Hanson Angela J
Published: December 2023

Background

ASL, a common MRI measure of cerebral blood flow (CBF), is thought to be a potential tool in the detection of preclinical Alzheimer’s disease. This exploratory analysis examined the relationship between CBF, mood, and fluid cognitive performance on the NIH Toolbox Cognition Battery (NIHTB‐CB) as part of an ongoing triglyceride intervention study.

Method

20 female older adults (age 65.6 ± 7.6) underwent ASL MRI when fasting and two hours after a triglyceride intervention. 3D pCASL MRI with background suppression was used to measure CBF in ml/100g/min using label duration = 1.8 s, post‐labeling delay = 2 s, labeling offset = 25‐30 mm, slices = 30, resolution = 2×2×4 mm3, SENSE‐factor = 2, TR/TE = 5000/18 ms. We also performed a reference scan (M0, 1 minute) identical to the one above but with no labeling or background suppression and TR = 10,000 ms. CBF was measured globally and in four regions of interest: angular gyrus (AG), posterior cingulate (PC), temporal lobe, and the hippocampus. Subjects completed the Generalized Anxiety Disorder Scale (GAD‐7) and MoCA at screening. The NIHTB‐CB was completed following the second MRI, and age‐adjusted scores were used in all analyses.

Result

Baseline global CBF, AG CBF, and hippocampal CBF negatively correlated with GAD‐7 scores (r = ‐.797, p<.0001; r = ‐.635, p = .0026; r = ‐.620, p = .0036, respectively). In contrast, global CBF and hippocampal CBF positively correlated with performance on the MoCA (r = .501, p = .0243; r = .546, p = .0126, respectively). Post‐intervention CBF in 3 of the 4 areas of interest positively correlated with fluid measures on the NIHTB‐CB, including the Flanker (AG: r = .528, p = .0166), Picture Sequence Memory Test (AG: r = .501, p = .0245; temporal lobe: r = .578, p = .0077), List Sorting Test (PC: r = .508, p = .0241), and fluid composite scores (AG: r = .610, p = .0043).

Conclusion

Greater anxiety correlated with lower baseline CBF overall and in the AG and hippocampus. Post‐lipid CBF correlated with better performance in working memory, executive function, and episodic memory. These results align with our predictions based on each of these regions’ functions. Further research exploring the relationship between mood and CBF is warranted, as well as investigating the effects of APOE4 status on these associations.
The influence of auditory change on cognitive processes associated with aging in virtual reality
Authors: Kamal Farooq , Segado Melanie , Perron Maxime , Lau Brian , Shaigetz Vincent Gagnon , Alain Claude , Choudhury Nusrat
Published: December 2023

Background

With increased age, older adults experience subtle changes in their cognitive functioning. For example, it is well established that our ability to complete dual‐tasking activities decreases with increased age and cognitive decline. One issue with current dual‐task paradigms is the lack of ecological value in lab‐based environments. The present study employed working memory (WM) tasks designed within an immersive and interactive virtual reality (VR) environment by the National Research Council Canada, to examine the processing of unattended input using event‐related potentials (ERPs) which measure the changes in the electrical activity of the brain.

Method

Twenty young adults (ages 17‐30) and twenty healthy older adults (ages 65+) were recruited from the Rotman Research Institute. Participants were engaged in a VR‐WM task while to‐be‐ignored auditory stimuli were presented. The difficulty of the VR tasks was designed to be either very easy or very difficult. Auditory stimulus with an average intensity of 60‐90 dB SPL were presented in a fast (low saliency) and a slow (high saliency) presentation rate.

Result

During the VR task, young adults’ accuracy was significantly higher in the easy condition than in the difficult condition (p < .001). When auditory stimuli were presented rapidly, a robust ERP was elicited at the frontal (p = 0.005) and central (p = 0.003) brain regions. The slowly presented auditory stimulus elicited a robust ERP at the central brain region (p = 0.003). Preliminary data indicates that accuracy was lower in older adults than young adults for both conditions. Older adults also had lower accuracy in the hard condition than in the easy condition.

Conclusion

The ERPs examined here show that participants were able to successfully switch processing priorities away from the VR‐WM task to salient auditory stimulus, but that older adults were less efficient than younger adults. These tools (VR, auditory stimuli, and ERPs) may be useful at detecting subtle electrophysiological and cognitive changes that occur with age and cognitive decline. They may offer promise to identify the pathology underlying cognitive impairment in aging and could reveal the electrophysiological changes associated with conversion to dementia at an individual level in clinical and non‐clinical settings.