bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin resistance, vascular dysfunction and inflammation biomarkers associations with an increased CAIDE risk score in APOE‐ε4 carriers with subjective cognitive decline from the PENSA study
Authors: Puig‐Pijoan Albert , Soldevila‐Domenech Natalia , Lorenzo Thais , Pizarro Nieves , Boronat Anna , Cuenca Aida , Gomis Maria , Sánchez‐Benavides Gonzalo , Grau‐Rivera Oriol , Suarez‐Calvet Marc , Minguillón Carolina , Fauria Karine , Gispert Juan Domingo , Forcano Laura , Molinuevo Jose Luis , de la Torre Rafael ,   PENSA Study Group
Published: December 2023

Background

The CAIDE (Cardiovascular Risk Factors –CVRF‐, Aging, and Incidence of Dementia) Dementia Risk Score is a validated tool to predict late‐life dementia risk based on midlife CVRF. Sex differences in metabolic pathways related to cognitive decline have been described. The aim of this study was to explore associations between measures of insulin resistance, biomarkers of endothelial activation and peripheral inflammation and an increased CAIDE risk score (CAIDE‐rs) in individuals at higher risk of Alzheimer’s disease (AD). Sex differences in these associations were explored.

Method

A total of 129 participants of the PENSA study were recruited. Participants were categorized into high (≥ 9 points) or low CAIDE‐rs groups (HR and LR respectively). Homeostatic model assessment was calculated (HOMA IR = fasting insulin (μIU/ml) × fasting glucose (mmol/ml)/22.5). The following biomarkers were analyzed: soluble intercellular adhesion molecule‐1 (ICAM‐1, ng/ml), vascular cell activation molecule‐1 (VCAM‐1, ng/ml), C‐reactive protein (CRP, mg/dl) and fibrinogen (mg/dl), using ELISA and Clauss method assays.

Result

Participants were 67.2 ±4.8 years, 65.1% were women and 32.6% were classified into the HR group. The HR group was older (68.5 vs. 66.5 years, P = 0.026) and presented higher levels of CRP (median of 0.08 vs. 0.06 mg/dL; P = 0.037) and HOMA‐IR (2.1 vs. 1.6; P = <.001). No differences were found for ICAM‐1, VCAM‐1 or fibrinogen.

Comparisons between sex groups showed higher fibrinogen median values in women both among the HR group and in the global sample (HR 372 vs. 327mg/dl; P = 0.011; GS 350.5 vs. 340.5mg/dl; P = 0.032). Higher HOMA‐IR and VCAM‐1 median values in men were found in the global sample (2.13 vs. 1.65; P = 0.006 and 495.8 vs. 434.5 ng/ml; P = 0.028). The HR female group showed higher HOMA‐IR and fibrinogen median values than the LR female group (2.06 vs. 1.58; p = <.001 and 372 vs. 343 mg/dl; P = 0.029 respectively). HR male group showed higher CRP values compared to LR male group (0.03 vs. 0.12 mg/dl; p = 0.026).

Conclusion

Associations of metabolic alterations and an increased CAIDE‐rs were found in individuals at higher risk of AD. Moreover, sex differences in metabolic alterations were also found. These results highlight the necessity of personalizing preventive interventions for AD taking into account sex‐related profiles.
Routes to standardisation for tau protein measurement in CSF
Authors: Giangrande Chiara , Vaneeckhoutte Hélène , Hirtz Christophe , Lehmann Sylvain , Jeromin Andreas , Delatour Vincent
Published: December 2023

Background

CSF biomarkers are the target of several commercially available in vitro diagnostic (IVD) kits allowing an early diagnosis of Alzheimer’s disease (AD) and eventually the monitoring of treatment effects in clinical trials. Tau hyper‐phosphorylation is one of the main hallmarks of AD and its measurement provides higher accuracy to stratify patients at an early‐stage.

Due to the rapid advancements in proteomics, standardisation of measurements can be achieved through the development of reference measurement procedures (RMPs) and certified reference materials (CRMs).

Method

SI‐traceable protein and peptide primary calibrators were developed for t‐tau and p‐tau: mass fraction was determined by amino acid analysis and purity was assessed by LC‐MS at high resolution. CSF pools at different tau concentration were used for the development and validation of LC‐IDMS candidate RMP and their commutability was assessed.

Result

An LC‐IDMS candidate reference method was develop and validated in CSF for t‐tau using a SI‐traceable candidate protein primary calibrator. Three different CSF pools (low, medium, high) were successfully quantified with a relative expanded uncertainty below 10%. The commutability of 13 matrix‐based CRMs was assessed involving 8 immunoassays from 5 IVD providers by measuring 40 single CSF donations.

According to the AT(N) classification, high levels of p‐tau(181) are highly correlated to tau pathology and commercially available immunoassays are able to target this specific epitope. We conducted a feasibility study on the development of a candidate reference method for p‐tau(181) in CSF relying on a SI‐traceable peptide primary calibrator and an antibody‐free sample preparation workflow.

New assays targeting p‐tau(217) in CSF and plasma were also developed, making it necessary the organisation of standardisation initiatives. We sourced and characterised multiple phosphopeptide primary calibrators as well as a GSK3beta‐phosphorylated protein primary calibrator for the development of an LC‐MS RMP including an immunoprecipitation step in the sample preparation workflow.

Conclusion

tau is considered as a priority for the IFCC WG on NDD and the development of SI traceable RMPs and CRMs is essential to underpin a worldwide standardisation of results. This will help IVD providers to address the traceability requirements of the IVDR thus facilitating regulatory approvals of the kits.
Dissecting the role of GGGGCC repeat RNA secondary structure in cellular toxicity associated with C9 FTD/ALS
Authors: Malik Indranil
Published: December 2023

Background

Aberrant expansions of simple nucleotide repeat sequences can cause more than fifty human diseases. For example, the most common genetic cause of Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) is the expansion of an intronic GGGGCC hexanucleotide repeat sequence in C9orf72 gene (C9 FTD/ALS). Transcribed GGGGCC repeat RNAs can form complex secondary structures, which facilitate unusual interactions with cellular RNA‐binding proteins (RBPs). Sequestration of crucial RBPs into nuclear foci can inhibit the normal functions of those proteins. In addition, expanded GGGGCC repeat RNAs can support the translation of highly toxic repetitive peptides through a non‐canonical process known as repeat associated non‐AUG translation (RAN translation), which may require some specialized factors. Here we sought to understand how RNA secondary structure influence GGGGCC RAN translation and repeat elicited toxicity in C9 FTD/ALS.

Method

We used chemical modification coupled with traditional high‐throughput sequencing and nano‐pore sequencing approaches to probe GGGGCC repeat RNA secondary structures inside cells. We further use in vitro and in vivo RAN translation assays to determine whether repeat RNA secondary structures influence RAN translation efficiency.

Result

Our RNA structural studies revealed that GGGGCC repeat RNAs form primarily form hairpin structures in cells. With nanopore sequencing, we were also able to detect the possible presence of unfolded and/or g‐quadruplex folded GGGGCC repeat RNAs in cells. Folding GGGGCC RNAs into hairpins supports RAN translation whereas folding repeat RNAs into g‐quadruplex structures strongly inhibits RAN translation in both in vitro and in vivo assays. Our results suggest that RNA secondary structure can affect the RAN translation elongation efficiency and g‐quadruplex structures may lead to the termination of elongating ribosomes.

Conclusion

We present a deep sequencing‐based chemical probing technique to evaluate the roles of repeat RNA secondary structures in RNA toxicity underlying dementia‐associated repeat expansion disorders. Repeat RNA structural information can be used to identify chemical compounds that can bind to the RNA and prevent cytotoxicity in cells.
Plasma biomarkers as prognostic markers in Alzheimer’s disease: Influence of age at onset
Authors: Guillén Núria , Tort‐Merino Adrià , Falgàs Martínez Neus , Esteller Diana , Sarto Jordi , Castellví Magdalena , Juncà‐Parella Jordi , Borrego‐Écija Sergi , Bosch‐Capdevila Beatriz , González Yolanda , Fernandez‐Villullas Guadalupe , Ruiz‐García Raquel , Naranjo Laura , Antonell Anna , Balasa Mircea , Sanchez‐Valle Raquel , Lladó Albert
Published: December 2023

Background

Little is known about the influence of age at onset (AAO) on plasma biomarkers and their use as prognostic biomarkers in Alzheimer’s disease (AD).

Method

We selected patients with AD diagnosis with available neuropsychological testing (NPS) at time of diagnosis and two years later, and plasma biomarkers at baseline.

NPS battery included Free and Cued Selective Reminding Test (FCSRT), Landscape test (visual memory), Boston Naming Test, Semantic Fluency, BDAE auditory comprehension, Constructional and Ideomotor Praxis, Visual Object and Space Perception (VOSP) Incomplete Letters and Number Location subtests, Trail Making Test (TMT) A and B, Phonemic Fluency, and Digit Span Forward and Backward. NPS scores were compared by AAO: early‐onset AD (EOAD; <65 years) vs. late onset AD (LOAD; >65y).

We analyzed plasma biomarkers phosphorilated‐tau181 (p‐tau181), total tau (t‐tau), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin C‐terminal hydrolase L1 (UCHL‐1) using the Quanterix Simoa p‐tau181 Advantage V2 and Neurology 4‐Plex A assays. Group comparisons and linear regressions adjusted by years of education (YOE) were performed in Stata/IC 16.1.

Result

Forty‐two participants were included, 23 LOAD and 19 EOAD. Plasma p‐tau181 and GFAP levels were higher in LOAD (Table 1). We did not find differences between LOAD and EOAD in NPS tests at baseline or +2 years (Table 2).

Plasma ptau‐181 was associated with progression in MMSE globally, VOSP‐Incomplete letters globally and in EOAD. Plasma NfL were associated to Boston Naming test globally and in EOAD, Semantic fluency test globally, VOSP‐incomplete letters in EOAD, and Free and Total Learning of FCSRT in LOAD. Plasma GFAP was associated to MMSE globally and in EOAD, Free learning of FCSRT in LOAD and VOSP‐Incomplete letters and number location globally. Plasma UCHL‐1 was associated to Semantic fluency test in LOAD (Table 3). Praxis and attention and executive function tests loss were not associated to plasma biomarkers.

Conclusion

Plasma p‐tau18, NfL, GFAP and UCHL‐1 were associated to pogression in memory, language and visual tests. They were predominantly associated to memory loss in LOAD and language and visual function loss in EOAD. Results need to be interpreted cautiously due to small sample size.
Associations between blood‐based biomarkers and cognitive decline among participants at risk of Alzheimer’s disease: the Memento cohort
Authors: Grasset Leslie , Bouteloup Vincent , Pellegrin Isabelle , Planche Vincent , Chêne Geneviève , Dufouil Carole ,   the Memento Study Group
Published: December 2023

Background

Blood‐based biomarkers for Alzheimer’s disease (AD) pathology and neurodegeneration are promising biomarkers due to their lower cost, accessibility, and minimally invasive nature. Higher levels of AD blood‐based biomarkers have been shown to be associated with the risk of AD and cognitive decline. Yet, the specific cognitive domains involved need to be further investigated. We thus aimed at estimating the association between levels of baseline AD blood‐based biomarkers with cognitive trajectories over 5 years of follow‐up across different domains in a large clinical based cohort.

Method

We selected the 2060 dementia‐free individuals aged 60 years and older included in the Memento study, a French nationwide cohort, following patients from 28 memory clinics with either isolated cognitive complaints or mild cognitive impairment. Amyloid‐β 40 and 42, P‐tau181, and Neurofilament Light Chain (NfL) concentrations were measured at baseline using Simoa HD‐X analyzer. Global cognition, episodic memory, semantic memory, and executive functioning were assessed every year up to 5 years using the Mini Mental State Examination, the Free and Cued Reminding test, the Animal fluency test, and the Trail Making Test B respectively. Linear mixed models adjusted for sex, education level, APOE‐ε4 status, and practice effect, with age as time scale and quadratic slopes were performed to examine how AD blood‐based biomarkers relate to longitudinal cognitive trajectories by domain.

Result

Mean age was 72.8 years, 62% were women, 28% were APOE‐ε4 carriers, and 58% had a Clinical Dementia Rating score of 0.5. Higher baseline plasma P‐tau181 was associated with significantly faster nonlinear cognitive decline in all four cognitive domains (p<0.001). On the opposite, baseline plasma Aβ42/40 ratio and NfL were not associated with cognitive decline whatever the domain. Associations between AD blood‐based biomarkers and faster cognitive decline were not modified by APOE‐ε4, sex, nor education level (p value for interaction > 0.05).

Conclusion

In a memory clinic population, plasma P‐tau181 is a marker of future cognitive decline. This marker is a good candidate for additional studies assessing biomarkers relevant for the identification of individuals who may benefit from treatment early in the disease course.
Atypical presentations of autosomal dominant familial Alzheimer’s disease: insights into genetic, neuropathological and clinical heterogeneity
Authors: Ryan Natalie S , Willumsen Nanet , Nicholas Jennifer M , Poole Teresa , Pavisic Ivanna M , Walsh Phoebe , Rice Helen , Lu Kirsty , O'Connor Antoinette , Weston Philip SJ , Abel Emily , Barkhof Frederik , Barnes Jo , Lashley Tammaryn , Fox Nick C
Published: December 2023

Background

Autosomal dominant familial Alzheimer’s disease (ADAD), caused by APP, PSEN1 and PSEN2 mutations, is clinically and pathologically similar to sporadic AD, with both typically presenting with memory impairment. However as in sporadic AD, atypical phenotypes and neuropathological heterogeneity occur, including variable vascular Aβ deposition as cerebral amyloid angiopathy (CAA). Investigating relationships between clinical, genetic and neuropathological heterogeneity in ADAD may provide insights into pathophysiological pathways relevant to AD in general.

Methods

256 symptomatic individuals from ADAD families seen at our Centre were included in a survival analysis, with detailed clinical phenotype data available for 138 (101 PSEN1, 37 APP). 33 of these individuals underwent brain donation (24 PSEN1, 9 APP), all demonstrating end‐stage AD pathology. Frontal and occipital cortex sections were stained immunohistochemically for Aβ and vessel counts used to determine the proportion of cortical and leptomeningeal blood vessels affected by CAA.

Results

Age at onset was, on average, seven years younger for PSEN1 than APP mutations and was influenced by mutation much more than survival was. Atypical (non‐amnestic) cognitive presentations with initial behavioral, language, dyscalculic or dysexecutive symptoms, and atypical clinical features (pyramidal, extrapyramidal and cerebellar signs) were more common in PSEN1 than APP cases, particularly those with post‐codon 200 mutations. Atypical cognitive presentations were associated with longer survival. There was some indication that APOE4 carriers had longer survival and that this effect may be restricted to PSEN1. In the post‐mortem cohort, atypical cognitive presentations occurred in 15%. Additional neurological features comprised myoclonus (45%), seizures (21%), pyramidal signs (21%) and extrapyramidal signs (15%), one individual had cerebellar signs. Increased frontal cortical and leptomeningeal CAA occurred in individuals with pyramidal and extrapyramidal signs, and in PSEN1 post‐codon 200 compared to pre‐codon 200 mutations. Atypical cognitive presentations were associated with increased frontal cortical CAA.

Conclusions

Phenotypic heterogeneity in ADAD is influenced by causative gene and mutation type, and atypical clinical presentations are associated with increased CAA. Exploring mechanisms by which certain mutations drive Aβ deposition towards the vasculature, and how these may be impacted by other genetic factors and by therapies targeting Aβ, is an important direction for future research.
Parkinson’s Disease Genetic Variants in Sporadic Early Onset Dementia: Results from the Longitudinal Early Onset Alzheimer’s Disease Study
Authors: Nudelman Kelly N. H. , Jackson Trever , Rumbaugh Malia C. , Eloyan Ani , Faber Kelley M. , Snoddy Casey , Foroud Tatiana M. , Carrillo Maria C. , Dickerson Brad C. , Rabinovici Gil D. , Apostolova Liana G. ,   the LEADS Consortium
Published: December 2023

Background

Much of the genetic etiology of sporadic early onset Alzheimer’s disease and frontotemporal dementia is largely unknown. Genetic investigation using whole exome sequencing (WES) data in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) aims to address this gap, with the hypothesis that some individuals with early onset cognitive impairment may carry pathogenic, potentially causative variants in Parkinson’s disease (PD) genes.

Methods

Whole exome sequencing data for cognitively impaired LEADS participants (N = 301) was processed using the GATK best practices pipeline with Sentieon software; joint‐called VCFs were annotated with Annovar, and the results were filtered to prioritize amino acid code‐altering variants with minor allele frequencies <1% that have not been reported as benign or likely benign in ClinVar. Variants in the acid beta‐glucocerebrosidase (GBA), leucine‐rich repeat kinase 2 (LRRK2), Parkin RBR E3 ubiquitin protein ligase (PRKN), PTEN‐induced putative kinase 1 (PINK1), protein kinase, interferon‐inducible double‐stranded rna‐dependent activator (PRKRA), and Parkinson disease 7, autosomal recessive early‐onset (PARK7) were reviewed. Heterozygous or homozygous carriers of variants meeting these criteria in GBA and LRRK2, as well as homozygous or potentially compound heterozygous variant carriers in the other genes, were reviewed for the presence of PD‐related symptoms documented with the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) collected at baseline (N = 283).

Results

There were no variants meeting inclusion criteria for PINK1, PARK7, PRKN, or PRKRA. However, we observed 21 individuals with predicted or reported functional variant(s) in GBA or LRRK2. The mean screening visit age for these carriers was 59 (range 53‐64), and all but two were amyloid positive. While only one case was documented with motor symptoms, several participants had peripheral nervous symptoms such as neuropathy. 17 carriers had amnestic‐type dementia, with similar frequency to non‐carriers.

Conclusions

While there are a small subset of individuals carrying functional variants in PD genes, they do not appear to substantially influence the phenotype of most cases at baseline. Future planned research efforts include assessing alpha synuclein pathology via alpha synuclein seeding assays, which will help clarify the potential role of mixed genetic etiology and pathology in risk for non‐familial early onset dementia.
Objects of hope: using object elicitation to open up conversations about hope for people affected by rarer forms of dementia
Authors: Harding Emma , Camic Paul , Harrison Charles R , Akthar Nasifah , Wilson James , Stott Joshua , Rice Helen , Herron Daniel , Mummery Catherine J , Crutch Sebastian J ,   RDS Impact Study team
Published: December 2023

Background

Hope is an essential component of the human experience and can play a critical role in sustaining wellbeing and a good quality of life. It can seem somewhat at odds however with the dominant societal discourses around dementia, which, stemming from a biomedical perspective, are often (naturally) focused on deficits and decline. With recent promising developments in the field of therapeutic interventions, it is of timely importance to explore the concept of hope for those affected by rarer forms of dementia, charactersised by atypical symptoms and associated with unique challenges, for whom emerging treatments may be too late. Here, we explored the use of an innovative methodology – object elicitation – to facilitate conversations on this complex and sensitive topic with these underrepresented groups.

Method

17 people affected by dementia and primary caregivers took part in 3 facilitated discussions using object elicitation to explore the concept of hope within the context of rarer forms of dementia, including: familial Alzheimer’s disease, behavioural variant frontotemporal dementia, and posterior cortical atrophy. Transcripts of the discussions were analysed thematically.

Result

Findings were organised into 4 themes: (i) Reframing and reconceptualising hope in the context of dementia; (ii) Temporality: from hopes for the future to finding hope in the moment; (iii) Hope for the individual and hope for the collective; and (iv) The other side of the coin: lost hope, false hope and barriers to hope.

Conclusion

The findings of this study shed light on some of the challenges to sustaining hope for people affected by lesser known forms of dementia and importantly, their resilience and resourcefulness in finding ways to continue to cultivate a sense of hope during difficult times within their everyday lives. These findings have implications for others living with these conditions and the unpaid carers and health and social care professionals supporting them, and are of particular relevance in the context of current treatment developments. This study has also demonstrated the utility and accessibility of the object elicitation method for opening up and facilitating conversations about emotionally charged topics for people living with and supporting people with different diagnoses of dementia.
EEG‐guided anesthetic titration and perioperative neurocognitive disorders
Authors: Evered Lisbeth A
Published: December 2023

Background

Postoperative delirium (POD) is a serious complication of surgery associated with prolonged hospitalisation, long‐term cognitive decline, dementia and mortality. There is increasing evidence that electroencephalography (EEG) monitoring may reduce the incidence of POD, however, the best method for achieving this is unclear.

Method

This presentation will present the results of a multicentre randomised clinical trial of 515 at‐risk patients undergoing major surgery from 8 centres in 3 countries who were assessed for POD for 5 days postoperatively. They also underwent cognitive screening at baseline, discharge, 30 days and one year postoperatively. Patients were assigned to light or deep anaesthesia. Additionally, this presentation will consider a meta‐analysis of available studies investigating EEG monitoring to prevent delirium and outline the importance of EEG spectrogram interpretation as part of EEG monitoring and consequent anesthetic titration when using this technique to reduce or prevent POD.

Result

The incidence of POD was lower (19%) in the light anesthesia group compared with the deep anesthesia group (28%) (OR 0.58 (95% CI 0.38 to 0.88), P = 0.010). Meta‐analysis results were fragile and depended on inclusion criteria of studies. Interpretation of EEG spectrograms is a developing field, but adds significant, critical information.

Conclusion

EEG monitoring looks to be a possible method for preventing POD and long‐term complications. EEG spectrogram interpretation will likely add critical information to enhance this technique.
Working Memory related Frontal Brainwaves are Associated with pTau181Plasma Biomarkers in Healthy Older Adults
Authors: Jiang Yang , Katsumata Yuriko , Foley Kate E , Neal Jennifer A , Sudduth Tiffany L , Norris Christopher M. , Jicha Gregory A , Wilcock Donna M.
Published: December 2023

Background

We have previously reported distinct frontal signature of working memory related potentials (WMRP) in older adults with Normal Cognition (NC) versus age‐matched older adults with Mild Cognitive Impairment (MCI) (Li et al., 2017; Fig 1A). Our Kentucky cohort demonstrates that asymptomatic older individuals with MCI‐like frontal brainwave patterns convert to MCI within a short 5‐year period, as opposed to individuals with NC‐like patterns that remain normal 10 years later (Jiang et al., 2021; Fig 1B). Leveraging blood‐based Vascular/AD biomarkers, we test the hypothesis that WMPR is associated with preclinical AD/ADRD pathologies.

Method

33 (19 women) cognitively intact older volunteers, average age 79 (SD 8.53) years old, from a longitudinal cohort followed by University of Kentucky ADRC participated. Each participant was assessed by electroencephalogram (EEG) recording (64‐ or 14‐channels headset) during a visual working memory task and vascular/AD plasma markers (Wilcock et al., 2022). Multiple linear regression analyses adjusting for age and sex were applied for examining several frontal WMRP difference waves (Target items held in working memory – Nontargets) and multiple vascular/AD plasma biomarkers Aβ 42/40, pTau181, and GFAP (astrocyte reactivity).

Results

We examined the association between WMRP and the percentage changes of Aβ 42/40, pTau181, GFAP levels from plasma Vascular/AD biomarkers. The decrease of WMRP levels (MCI‐like) was significantly associated with increased level of pTau181 at the left frontal F7 site after adjusting for age and sex (b = ‐0.035 and p = 0.043) (Fig. 2). Aβ42/40 and GFAP levels were not significantly associated with working memory related brainwaves.

Conclusion

Our results indicate that predictive WMRP are associated with tau pathologies. Working memory‐related EEG neuromarkers and plasma AD biomarkers are sensitive and affordable screening tools to predict continuous cognitive decline risk in healthy normal older adults.

References

Jiang, Y. et al. (2021). Memory‐Related Frontal Brainwaves Predict Transition to Mild Cognitive Impairment in Healthy Older Individuals Five Years Before Diagnosis. J. Alzheimer’s Dis. 79, 531‐541.

Li, J et al. (2017). A cognitive electrophysiological signature differentiates amnestic mild cognitive impairment from normal aging. Alzheimer’s Res & Therapy, 9, 3.

Wilcock D, et. al… (2021). MarkVCID cerebral small vessel consortium: I.Alzheimers Dement. 17:704‐715.
Reprogramming to alleviate Alzheimer’s disease through ameliorating microglial inflammation and neuronal damage
Authors: Shen Lu , Wan Meidan , Liu Xixi , Jiao Bin , Wang Zhenxing , Xie Hui
Published: December 2023

Background

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized by glial cell dysfunction and progressive neuron loss, leading to varying degrees of neuropathology and cognition impairment. Aging and epigenetic alterations accompany the progression of AD and disrupt cellular functions; therefore, whether reprogramming could restore epigenetic information while maintaining cellular identity remains unclear.

Method

The polycistronic expression cassette contained multiple transcription factors of the Oct4, Sox2, and Klf4 genes (OSK) that were cloned into a coexpression vector (Ad‐OSK). The effects of OSK on cognitive function and neuropathology were explored in 4‐month‐old and 6‐month‐old APP/PS1 transgenic AD model mice via stereotaxic injection into the bilateral hippocampus.

Result

Ad‐OSK maintained microglial and neuronal cellular identities while attenuating microglia‐induced neuroinflammation and neuronal apoptosis. Ectopic expression of OSK in mouse brain tissue alleviates and restores cognitive function, youthful neuronal pathogenesis, Aβ plaque deposition, microglial activation, and myelin damage in early stage and later stage AD mice, respectively. The DNA demethylation process is required for the beneficial effects of OSK induced reprogramming in brain health.

Conclusion

These results suggest that brain tissues preserve youthful epigenetic information, which is primarily stored by DNA demethylation during OSK reprogramming and can be accessed to improve brain health in AD mice. Our findings provide the foundation for the future use of OSK adenovirus or mRNA medicine to treat AD.
Two novel beta synuclein specific assays for the detection of Alzheimer’s disease
Authors: Bayoumy Sherif , Goossens Julie , De Rocker Charlotte , Verberk Inge M.W. , Teunissen Charlotte E. , Vanmechelen Eugeen
Published: December 2023

Background

Recent studies reported the potential use of elevated CSF β‐synuclein levels as an AD‐specific synaptic biomarker. These results were obtained with a sandwich ELISA where one of the antibodies recognizes both alpha‐and β‐synuclein1. Blood contamination can affect alpha‐synuclein concentrations in CSF, which is not observed for β‐synuclein2. Therefore, we aimed to develop a β‐synuclein‐specific assay to avoid possible interference with alpha‐synuclein.

Methods

Two novel sandwich CSF ELISA assays were established using only β‐specific synuclein monoclonal antibodies: a mid‐region and C‐terminal assay. Both assays use a monoclonal capture antibody that maps to C‐terminal. The mid‐region assay involves a detection antibody mapping to an epitope that overlaps with the SRM peptide used for CSF mass‐spectrometry quantification3. The C‐terminal assay includes a detection antibody targeting a less well‐defined C‐terminal epitope. Forty‐four remnant routine CSF samples were analyzed in duplicate (22 individuals with AD biomarker profile based on pTau181 and amyloid‐beta(1‐42), age70±7 years, 38%F and 22 control profiles, age70±7, 38%F).

Results

The mid‐region assay showed a precision of 4%CV in clinical samples and a sensitivity of 1.25 pg/ml compared to 10%CV and 4.22 pg/ml with the C‐terminal assay (Fig. 1). CSF β‐synuclein levels were significantly elevated in patients with an AD CSF‐profile compared to individuals with negative‐AD CSF‐profiles, with AUCs of 0.77 [95%CI: 0.62‐0.90] for the C‐terminal assay and 0.71 [0.55‐0.87] for the mid‐region assay (Fig. 2). The assays showed comparable (Delong’s P = 0.53) clinical performance and their results correlated (r = 0.61, P = <0.001)(Fig. 2). Both C‐terminal and mid‐region β‐synuclein associated with CSF pTau181 (Spearman’s rho = 0.58 (p<0.001), rho = 0.51 (P = <0.001), respectively), and did not correlate with CSF Abeta(1‐42) (Fig. 3). Both assays are specific for recombinant beta‐synuclein, but the C‐terminal assay showed higher selectivity for β‐synuclein compared to the mid‐region assay, as increasing signals were observed with the latter with increasing concentrations of spiked recombinant alpha/gamma‐synuclein.

Conclusion

The two novel β‐synuclein assays show clinically relevant changes in relation to AD CSF biomarker positivity. Both assays are specific to β‐synuclein. The assays will be transferred to SIMOA, which provides a wider dynamic range, and thus we will further assess the selectivity in plasma/serum.
Cerebral amyloid angiopathy‐related inflammation presented with posterior reversible encephalopathy syndrome
Authors: Chung Ji Yeon , Lee Chang Ju , Kim Ju Hye , Moon Hyeo Seo , Lim Da‐Hye , Kim Hoowon
Published: December 2023

Background

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid beta protein deposits within the media and adventitia of small and medium‐sized leptomeningeal and cortical blood vessels of the brain. CAA‐related inflammation (CAA‐ri) is a relatively rare and aggressive subtype of CAA with diverse neurologic deficits and characteristic radiological findings. Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder of acute or subacute onset characterized by various neurological symptoms and reversible entity both radiologically and clinically. We report a case of CAA‐ri presented with PRES.

Method

A 80‐year‐old man with a history of hypertension presented to the Emergency department with sudden onset of drowsy mentation and disorientation. At admission arterial blood pressure was 210/100mmHg. Brain computed tomography revealed hypodense lesion in both parieto‐occipito‐temporal lobes with the predominance on the left side. Brain MRI susceptibility weighted imaging (SWI) presented multiple microbleeds with diffuse cerebral edema in both parieto‐occipital and left temporal cortex and subcortex as can be seen in cerebral amyloid angiopathy (CAA). Obtained images suggested CAA coexisting with posterior reversible encephalopathy syndrome (PRES). Electroencephalopgraphy (EEG) revealed regionalized sharp wave in the right parieto‐occipital area. There was no evidence of venous thrombosis. CSF analysis showed no pleocytosis with protein elevation of 105 mg/dl. PRES was considered due to neurologic deficit of acute onset, elevated arterial blood pressure and vasogenic edema on MRI. 18F‐Florbetaben PET CT showed amyloid positivity.

Result

A diagnosis of CAA‐ri was considered, and the patient was started on intravenous steroid for 5 days and valproic acid with clinical improvement. Arterial blood pressure showed gradual normalization within 5 days of hospitalization. After 2 weeks of hospitalization, the patient was able to walk without assistance. MMSE score was 17 with normal orientation of place, acalculia and memory impairment. The modified Rankin Scale was 1 and Barthel index score was 20 at the time of discharge.

Conclusion

CAA‐ri may present with PRES‐like features. Early detection and appropriate management of trigger factors of PRES which may caused by CAA‐ri would facilitate acute phase recovery and long term prognosis.
Telomere length in the superager sample of the Vallecas Project cohort
Authors: Pascual Marta Garo , Zhang Linda , Calero Miguel , Medina Miguel , Defelipe Javier , Strange Bryan A
Published: December 2023

Background

Superagers are individuals aged 80 and over with youthful episodic memory that can provide insights into protective mechanisms against age‐related memory loss and dementia. We aim to study telomere length in human superagers since telomere attrition is considered a hallmark of ageing and can explain some structural and functional changes occurring in an ageing organism. We therefore tested whether telomere length is associated with successful episodic memory of superagers.

Method

Telomere length was measured in peripheral blood cells from 57 superagers (mean age 81.9 years ± 2.0 std, 61.4% women) and 48 age‐matched typical older adults with normal memory for age (mean age 82.4 years ± 1.9 std, 64.6% women) selected from the Vallecas Project cohort. A high‐throughput quantitative fluorescence in situ hybridization technique (HT Q‐FISH) (Life length, Spain) was used. This technology has a low detection limit of < 100 bp, enabling the quantification of short telomeres that can be more informative of telomere dysfunction than centrality measures.

Result

Superagers have significantly shorter median telomere lengths than typical older adults (p = 0.0009, t = ‐3.4) and show a higher proportion of short telomeres (<6 Kbp) (p = 0.0005, t = 3.6) and extremely short telomeres (<3 Kbp) (p = 9. 4×10−5; t = 4.1) than typical older adults. Thus, superagers have shorter average telomere lengths and a higher proportion of short telomeres, which are most associated with genome instability.

Conclusion

The successful episodic memory of our superager population is not associated with long telomere length or the presence of fewer short telomeres measured in a cross‐sectional setting. Further analysis exploring telomere attrition rate of these two groups over time may help to interpret the current findings.
Dissociations between APP pathology and metabolic signalling in the neuron‐specific hBACE1 knock‐in PLB4 mouse
Authors: Franklin Zara J , Delibegovic Mirela , Platt Bettina
Published: December 2023

Background

Patients with Alzheimer’s Disease (AD) frequently suffer comorbidities such as type 2 diabetes mellitus (T2DM) alongside shared common pathologies e.g. increased inflammation, endoplasmic reticulum (ER) stress, and impaired energy homeostasis (Plucinska et al., 2016, https://doi.org/10.1007/s00125-016-3960-1). The complexity of neurodegenerative and metabolic diseases requires a systems‐based approach that examines the interplay between brain pathology and metabolic regulation. Emerging evidence points towards abnormal cellular energy regulation as a common denominator, investigated here in hBACE1 associated pathologies (Findlay et al., 2015, https://doi.org/10.3389/fncel.2015.00382).

Method

Glucose tolerance tests were performed in male PLB4 and PLB‐WT controls (3 – 8 months) to determine diabetic status (Plucinska et al., 2014, https://doi.org/10.1523/JNEUROSCI.0433-14.2014). Protein analysis was employed to characterise beta‐amyloid/APP processing, ER stress, glucose regulatory signalling, and bioenergetic metabolites in brain, liver, muscle or plasma, and gene expression analysis examined hypothalamic alterations in energy regulation.

Result

Neuronal hBACE1 expression caused early pathological cleavage of APP, in parallel with increased brain ER stress (p‐eIF2α) and the chaperone binding immunoglobulin protein (BIP). APP processing declined over time, alongside increased ER stress (IRE1α) in brain and liver. Systemic glucose intolerance was evident from 3 months, varied between tissues and ages, and was confined to the periphery. All key markers normalised to control levels at 8 months. Evidence for altered bioenergetics metabolites (LDH‐A and BCKDH) in brain and liver, also affected by ageing, were detected in PLB4 mice. Furthermore, hypothalamus‐specific changes in energy and appetite regulators (NPY and GLP‐1 receptor) were uncovered in the hBACE1 mice.

Conclusion

hBACE1 resulted in early APP misprocessing alongside ER stress but not post‐insulin receptor signalling changes. Peripheral metabolic and bioenergetic alterations were age‐ and tissue‐specific but did not correlate with APP processing. Further tissue analyses are ongoing to determine cellular consequences of hBACE1 expression on systemic bioenergetics.
A novel function of CD44 in the pathogenesis of Alzheimer’s disease
Authors: Lee Yeongyeong , Lee Jeongmi , Jo Dong‐Gyu
Published: December 2023

Background

Alzheimer’s disease is the main cause of dementia, which is believed to progress with Aβ, neurofibrillary tangle (NFT) and neuroinflammation. CD44 is a transmembrane glycoprotein acts as a receptor for extracellular matrix (ECM). It was firstly found as a receptor for hyaluronic acid (HA). CD44 is cleaved by α‐ or γ‐secretase, becoming soluble form. This fragment activates and modulates several genes related with cell survival. The binding of low molecular weight of HA and CD44, activates NLRP3 inflammasome, and inflammatory cytokines boosts cohesion of HA and CD44. Previous reports indicated that CD44 upregulation was shown in early stage of AD, and amyloid increases CD44 expression. Other researchers illustrated that applying siRNA of CD44 reduced Aβ toxicity, indicating that CD44 participates in Aβ metabolism.

Method

A total of 38 mice were randomly divided into 4 groups according to their genotype; WT (Control group), CD44−/−, 5xFAD (AD model), and 5xFAD;CD44−/−. Behavioural tests were conducted during the age of 8.5 months. We performed Morris Water Maze (MWM) to analyze cognition level. After 7 days of behaviour test, brain tissue was collected by PBS perfusion and analyzed through quantitative real‐time‐PCR(RT‐qPCR), western blot, and immunofluorescence.

Result

In MWM, 5xFAD;CD44−/− male mice showed restored cognition level through probe day result. In molecular analysis, Aβ plaque significantly reduced in both cortex and hippocampus of 5xFAD;CD44−/− mice compared to 5xFAD mice. Inflammatory factors, such as nlrp3, il‐1b, also reduced in the cortex of 5xFAD;CD44−/− mice.

Conclusion

Our data indicated that CD44 plays a pivotal role in Aβ plaque formation, leading to cognition impairment. Significant changes in amyloid plaque level were shown, as well as an reduction of inflammatory factors in the brains of 5xFAD;CD44−/‐ mice. With these results, drugs blocking CD44 would be a strong candidate for the treatment of Alzheimer’s disease. Further studies are needed to clear the mechanism of AD pathology associated with CD44.
APOE genotypes and oxidized lipids in Alzheimer’s Disease
Authors: Diaz‐Sanchez Lorena , Hill Eric J , Griffiths Helen R , Dias Irundika
Published: December 2023

Background

The APOE4 allele is a strong risk factor for late‐onset and early‐onset forms but APOE4 is neither a prerequisite for, nor sufficient to cause, AD. Despite decades of research, the exact mechanisms underlying how ApoE4 contributes to AD pathogenesis remain incompletely defined. Astrocytes are homeostatic cells of the central nervous system and play a pivotal role in maintaining neuronal health and survival. Brain metabolic enzyme activity is altered in ApoE4 carriers where mitochondrial oxidative phosphorylation is disrupted and is accompanied by increased oxidative stress. In this study, we aim to investigate the hypothesis that the astrocytic oxidised phospholipids and oxysterol profile is affected by ApoE genotype influencing mitochondrial bioenergetics and altering redox state.

Method

Human iPSC lines for APOE3/3, APOE 4/4 and APOE knockout were maintained in mTeSRTM1 culture medium and transformed to neural precursor cells. Neural precursor cells were then transformed to pure astrocyte cultures using published protocols. Cells were collected and lipids were extracted using methyl‐tert‐butyl ether (MTBE). Oxidised phosphatidylcholines and oxysterols were measured using liquid chromatography mass spectrometry (ABSciex 5500). Mitochondrial bioenergetics were measured by Seahorse technology.

Result

Compared to APOE3/3 astrocytes, a slower growth rate was observed for APOE4/4 cells. APOE4/4 cells showed increased levels of oxysterols (24‐hydroxycholesterol (24‐OHC), 27‐hydroxycholesterol (27‐OHC), 7β‐hydroxycholesterol (7β‐OHC) and 7‐ketocholesterol (7KC) and increased levels of short‐chain, oxidised phosphatidylcholines (POVPC; 1‐palmitoyl‐2‐(5‐oxovaleroyl)‐sn‐glycero‐3‐phosphorylcholine, PONPC; 1‐palmitoyl‐2‐(9‐oxo‐nonanoyl)‐sn‐glycero‐3‐phosphocholine and PGPC; 1‐palmitoyl‐2‐glutaryl‐sn‐glycero‐3‐phosphocholine).

Conclusion

This study shows that the potential to investigate discrete oxidised lipids in APOE genotypes. By studying the profile of oxylipids and mitochondrial bioenergetics, this work will inform future studies into mitochondrial metabolism and targeting oxylipids in mitochondria to improve brain cell health and in AD.
Visceral adipose tissue triggers tau pathogenesis in transgenic mice
Authors: Bettinetti‐Luque Miriam , Trujillo‐Estrada Laura , Andreo‐Lopez Juana , Cantero‐Molina Francisco , Da Cunha Celia , Sanchez‐Mejias Elisabeth , LaFerla Frank , Gutierrez Antonia , Baglietto‐Vargas David
Published: December 2023

Background

Alzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences have suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses, are risk factors for AD. These two overwhelming diseases are associated with a significant expansion of visceral adipose tissue. Here, we hypothesize that the visceral adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses and affecting both types of disorders.

Method

We used histological stains, immunohistochemistry and biochemical means to determine changes in the visceral adipose tissue from WT and db/db mice. Moreover, similar techniques were used in 3xTg‐AD mice that received white fat pads from WT and db/db donors to determine any changes in amyloid and tau pathology.

Result

Our study shows that recipient 3xTg‐AD mice from db/db fat pads mice develop profound changes in tau pathology due to increased CDK5 expression compared to 3xTg‐AD mice that received fad pads from WT mice. This increment in tau level was associated with elevated levels in IL‐1β and profound microglia activation. Moreover, we found the opposite effect on amyloid pathology, in which insoluble Aβ levels and Thioflavin positive plaques were reduced in recipient 3xTg‐AD mice from db/db fat pads compared to 3xTg‐AD mice that received fad pads from WT mice. These reduction in Aβ levels were correlated with an increment in microglia phagocytic capacity.

Conclusion

Overall, our study demonstrate a novel important crosstalk between Alzheimer´s disease and obesity/diabetes type II through visceral adipose cells and a differential effect on tau and Aβ pathology mediated by an activated immune response.

This study was supported by Minister of Science and Innovation grant PID2019‐108911RA‐100 (D.B.V.), Alzheimer’s Association grant AARG‐22‐9282/9, Beatriz Galindo program BAGAL18/00052 (D.B.V.), University of Malaga grant PPIT.UMA.B1‐2021_32(LTE) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) co‐financed by FEDER funds from European Union.
Association between monolinguals, multilinguals and cognition
Authors: Menon Anjana J , Issac Thomas Gregor , Sundarakumar Jonas S. , Stezin Albert , Malo Palash Kumar , Arvind Prathima , Mallikarjun Divya N , Hameed Shafeeq K Shahul , Lingegodwa Abhishek Mensegere , Narayanasamy Rajitha , Menon Meenakshi , Rai Pooja , Singh Sadhana , Velavarajan Goutham , Partha Ajith , M Amitha C , R Meghana
Published: December 2023

Background

Recent research suggests that multilingualism may play an important role in enhancing cognitive health. The process of language acquisition constitutes a form of natural brain training, which in turn is thought to increase the neuroplasticity. The aim of this study is to examine the association between multilingualism and cognitive performance.

Method

This study utilized cross‐sectional (baseline) data from the Srinivasapura Aging Neuro Senescence and COGnition study (SANSCOG), which is an ongoing community‐based, longitudinal aging cohort study conducted in a rural setting in Southern India. Study participants were dementia‐free, aging adults (45 years and above) from the villages of Srinivaspura. This study site is located in the state of Karnataka, close to the border of an adjoining state, Andhra Pradesh. The subjects are separated into two groups, namely monolinguals, participants knowing one language and multilinguals, participants knowing more than one language, to assess if language has any role in cognitive performance. The cognitive performance of the participants was assessed using Hindi Mental State Examination (HMSE) and Clinical Dementia Rating (CDR). A total of 3283 subjects for HMSE, and 3634 for CDR, including both normal and cognitively impaired subjects were considered for the study. Dementia free patients with HMSE scores below 24 and CDR scores of 0.5 are considered as the inclusion criteria. The data analysis was performed using chi‐square test.

Result

The study showed a statistical significance for the association between number of languages spoken and cognition. Multilinguals achieved better cognitive scores, which shows their greater flexibility in cognition. The p value and chi‐square (p value:< 0.001; chi‐square: 59.448) of monolinguals and HMSE scores shows that the analysed data is significant. The odds ratio is 2.562 and it indicates that monolinguals have higher odds of developing cognitive decline than multilinguals. The analysis indicates that exposure to multiple languages has the upper hand, as it is thought to enhance the brain function.

Conclusion

This study highlights that learning multiple languages might have a profound impact on cognitive health, thereby reducing the likelihood of developing cognitive impairment.