bluuebunny/crossref_metadata_2025 huggingface dataset:
Elucidating the Role of Brain Senescence and Telomere Attrition in Alzheimer’s Disease Tauopathy
Authors: Palomares Debora , Caballol Nuria Suelves , Saleki Shirine , Kienlen‐Campard Pascal
Published: December 2023

Background

Neurodegenerative diseases are the most common age‐related pathologies, including Alzheimer’s disease (AD). Recent studies suggest that telomere attrition, the main trigger of cellular senescence, might contribute to brain dysfunction and neurodegeneration with age (Forero et al., 2016). Senescent brain cells have been found in AD patients (Musi et al., 2018), and studies in a transgenic mouse model of tauopathy have shown that the elimination of senescent cells led to an improvement in tau‐related neurodegeneration and cognitive decline (Bussian et al., 2018). However, little is known about the exact connection between senescent brain cells and neurodegenerative disorders on a cellular and molecular level. Here, we studied how brain senescence relates to the onset and progression of AD‐related tau pathology.

Method

We used a mouse model of senescence (TercKO), which is deficient for the RNA component of the telomerase, and presents telomere attrition and premature ageing with increasing generations (Blasco et al., 1997). We crossed it with the tauopathy mouse model Tau P301S (PS19), which carries the P301S mutant form of the human microtubule‐associated protein tau gene (MAPT), exhibiting tau pathology features observed in AD (Yoshiyama et al., 2007). By taking advantage of primary cultures, brain sections and brain extracts, and using biochemistry and molecular biology techniques, we examined the expression of tau neuropathological features in a senescent context. Furthermore, we evaluated the changes in classical and novel markers of senescence in a neurodegenerative context.

Result

We observed that telomere attrition induces several known senescence markers (i.e., senescence‐associated beta‐galactosidase or SA‐β‐gal activity, upregulation of interleukins IL‐1β and IL‐6, and cell cycle regulator p16) and this exacerbates tau phosphorylation in primary neurons and hippocampal tissue. Additionally, our results suggest that the senescent context might enhance tau‐induced neurodegeneration.

Conclusion

Our work indicates that senescence might be an upstream regulator of tau pathology, aggravating it and triggering tau‐related neurodegeneration. Our results further suggest that TercKO mice could be a useful animal model to study the pathological role of age‐associated brain senescence. Elucidating this process in more detail could lead to the identification of suitable intervention targets for AD treatment.
Inferring Iron Modality Interactions Using Brain Image Based Neural Networks to Predict Blood Iron Levels in UK Biobank
Authors: Sammet Joshua , Liu Qiang , Patel Raihaan , Suri Sana , Nevado‐Holgado Alejo J , Winchester Laura M
Published: December 2023

Background

Disturbance of iron homeostasis in the brain is linked to cognitive impairment and neurodegenerative diseases. Interactions between changes of iron loads in the blood and changes in the brain are poorly understood. No strong and complete understanding of structural changes in the brain associated with changing values of blood measurements such as haemoglobin concentration has been established. We aimed to establish a link between changes in blood measurements and the accompanying structural changes in the brain.

Method

We analysed 4436 participants from Visit 2 with a mean age of 61.92 years (standard deviation = 7.42). T2* image derived phenotypes, age, sex and blood count to represent iron were used in a linear correlation analysis. We used age, sex, blood count, head volumes, scanning positions and differences between T1 and swMRI for correction in a linear model approach predicting swMRI voxel values. We applied linear correlation analysis and a general linear model using all extracted information. Further, we built a convolutional neural network (CNN) to compare approaches. The CNN used swMRI as input and blood values as output. The blood values were grouped based on percentiles to create classes. Attention maps were extracted from the CNN using Integrated Gradients to identify possible regions driving the decision process of the network for the correct classifications.

Result

No linear relation between blood count and brain imaging was detected in the Visit 2 participant subset we analysed. However, we achieved an accuracy of over 0.99 for predicting haemoglobin concentration values split into 3, 10 or 20 classes for our CNN model. The attention maps showed high attention in the thalamus and the parietal, occipital and temporal lobe.

Conclusion

We were able to predict blood iron using MRI imaging. This suggests an association between the two measures. Furthermore, it was possible to show which brain areas were used by the CNN for decision‐making. Using such an integrated model of iron modalities may give a more complete view of iron homeostasis and the potential associations with related diseases such as dementia.
Physiological Confounders of Blood‐Based Alzheimer’s Disease Biomarkers in Middle‐Aged Asymptomatic Individuals
Authors: Tristão‐Pereira Catarina , Fuster Valentin , Sanchez‐Gonzalez Javier , Ibañez Borja , Zetterberg Henrik , Blennow Kaj , Gispert Juan Domingo , Cortes‐Canteli Marta
Published: December 2023

Background

Blood‐based biomarkers represent a promising tool for Alzheimer’s disease (AD) clinical diagnosis and patient management. However, the identification of physiological factors that may influence their concentration levels in plasma is fundamental to warrant their clinical use, but more data is needed on whether such possible confounders result in clinically relevant changes. Here, we aim to identify physiological confounders of blood‐based AD biomarkers in a middle‐aged asymptomatic population.

Method

The Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal study following >4000 asymptomatic middle‐aged individuals. This study included 537 PESA participants, 370 of them with follow‐up data 4.7±0.6 years later. The concentrations of Aβ40, Aβ42, p‐tau181, GFAP and NFL in plasma were quantified using the Simoa pTau‐181 V2 and Neurology 4‐Plex E Advantage Kits. Potential confounders were also measured and included body mass index (BMI), as a proxy of blood volume; creatinine, as of kidney function; and aspartate (AST) and alanine aminotransferase (ALT), as of liver function. Stepwise regression was used to determine which confounders (predictors) are associated with plasma biomarkers (outcomes), adjusting for age, sex and APOE, both cross‐sectionally and in annual change rates (p<0.05). Participants were classified into normal and abnormal, based on standard cut‐off values for all potential confounders. Between‐group differences in plasma biomarkers were sought, and the abnormal group’s fold‐change was calculated.

Result

The studied sample had a mean age of 50.4±4.3 years, 441 were males and 88 APOE‐ε4 carriers (Figure 1). All blood‐based biomarkers but Aβ42/40 were negatively correlated with BMI and positively correlated with creatinine (Figure 2). ALT and AST were associated with Aβ40, Aβ42 and p‐tau181 but with opposite effects. Increases in BMI were associated with a decline in NFL and GFAP, while an increase in AST with a decline in amyloid and tau accumulation in plasma. Abnormally high BMI was associated with lower biomarker plasma concentrations, except for in Aβ42/40, with a maximum fold‐change of ‐12% for GFAP (Figure 3).

Conclusion

BMI, kidney and liver function are associated with plasma brain biomarkers levels in asymptomatic middle‐aged individuals. However, the magnitude of their effect is minor, with limited impact for their clinical applicability in individual patients.
Brains in focus: Uncovering protein aggregate changes across Alzheimer’s disease with single‐molecule imaging
Authors: English Lizzie A , Boeken Dorothea , Cheetham Matthew R , Danial John SH , Klenerman David
Published: December 2023

Background

Oligomers are increasingly implicated in Alzheimer’s disease (AD)1. The characteristics of these protein aggregates remain largely unknown due to their low biological concentration, solubility, small size and structural heterogeneity. This study aims to better classify the diverse protein aggregates found in human brains across AD onset and progression.

Methods

Post‐mortem flash‐frozen brain samples (n = 28) spanning the full range of AD stages (Braak 0‐VI) were obtained from London Neurodegenerative Diseases Brain Bank: two brain regions, middle temporal gyrus (MTG) and primary somatosensory cortex (SOM), were obtained from 14 donors. The post‐mortem tissues were homogenised to extract proteins into liquid fractions for single‐molecule studies. Antibodies, including 6E10, HT7, AT8 and SC‐12767, were selected to bind aggregates of amyloid‐β, tau, phosphorylated tau and α‐synuclein respectively. Ultra‐sensitive single‐molecule array (Simoa®) assays measured protein aggregate quantities in the homogenates. Single‐molecule pull‐down (SiMPull) assays, imaged by super‐resolution fluorescence microscopy, measured aggregate size and shape within the homogenates. BCA assays quantified the total protein content of the homogenates for normalisation.

Results

Morphological differences in tau aggregates were observed between disease stages with super‐resolution microscopy. Quantities of phosphorylated and total tau aggregates tend to increase significantly in the MTG and SOM from mid‐stage AD onwards according to Simoa® assays. In comparison to tau, aggregate quantities of amyloid‐β and α‐synuclein displayed less variation between non‐diseased controls and different AD stages.

Conclusions

Single‐molecule techniques can sensitively detect a broad range of protein aggregates from human brains. Novel differences in the morphologies and quantities of aggregates have been identified across AD stages. There is strong potential for uncovering the specific protein aggregates responsible for AD with these methods. This could facilitate earlier disease detection and more effective treatment targeting.

1 Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353‐356 (2002).
Analysis of the screening process in the Brazilian Subjective Cognitive Decline Cohort
Authors: Souza Victória Tizeli , da Mota Simone Sieben , De Marchi Bruno De Oliveira , Formoso Carolina Rodrigues , Rivas Gabriela Raquel Paz , Carvalho Guilherme Da Silva , De Souza Haniel Bispo , Beltrami Lucas Bastos , Suwa Samuel Masao , Slaviero Wesley , Santos Rhaná Carolina , Carnevalli Sarah Vitoria Bristot , de Albuquerque Ana Letícia Amorim , Giordani Manuella Edler Zandoná , Strelow Matheus Zschornack , Borelli Wyllians Vendramini , Carello‐Collar Giovanna , Chaves Marcia L Fagundes , Zimmer Eduardo R , Castilhos Raphael Machado
Published: December 2023

Background

Subjective Cognitive Decline (SCD) is conceptualized as cognitive complaints in cognitively unimpaired (CU) individuals and is associated with progressive cognitive decline. Recruiting these individuals can be challenging, especially due to the low education levels and limited access to information by a portion of the Brazilian population.

Objective

We aimed to analyze the profile of the screened individuals during the recruitment process in the ongoing Brazilian Subjective Cognitive Decline (BRASCODE) Cohort at the Hospital de Clínicas de Porto Alegre (HCPA), Southern Brazil.

Methods

We analyzed the sociodemographic characteristics of the screened individuals recruited predominantly through social media and newspaper invitation. This study evaluated CU individuals aged 65+ years‐old with cognitive complaints. Exclusion criteria were the presence of uncontrolled psychiatric/clinical illness, cerebrovascular disease, and the use of psychotropic drugs. The recruitment was carried out exclusively by phone calls in two phases. In the first one, the exclusion criteria were applied and, in the second, the following scales were performed: Modified Telephone Interview for Cognitive Status (TICS‐M); Generalized Anxiety Disorder Assessment (GAD‐2); Geriatric Depression Scale; and the Subjective Cognitive Decline Scale.

Results

From February to December 2022, 406 individuals were recruited. Most were women (74.6%; n = 303), with a median (SD) age of 71.6 (5.8) years‐old and 11 (5.2) years of formal education. The main reasons for exclusion in phone call 1 were clinical illness (39.9%; n = 59) and cerebrovascular disease (10.1%; n = 15). In those individuals evaluated in the phone call 2 (62.3%; n = 256), most were excluded because presented TICS‐M score below cut‐off (31.6%; n = 80), absence of cognitive complaints (29.6%; n = 75), and GAD‐2 (7%; n = 18) and GDS (3.5%; n = 9) scores above the cut‐off (Figure 1). Only 74 (18.2%) individuals were included in the cohort.

Conclusion

The high screening failure seen in our study and the predominance of women with high educational level reveal the difficulty in screening SCD individuals and indicate the need for alternative recruitment methods, especially in a setting with low education.
TREM2 Burden associates solely with Alzheimer’s Disease, and decreases the Chance to become a Centenarian
Authors: Dijkstra Janna I.R. , Vermunt Lisa , Biessels Geert Jan , Braber Anouk , Claassen Jurgen A.H.R. , De Deyn Peter Paul , Ghanbari Mohsen , Huisman Martijn , Hulsman Marc , Ramakers Inez H.G.B. , Reinders Marcel J. T. , Seelaar Harro , Tesi Niccoló , Visser Pieter Jelle , van der Flier Wiesje M. , Teunissen Charlotte E. , Holstege Henne , Van Der Lee Sven J
Published: December 2023

Background

Rare TREM2 variants are major risk factors for Alzheimer’s disease (AD), but TREM2 variants may also confer a higher risk for other neurodegenerative diseases and a lower probability for cognitively healthy aging. We studied the TREM2 burden associated with different types of dementia and cognitively healthy centenarians (CHCs).

Method

We included participants of the 100‐Plus Study, Amsterdam Dementia Cohort, Longitudinal Aging Study Amsterdam and various Dutch memory clinics. TREM2 variants (R47H, R62H, Q33X, R62C, T96K) were genotyped with a high density array or imputed using standard methods (TOPMED reference panel). To avoid family bias and ethnic differences, related individuals and those of non‐European ancestry were excluded. Frequencies of individual variants and the burden of TREM2 variants were compared in AD dementia, dementia with Lewy Bodies (DLB), frontotemporal dementia (FTD), cognitively normal controls and CHCs (correcting for 5 principal components).

Result

We identified 242 carriers of TREM2 mutations and 6,683 controls without a TREM2 mutation with a mean age of 69 years (SD ±14 years), 50% female (Table 1). TREM2 variants were significantly associated with AD dementia (OR 1.4, 95%CI 1.1‐1.8, p = 0.01) (Table 2). R47H conferred the highest risk for AD (OR 2.8, 95%CI 1.4‐5.6, p = 0.004), compared to 1.3‐fold increased risk of R62H (95%CI 0.9‐1.7, p = 0.11). The carrier frequency was not increased in DLB (OR 1.4, 95%CI 0.7‐2.6, p = 0.34) and was not increased in FTD compared to controls (OR 0.59, 95%CI 0.3‐1.3, p = 0.18). Of interest, the allele frequency of TREM2 variants in centenarians is half of the expected frequency (OR = 0.46, 95%CI 0.1‐1.1, p = 0.10), and only concerns R62H.

Conclusion

We replicate the association of TREM2 with increased risk of AD. In contrast to previous reports no association was observed with DLB or FTD. Cognitively healthy centenarians show a negative trend for TREM2 allele frequency suggesting that carrying a TREM2 variant decreases chances of survival to extreme age.
The frequency of psychotropic drug use in early‐onset Alzheimer’s disease ‐ experience from the Center for Memory Disorders in Serbia
Authors: Šarčević Maksim , Stojkovic Tanja , Stojmenovic Gorana Mandic , Obradovic Dragan , Stefanova Elka
Published: December 2023

Background

Neuropsychiatric symptoms (NPS) occur frequently in patients with young onset Alzheimer’s Disease (YOAD). However, studies on psychotropic drug use (PDU) mainly focus on elderly patients with dementia. It is important to know the prevalence of PDU in patients with YOAD in order to reduce excess use of these medications in this group. Our study aim is to investigate the frequency of PDU among patients with YOAD.

Method

This is a retrospective study on 135 patientsfrom Memory Centre of Neurology Clinic, Clinical Centre of Serbia, with clinical diagnosis of YOAD. We included outpatients that had first visit to our clinic from 01.04.2012. to 01.04.2017. The data on psychotropic drug use werecollected from medical records. Statistical analyses were done using SPSS20.

Result

Mean age of our patients at inclusion was 60.07±5.27 and mean disease duration was 3.42±1.53. 85.18% patients received PT drugs. Antidepressants were prescribed most frequently, in 63.7% of patients, while antipsychotics were used by 45.93% of patients, and benzodiazepines by 61.5%. The earliest prescribed PTs were antidepressants, 3.66 years from the first symptoms and 1.45 years after diagnosis and antidepressants were used the longest in our group, 3.15 years.

Conclusion

The frequency pf PDU in our cohort is high and comes close to PDU in patients in nursing homes in other European countries. The reason might be the high frequency of NPS in YOAD but also prescribing practice in the absence of systematic non pharmacological measures and that is something we have to take notice of.
Amyloid‐beta immunotherapy induces novel methylomic changes in Alzheimer’s disease brain
Authors: MacBean Lachlan Ford , Smith Adam R. , Boche Delphine , Lunnon Katie
Published: December 2023

Background

Post‐mortem neuropathological examinations following the first active immunotherapy strategy (AN‐1792, Elan Pharmaceuticals, 2000) for Alzheimer’s disease (AD) have evidenced amyloid‐β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals. This study characterises the epigenetic profiles of individuals who underwent Aβ immunotherapy with the aim of discovering novel therapeutic targets and biomarkers.

Method

DNA was isolated from post‐mortem prefrontal cortex tissue of 16 immunised AD cases who received varying doses (ug) and number of doses during the trial period, including placebos. DNA methylation was quantified using methylation arrays and the raw intensity values processed and normalised for subsequent statistical analysis to identify differentially methylated positions (DMPs) across the genome associated with Aβ immunotherapy. Additional analyses included regions of enrichment analysis for identification of differentially methylated regions (DMRs) and weighted gene co‐expression network analysis to identify gene clusters with highly correlated methylation levels.

Result

After correcting for known (age, sex, cell type composition) and unknown variables, a DMP located within Chromosome 19 Open Reading Frame 12 (C19Orf12) at the genome‐wide significance level (P < 9.00E−08) was associated with Aβ immunisation. 10 DMRs were further associated with immunisation, with three regions consisting of ≥ 3 CpG sites and having a Sidak‐corrected P < 0.05. These regions were located within the CRISP2 (chr6; 49681178:49681391 [8 probes], Sidak‐corrected P = 8.29E‐05), CTTNA1 (chr5; 138210906:138211184 [8 probes], Sidak‐corrected P = 5.96E‐06), and RNF39 (chr6; 30038859:30039025 [12 probes], Sidak‐Corrected P = 2.60E‐05) genes.

Conclusion

Indicating better inflammatory markers can help inform of effective preventative care strategies for elders. This study provides evidence for altered epigenetic processes in the pathophysiology of AD and identifies novel processes specific to Aβ immunotherapy. The next step for this project includes analysing RNA sequencing data, to determine if observed methylomic changes correlate with gene expression, and genotyping array data.
Reframing dementia: can a human rights approach bring hope?
Authors: McGettrick Grainne
Published: December 2023

Dementia discourse is largely medicalized and the voice of the person with dementia is not often heard in public or policy discourse. Dementia still remains stigmatized and hidden, and in many societies, is often associated with shame due to its social construction. As a result, people living with dementia and their carers retreat, live lesser lives and largely exist on the margins of our society. However, if we were to reframe dementia as a human rights issue (as set out the United Nations Convention on the Human Rights of Persons with Disabilities) and use the rights model of disability to begin to tackle the societal, attitudinal and physical barriers that limit participation, then perhaps there is hope that people living with dementia continue to be valued and respected a central part of our families, communities and society after diagnosis.

A Human Rights Based Approach (HRBA) would ensure that the person’s agency is recognized, they are treated as equal and active citizens with rights, and make certain they are involved in all the decisions that impact their lives in multiple spheres, including policy, public discourse, research, services, civic life and advocacy. This reframing of the discourse requires the broad range of actors to engage and change their practice. From a policy and systems perspective, it would demand a significant shift in the current approach and an adopting of the PANEL principles (Participation, Accountability, Non‐discrimination and Equality, Empowerment and Legality) in how we develop policy and service responses. A HRBA requires a move from the traditional ‘doing for’ to a model of enablement, active engagement and working together. By challenging the medical model and the current status quo, can we reduce stigma, bring people with dementia and their families in from the margins and offer hope for a better life living with dementia using a human rights lens?
Voxel‐level of abnormal β‐amyloid accumulation and spatiotemporal distribution patterns in Alzheimer’s Disease
Authors: Sun Pan , Cai Yue , Li Anqi , Zhu Yalin , Ma Shaohua , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

The spatial patterns of β‐amyloid (Aβ) accumulation are critical for early diagnosis and clinical trials of Alzheimer’s Disease (AD). In this study, we explored a new voxel‐level Aβ index and investigated spatial patterns of voxels with abnormal Aβ deposition in different stages of AD.

Method

We identified 944 ADNI participants with Aβ 18F‐florbetapir positron emission tomography (PET) image. All Aβ PET images were co‐registered with their corresponding magnetic resonance imaging (MRI) scans, intensity‐normalized to the whole cerebellum, and spatial‐normalized to the Montreal Neurological Institute (MNI) space. We defined the threshold of each voxel as the mean+2SD of 18F‐florbetapir PET images of 51 participants who were Aβ PET negative (A‐), CSF p‐Tau181 negative (T‐), hippocampal atrophy negative (N‐), and cognitively unimpaired (CU) at both baseline and follow‐up. The positive voxel number (NoVoxel+) was counted based on the threshold of each voxel. The cross‐sectional and longitudinal correlations between NoVoxel+ and cortical summary Aβ standard uptake value ratio (SUVR) were determined in A‐ and Aβ‐positive (A+) separately. We compared baseline NoVoxel+ among different stages of AD, as well as how it related to longitudinal changes of Aβ SUVR, CSF p‐Tau181, residual hippocampal volume (rHCV), temporal meta‐ROI cortical thickness, and preclinical Alzheimer cognitive composite (PACC) score, and follow‐up tau PET levels, controlling for age, sex and APOE4. Finally, we investigated the spatial patterns of NoVoxel+ in different stages of AD.

Result

The new Aβ index NoVoxel+ was strongly correlated with the cortical summary Aβ SUVR cross‐sectionally and longitudinally regardless of Aβ positivity (Figure 1). Cognitively impaired (MCI and dementia) individuals showed larger (p<0.001) NoVoxel+ than the CU individuals, A+ group had greater NoVoxel+ than the A‐ group (Figure 2). NoVoxel+ was related to faster rates of increases in Aβ SUVR and CSF p‐Tau, decreases in rHCV, temporal meta‐ROI cortical thickness, and PACC. Abnormal Aβ voxels were primarily located in precuneus, medial orbital frontal and anterior/posterior cingulate regions in A‐/CU group (Figure 3).

Conclusion

The proposed voxel‐level Aβ deposition NoVoxel+ may be useful to investigate the spatial and temporal patterns of Aβ accumulation in AD, particularly in early amyloidosis stage.
MR1/MAIT cell axis in the temporal development of Alzheimer’s disease pathology
Authors: Johnson Season Kealyn , Kersey Holly N , Codocedo Juan F , Newell Kathy L , Landreth Gary E , Lamb Bruce T , Oblak Adrian L , Brutkiewicz Randy R
Published: December 2023

Background

Neuroinflammation is a hallmark feature of Alzheimer’s disease (AD). A major producer of inflammation is mucosal‐associated invariant T (MAIT) cells, a novel subpopulation of innate‐like T cells that recognize unique antigens presented by the MR1 molecule. This study aims to determine the contributions of the MR1/MAIT cell axis in humans and animal models of AD.

Method

Brain tissue from various ages of 5XFAD mice and those that are MR1‐deficient (MR1KO), and from AD and non‐AD individuals, was analyzed for correlative relationships between MR1 and Aβ expression, and the presence of MAIT cells. qPCR was used to determine transcriptional changes in Mr1. Immunofluorescent microscopic analysis of MR1 expression and MAIT cell numbers in the brain was performed with antibodies against MR1, microglia, Aβ, and MR1 tetramers for MAIT cells. The activation state of brain MAIT cells was analyzed by flow cytometry with antibodies against CD69 and CD25.

Result

In brain sections from AD patients and 5XFAD mice, MR1 expression was substantially elevated in microglia surrounding plaques versus those further away (human AD: P < 0.05; 5XFAD: P < 0.001). In 5XFAD/MR1KO mice, the development of amyloid‐beta plaque pathology occurred at a significantly slower rate than in normal 5XFAD mice. Furthermore, there was a temporal increase in MAIT cell numbers (P < 0.01) in the brains of 5XFAD mice. These MAIT cells were highly activated, with elevated expression of both CD69 (P < 0.05) and the interleukin‐2 receptor alpha chain (CD25) (P < 0.05); such was not the case with brain‐resident classical T cells.

Conclusion

The MR1/MAIT cell axis augments the temporal development of Aβ plaques. Thus, our data indicate a potential detrimental role for MR1 and/or MAIT cells in AD pathology. Understanding the contribution of this innate immune axis could provide novel clues as to the overall role of innate immunity in AD, leading to its identification as a potential therapeutic target in AD.
Assessing reactive astrogliosis in Parkinson’s brain with astroglial tracers BU99008 and deprenyl
Authors: Rocha Filipa Monteiro , Nordberg Agneta K , Kumar Amit
Published: December 2023

Background

The knowledge regarding the role of reactive astrogliosis in Parkinson’s disease (PD) is still at the surface level, however, a few in vivo PET studies have speculated that reactive astrogliosis could be an early event in PD pathology. Moreover, a direct link between α‐synuclein pathology and astrocytes in PD has been also shown, where astrocytes play a key role in α‐synuclein propagation by shuttling α‐synuclein between neurons and astrocytes. The PET imaging field is advancing very fast and different astrocytic‐tracers are now available, such as 11C‐Deprenyl (DED) (targeting MAO‐B) and 11C‐BU99008 (detect imidazoline‐2‐binding sites (I2Bs)), which we believe is crucial to explore the role of reactive astrogliosis, including astrocytic heterogeneity in PD. Hence, we used a multi‐tracer approach to understand the role of reactive astrogliosis and to validate its reliability as a potential biomarker in PD and related synucleinopathies.

Method

We used specialized postmortem saturation radioligand binding assay and small frozen human brain section autoradiography in PD and controls (CN) brains.

Result

The 3H‐BU99008 and 3H‐DED saturation binding studies in the frontal cortex (FC) brain homogenate (BH) of PD (n = 2‐3) and CN (n = 2) cases demonstrated relatively higher 3H‐DED binding as compared to 3H‐BU99008 with following Bmax (binding‐density) and Kd values: 3H‐BU99008 CNBmax – 59.1fmol/mg, Kd‐ 2.9nM vs. PDBmax – 51.6fmol/mg, 2.3nM; 3H‐DED CNBmax – 190.6fmol/mg, Kd‐ 2.7nM and PDBmax –244.2fmol/mg, Kd‐ 6.7nM. 3H‐BU99008 binding in the Cau in PD was ∼3‐fold higher than in CN. In contrast, the 3H‐DED binding between CN and PD brains in the Cau BH was almost comparable. Interestingly, qualitative, and semi‐quantitative assessment of small frozen brain section autoradiographies showed increased specific binding of 3H‐BU99008 and 3H‐DED in PD (n = 4) frontal & temporal cortices as compared to CN (n = 2‐3). In Cau, 3H‐BU99008 again showed higher binding than CN whereas 3H‐DED binding was comparable to CN, further complementing our saturation data.

Conclusion

The first study to assess reactive astrogliosis signature in postmortem PD brains with astroglial tracers BU99008 and DED. The findings clearly highlight regional differences in BU99008 and DED binding in PD brains and suggest increased reactive astrogliosis at the end stages of the disease warrants further investigation.
Geographic bias in hand preference within posterior cortical atrophy
Authors: Chapleau Marianne , Seaman Julia , Allen Isabel Elaine , Bogley Rian , Montembeault Maxime , Miller Bruce L , Tempini Maria Luisa Gorno , La Joie Renaud , Rabinovici Gil D. , Miller Zachary ,   International PCA Work Group
Published: December 2023

Background

Posterior cortical atrophy (PCA) is a neurodegenerative disorder of visuospatial and visuoperceptual impairment with high association to underlying Alzheimer’s disease (AD) pathology. In contrast to typical amnestic AD, risk factors for PCA remain largely unknown. Previously, we observed higher rates of neurodevelopmental differences in PCA, including an increased prevalence of non‐right‐handed individuals (left‐handed, ambidextrous, and/or forced‐right‐handed) compared to the general population. Non‐right‐handedness has been associated with many neurologic and psychiatric conditions, and we have found is overrepresented in early and non‐amnestic forms of AD. In this study, we sought to investigate handedness within an international PCA cohort.

Method

We contacted 55 research centers conducting PCA research identified in a literature review (n = 1353 papers), as well as additional sites recruited through the Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Atypical AD Professional Interest Group (n = 7 sites) requesting de‐identified, single‐subject data from PCA patients. Single‐subject demographic, clinical, fluid, neuroimaging and neuropathological data were collected from 1121 participants evaluated at 34 sites in 16 countries. In this sub‐project, the sample size was restricted to the 901 PCA participants with reported handedness. Descriptive analyses were performed across the entire cohort and across three different geographic levels: by 1) center, 2) country/region, and 3) continent. Statistical analyses were restricted to the continental view given sample size constraints.

Result

Within the total consortium PCA cohort, 10.3% (93/901) were non‐right‐handed. Figure 1 shows the distribution of non‐right‐handedness across country/region. Comparisons across continents revealed differences in handedness (p = 0.04, Yate’s corrected). Sample sizes in Asia, Australia, and South America did not permit comparisons of observed vs. expected rates of non‐right‐handedness, whereas Europe displayed significantly less and North America significantly more non‐right‐handedness than expected (p = 0.04 and p = 0.02, respectively, employing a 10% non‐right‐handedness rate for the general population).

Conclusion

Within the international PCA consortium, differences in hand preference presented across centers in a manner that could not be explained by normal variation in the data. Uncovering this global bias in hand preference not only holds relevance towards understanding the etiology of PCA but may have implications for neuroscience research more broadly.
Levels of activating transcription factor 6 alpha (ATF6α) in Alzheimer’s disease
Authors: Chauvet Mariana Gomes , Isaac Alinny Rosendo , Ferreira Sergio T. , Lourenco Mychael V.
Published: December 2023

Background

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide. More than 40 million people currently suffer from AD, and such prevalence tends to increase considerably in the coming decades due to increased human longevity. Nonetheless, despite intense research efforts, no therapy has yet proven effective in attenuating or reversing the progression of AD. The unfolded protein response (UPR) is an adaptive signaling mechanism that aims to maintain cell viability under protein folding stress. The accumulation of misfolded proteins is associated with several neurodegenerative diseases, such as AD, leading to synaptic loss and neuronal death. UPR activation depends on stress sensors such as ATF6α (activating transcription factor 6 α). Recently, ATF6α factor gained importance as a therapeutical target in some disorders and pharmacological activation of this pathway has already been shown to be protective in heart disease. Nonetheless, the association between the ATF6α pathway and AD is not fully understood yet. Here we investigated whether dysfunctional ATF6α associates with AD.

Method

ATF6α protein levels were measured in postmortem tissue from the cerebral cortex and in hippocampus of APP/PS1 transgenic mouse model of amyloid patholy by western blotting. ATF6α mRNA expression was analysed using an online database (Aging, dementia and TBI study from the Allen Institute.

Result

Initial results using postmortem tissue from the cerebral cortex suggested that ATF6α protein levels are reduced in AD patients. Using an online database (Aging, dementia and TBI study from the Allen Institute), we found reduced ATF6α mRNA expression, in relation to the Braak scale of tau pathology in the parietal neocortex and hippocampus. Conversely, we found increased ATF6α protein levels in the hippocampus of APP/PS1 transgenic mouse model of amyloid pathology.

Conclusion

Together, our initial results suggest that ATF6α may be differentially altered in AD. Further investigation of the ATF6α pathway in AD may offer a novel therapeutic perspective for cognitive decline.
Multiomic analyses suggest a divergent aging trajectory in dementia
Authors: Coenen Loet , de Vries Helga E , Middeldorp Jinte
Published: December 2023

Background

Aging is the main risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD) and other forms of dementia. Both aging and dementia have been shown to leave a molecular signature in the plasma proteome. Understanding how the Dementia Plasma Proteome (DPP) diverges from the Aging Plasma Proteome may provide insights in pathological changes in the brains of dementia patients, or resilience mechanisms in the brain of cognitive healthy individuals. Here, we provide a more detailed overview on the aging trajectories of the DPP across ‘normal agers’ and dementia patients using a multiomic analysis approach.

Method

Using publicly available datasets such as the Human Protein Atlas, GTEx, and the Aging, Dementia and TBI study, we aim to link changes observed in the plasma to age‐associated changes in the brain and AD pathology. For this, we used publicly available databases. Using immunohistochemistry, we attempt to validate our findings in brain tissue.

Result

We show that differences in expression levels of proteins belonging to the DPP (Dementia Proteins) between non‐demented controls and demented cases are positively associated to previously identified aging associations. Furthermore, we show that Dementia Proteins are preferentially expressed in the brain and among multiple brain cell types, such as neurons, oligodendrocyte precursor cells and astrocytes. Expression trajectories during aging of brain‐expressed Dementia Proteins in the healthy brain appear largely similar as identified in the aging plasma proteome. However, we identified several proteins displaying differential aging trajectories in the brain of demented patients. Lastly, we present how these altered aging trajectories associate to several pathological measures, such as levels of Tau and Amyloid beta.

Conclusion

These results suggest differences in aging trajectories between non‐demented controls and dementia patients, which may be reflected in both the plasma and in brains of dementia patients. Together, these results may provide novel insights in proteins associated with dementia‐associated pathology and their contributions to the disease progression. Future studies are needed to further validate these findings and to discover the underlying mechanisms.
Associations between insulin‐like growth factor‐1 and executive function in normoglycemia, prediabetes, and type 2 diabetes mellitus
Authors: Ryoo Si Won , Anita Natasha Z. , Perlman George , Xiong Lisa Y. , Wu Che‐Yuan , Mitchell Jane , Swardfager Walter
Published: December 2023

Background

The relationship between insulin‐like growth factor‐1 (IGF‐1) and cognition has been studied in healthy individuals, yet the results have been inconclusive. The aim of this study was to determine whether the association between IGF‐1 and executive function differs in individuals with normoglycemia, prediabetes, and type 2 diabetes mellitus (T2DM).

Method

The Midlife in the United States (MIDUS) study used the Brief Test of Adult Cognition by Telephone (BTACT) to assess cognitive function. A composite z‐score for executive function was created from the following tests: Digits backward span, category fluency, number series, backward counting, and Stop and Go Switch Task (SGST). IGF‐1 levels were measured from fasting blood samples using an immunochemiluminescent assay. Normoglycemia was defined as individuals without a physician diagnosis of diabetes and glycated hemoglobin (HbA1c) < 5.6%. Prediabetes was defined as those without a physician diagnosis of diabetes and HbA1c between 5.7%‐6.4%. T2DM was defined as anyone with a physician diagnosis of diabetes, or HbA1c ≥6.5%, or use of oral hypoglycemic medication. Multiple imputation was used to handle missing covariate data. A linear regression model controlling for demographic factors, homeostatic model of insulin resistance (HOMA‐IR), C‐reactive protein (CRP) levels, exercise, smoking, sleep disturbance, alcohol intake and medication use, was used to determine the cross‐sectional association between IGF‐1 and executive function across subgroups.

Result

The MIDUS dataset included 447 normoglycemia (47.0% female, mean age 53.4±9.6), 467 prediabetes (57.4% female, mean age 56.8±10.6), and 271 T2DM participants (53.1% female, mean age 57.5±9.8). In participants with prediabetes, IGF‐1 levels were associated with better executive function (β = 0.126, p = 0.007), particularly in males (β = 0.258, p<0.001). This association was absent in individuals with normoglycemia or T2DM. Compared to males with prediabetes, the opposite trend was observed in males with T2DM (β = ‐0.181, p = 0.062).

Conclusion

The findings of this study suggest that the association between IGF‐1 and executive function may be influenced by insulin resistance or T2DM. Gaining a better understanding of why the associations differ in T2DM compared to prediabetes may explain the inconsistency observed in the literature and help elucidate the mechanism behind cognitive decline in T2DM.
Characterising the D409V/WT mouse as a novel model of Lewy body dementia
Authors: Sander Millie , Brown Jonathan T , Lunnon Katie , Ballard Clive G
Published: December 2023

Background

The overlap in both pathological and symptomatic traits observed among Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) patients make accurate diagnosis difficult. Novel models to further study DLB are therefore imperative, and previous research suggests mice with heterozygous mutations in the GBA gene (D409V/WT) to be a viable option. These mice display age‐related cognitive decline and α‐synuclein deposition in the brain (Clarke et al., 2019), and our prior work found there to be significant atrophy in the brain by 12 months of age.

Method

We aimed to further characterise disease‐associated pathology exhibited by these mice. Cortical thickness and vesicle size was measured among mice of 3, 6, 9, 12, and 18 months of age in order to assess atrophy progression with age. Neuronal firing in the medial septum was measured at both baseline and following application of NMDA – a drug used to elicit neuronal activity. Firing rate and latency to reach peak NMDA response were used to assess neuronal dysfunction. Finally, differential expression and weighted gene co‐expression network analysis (WGCNA) was conducted to assess transcriptomic changes in the medial septum. All studies used wild‐type littermates as controls.

Result

Age‐associated cortical thinning and ventricle enlargement were observed, with all six measures reaching statistical significance by 12 months of age. Although latency to reach peak neuronal firing showed no difference between groups, firing rate was significantly reduced in D409V/WT mice across all conditions. Differential expression analysis found significant downregulated genes in the medial septum of the D409V/WT mice compared to the WT controls, and WGCNA analysis found various clusters of genes to be associated with both genotype and sex.

Conclusion

These results present examples of DLB‐associated pathology exhibited by the D409V/WT mice, supporting their potential as a novel model of disease. However, further characterisation is needed in order for these mice to be considered a reliable model, and to be employed in wide‐scale research.

References: Clarke, E. et al. (2019) ‘Age‐related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia’, Neurochemistry International, 129. https://doi.org/10.1016/j.neuint.2019.104502.
Dyslexia phenotypes in Chinese‐speaking individuals with Primary Progressive Aphasia
Authors: Tee Boon Lead , Tempini Maria Luisa Gorno , Chen Lorinda Li‐Ying Kwan , Lo Raymond Y. , Chen Ta‐Fu , Tsoh Joshua , Yan Connie TY , Chan Andrew LT , Lu Chien Jung
Published: December 2023

Background

There are more than 7,000 living languages worldwide with wide heterogeneities in their linguistic features. Varying dementia symptomatology has been noted across speakers of different languages. Chinese languages adopt logographic scripts that contrast greatly from Indo‐European languages with alphabetic writing systems. For instance, Chinese characters have weak grapheme‐phoneme correspondence, with only 19‐ 39% pronounced per their phonetic components. Chinese characters also have 20 different spatial configurations with varying visuospatial complexity and abundant heteronyms. Past literature has focused on the reading presentations of primary progressive aphasia (PPA) patients that adopt Indo‐European languages. This study outlined the reading presentations of Chinese‐speaking PPA patients.

Method

The CLAP (Chinese Language Assessment for PPA) battery is designed to characterize the neurolinguistics features of Chinese‐speaking PPA individuals. In CLAP character reading test, participants are tasked to read aloud 50 Chinese characters that vary in lexicality (pictographic, regular compound, and irregular compound characters), character frequency and concreteness. Voxel‐based morphometry(VBM) was performed to examine the neural basis of reading performance. Participants are also tasked with reading pairs of compound words with heteronyms (e.g., “bow tie” vs “bow down).

Results

A total of 15 Mandarin‐speaking controls and 38 PPA individuals [6 nonfluent variant (nfv) PPA, 9 semantic variant (sv) PPA and 23 logopenic variant (lv) PPA] completed CLAP reading task. In character reading test, svPPA scored significantly lower than controls and nfvPPA (pictographic: p = 0.026; regular compound: p = 0.007; irregular compound characters: p<0.001). Regardless of lexicality, the reading score significantly correlated with volumetric changes over left temporal pole. While over‐regularization errors/surface dyslexia was the most common reading error across control and PPA groups, it was not specific to svPPA (p = 0.109). Conversely, on heteronym word reading test, svPPA and lvPPA scored significantly lower in accuracy, with over‐regularization errors more frequently noted in svPPA group.

Conclusion

Contrary to English svPPA patients that struggled specifically with irregular word reading and showed frequent surface dyslexia, Chinese PPA patients showed no variant‐specific differences across lexicality, and svPPA‐specific over‐regularization phenomenon were found at the lexical (i.e., heteronym‐reading) and not sub‐lexical reading. Diagnostic criteria for PPA syndrome vary with languages and should ideally be tailored linguistically.
Repurposing verbal fluency: Word‐property analysis reveals neurocognitive markers of Hispanics with Alzheimer’s disease and mild cognitive impairment
Authors: Garcia Adolfo M , Ferrante Franco , Pérez Gonzalo , Migeot Joaquín , Ibanez Agustin
Published: December 2023

Background

Though central to dementia assessments, verbal fluency tasks are suboptimally exploited. Performance is typically measured by counting valid responses. This precludes insights on which word types are least accessible to patients, while failing to discriminate among disorders. Alternatively, each word can be decomposed into relevant properties that drive semantic memory retrievability. Recently, our team has combined objective lexical measures with multimodal imaging to examine whether this approach is sensitive to Hispanics with Alzheimer’s disease (AD) and mild cognitive impairment (MCI), vis‐à‐vis others with behavioral variant frontotemporal dementia (bvFTD).

Method

In Experiment‐1, we recruited 32 AD patients and 32 bvFTD patients, matched with 27 HCs. Experiment‐2 involved 60 persons with MCI and 60 matched HCs. Participants performed phonemic and semantic fluency tasks. We counted valid responses and, using normative databases, extracted quantitative data of six word properties: frequency (occurrences in everyday use), granularity (conceptual specificity), neighborhood (words with similar phonological structure), length (number of syllables), familiarity (subjective recognizability), and imageability (ease of mental visualization). We examined whether these variables were robust to discriminate between groups (via ANOVAs), identify individuals from each cohort (via linear regressions), and capture cognitive, neuroanatomical, and functional connectivity disruptions.

Results

In Experiment‐1, while both patient groups produced fewer valid responses than HCs, only AD patients showed distinct word properties (higher frequency, lower granularity, more phonological neighbors). Multivariate word properties robustly identified individual AD (but not bvFTD) patients from HCs (AUC = .89), driven by the abovementioned properties. These features correlated with executive outcomes only in AD, and they predicted patients’ anatomical and functional disruptions along temporal, frontal, and cingulate regions. In Experiment‐2, the same word properties differentiated MCI individuals from HCs, with multivariate classification reaching an AUC of .75. These features correlated with the volume of, and connectivity between, temporal and frontal regions that partly overlapped with those observed in AD.

Conclusion

Verbal fluency tasks can be repurposed to reveal condition‐specific markers of persons with and at increased risk for AD. New avenues emerge towards scalable, low‐cost assessment of Hispanics and, potentially, other underrepresented populations.