bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex and family history differences in Aβ and tau vulnerability in preclinical Alzheimer’s disease
Authors: Ourry Valentin , St‐Onge Frederic , Mohammediyan Bery , Yakoub Yara , Soucy Jean‐Paul , Poirier Judes , Breitner John C.S. , Villeneuve Sylvia
Published: December 2023

Background

Females and individuals with a family history (FH) of Alzheimer’s disease (AD) are considered at higher risk of sporadic AD. However, how sex and maternal/paternal heredity affects in vivo AD biomarkers is not well understood. Our objectives were to 1) assess if females or individuals with a first‐degree maternal FH of AD accumulate amyloid‐beta (Aβ) and/or tau faster than males or individuals with a first‐degree paternal FH of AD and 2) assess if both could influence the rate of Aβ driving tau in preclinical AD.

Method

Two hundred and thirty‐five older adults (age 68.3 ± 5.1 years, 69.8% female) from the PREVENT‐AD cohort, cognitively unimpaired at baseline, underwent [18F]‐NAV4694 and [18F]‐AV1451 positron emission tomography (PET) scans. Longitudinal PET scans were available for 106 individuals (4.3 ± 0.4 years follow‐up). We extracted and averaged the standard uptake value ratio (SUVr) in fronto‐parietal regions for Aβ and in temporal regions for tau. We performed t‐tests and ANOVA models to assess sex or maternal/paternal FH (FHsex) differences in Aβ and tau burden or annual change. We then performed linear regression models with an interaction term between Aβ and sex (or Aβ and FHsex) on tau burden and annual change, plus additional models to adjust for age and education.

Result

Sex and FHsex differences on Aβ and tau burden or annual rate of change did not reach significance although females tended to have higher tau SUVr at baseline (p = 0.053) (Figure 1 & 2). We found an interaction between Aβ and sex (𝛽 = ‐0.13, p = 0.008), and between Aβ and FHsex (𝛽 = 0.11, p = 0.03), on tau at baseline (Figure 3) suggesting that, for the same level of Aβ burden, females and individuals with paternal FH of AD had higher tau burden than males and individuals with maternal FH of AD. Results were similar when adjusted for age and education.

Conclusion

Females and individuals with a paternal FH of AD might need less Aβ before developing AD‐related tau, but did not accumulate tau faster. Identifying individuals more vulnerable to AD pathology, by disentangling sex‐specific effects, would help to design personalized interventions for AD.
Immunohistochemical and behavioral assessment of FKBP51‐Hsp90 interaction‐deficient mouse crossed with Alzheimer tau transgenic Tg4510 mice
Authors: Winblad Bengt , Wang Lisha , Zhao Zhe , Sun Xuelian , Shimozawa Makoto , Nilsson Per , Pavlov Pavel F.
Published: December 2023

Background

FK506‐binding protein 51 kDa (FKBP51) is a heat shock protein 90 (Hsp90) associated co‐chaperone which has recently emerged as a possible Alzheimer disease (AD) therapeutic target involved in tau metabolism. Increased expression of FKBP51 was found in brains of aged mice and AD patients and overexpression of FKBP51 in mice impairs cognitive function in vivo. To elucidate the role of FKBP51‐Hsp90 complex in tau biology in vivo we have crossed well characterized tau transgenic Tg4510 mice with our novel FKBP51‐Hsp90 interaction‐deficient mice (Fkbp5TPRmut).

Methods

• Using PCR amplification, we have confirmed correct genotype of crossings.

• Immunohistochemical staining of brains of 4 months‐old animals with total tau and phospho‐tau antibodies.

• Behavior assessment of cognition and memory using open field, novel object recognition, Y‐maze, and fear conditioning tests.

Results

• Successful crossings between Fkbp5TPRmut and Tg4510 mice have been obtained

• We have confirmed phospho‐tau expression in the cortex and hippocampus of 4 months‐old transgene‐expressing animals (positive controls).

• Immunohistochemical assessment of phospho‐tau expression in the cortex and hippocampus of wild‐type and Fkbp5TPRmut x Tg4510 crossings is ongoing.

• Behavioral assessment of Wt x Tg4510 and Fkbp5TPRmut x Tg4510 crossings is ongoing.

Conclusion

• Fkbp5TPRmut crossings with Tg4510 mice do not display harmful phenotype.

• Behavioral and immunohistochemical evaluation experiments are ongoing and will soon be completed.
The prioritization of biomarkers in the diagnostic workup of Lewy body disease
Authors: Aarsland Dag
Published: December 2023

The term Lewy body disease (LBD) encompasses a spectrum of neurodegenerative conditions, particularly Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB), associated with abnormal deposits of alpha‐synuclein in the brain and representing up to 20% of all neurocognitive disorders in memory clinics. Mild cognitive impairment or mild dementia precede or concur with Parkinsonism in the early stages of DLB and in a third of patients with PD at diagnosis. However, when Parkinsonism is slightly detectable, the differential diagnosis from other dementing conditions, such as Alzheimer’s disease (AD), may be challenging. For this reason, neuroimaging and electrophysiological biomarkers, divided into indicative or supportive based on their diagnostic performance over or below 80%, assist the clinical reasoning to increase the likelihood that MCI/early dementia is associated with LB. The European Intersociety Consensus Diagnostic Task Force recommends prioritizing the Dopamine transporter (DaT)‐SPECT imaging to investigate nigro‐striatal degeneration as the first biomarker (sensitivity 76%, specificity 88%), and suggests subsequently [123I]‐MIBG cardiac scintigraphy to evaluate the postganglionic sympathetic denervation in those cases (about a quarter) where DaT‐SPECT is negative but DLB is still clinically possible (AD pathology is estimated to be underlying in about 86% of these cases). In the absence of well‐validated techniques to establish the presence of brain alpha‐synuclein aggregates in vivo, the proposed sequence of biomarkers will provide the most accurate and cost‐effective biomarker‐based diagnosis of LBD.
Oligodendrocytes and Oligodendrocyte Precursor Cells (OPCs) in aged human brain. A Neuropathology study.
Authors: Hainsworth Atticus H , Bridges Leslie , Jeevahan Jamuna , Fang Wen Yung Stephanie , Keefe Jemma
Published: December 2023

Background

Cerebral Small Vessel Disease (CSVD) represents a variety of pathological processes affecting the cerebrovascular system. We tested whether the populations of oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs), associate with ageing and with CSVD.

Method

We examined deep subcortical white matter of individuals aged 78.5 (18.3) (mean (SD); range 20‐97, n = 24 (no information were given for 2 of them, only ‘young’)) with and without CSVD. All had minimal AD pathology (Braak stage II or less). Immunohistochemistry was performed, using the markers NogoA (specific for mature OLs), CD140A (for OPCs) and Sox10 (both OPCs and OLs) followed by digital image analysis.

Result

All samples had a substantial density of small, parenchymal cells with robust expression of each marker (NogoA, CD140A, Sox10). The density of NogoA‐positive cells was correlated with age (rs = 0.619, p = 0.011). There was a lower density of CD140A‐positive cells in individuals aged >70 with CVSD compared to those without CVSD (p = 0.016).

Conclusion

Our results indicate that there may be changes in OL and OPC density with age, and in CSVD.
Validating noninvasive techniques for 11C‐ER176 PET quantification in controls and Alzheimer’s disease patients
Authors: Rossano Samantha , Talmasov Daniel , Johnson Aubrey S. , Smith Anna C. , Guzmán Diana S. , Okafor Amarachukwu , Kreisl William Charles , De Jager Philip L , Lao Patrick J.
Published: December 2023

Background

Noninvasive yet accurate PET quantification methods are crucial for safe yet meaningful PET studies. [11C]ER176 is a PET radioligand that images neuroinflammation via the 18‐kDa translocator protein (TSPO), which is upregulated in activated microglia and has previously been a PET target in Alzheimer’s disease research. Currently, the gold‐standard method for quantifying ER176 PET is kinetic modeling of the dynamic PET data using the arterial input function (AIF), which is invasive and expensive. The current study explores a pseudo‐reference region (RR) technique to noninvasively quantify ER176 scans to facilitate clinical PET studies.

Method

Dynamic 90‐min [11C]ER176 PET scans were acquired in 11 participants, 5 controls (5M/0F) and 6 patients (3 MCI‐3M/0F; 3 AD‐2M/1F). Arterial blood data were collected throughout the duration of the scan and were used along with the dynamic imaging data to determine regional total volume of distribution (V
T) using the two‐tissue compartment model. Standardized Uptake Value Ratio (SUVR) was calculated by normalizing the radioactivity in each region by that of the reference region (cerebellar gray matter). We explored differences across methods (AIF‐derived V
T vs. RR‐derived SUVR) and across groups (controls vs. patients).

Result

Within each group, the outcome measures from AIF and RR methods were well correlated (Controls: R2 = 0.986, p < 0.001; Patients: R2 = 0.983, p < 0.001; Figure 1). Both methods showed greater TSPO expression in patients compared to controls, with mean differences in the medial temporal cortex of 14.99% between groups for V
T and 10.65% between groups for SUVR, but lower variance for SUVR compared to V
T (Figure 2). Both quantification methods showed similar regional patterns of percent differences between groups, corresponding to tau progression along Braak staging (Figure 3).

Conclusion

Results suggest that using the cerebellum, which does not accumulate amyloid plaques or tau aggregates until end‐stage disease, as a reference region for [11C]ER176 may be a valid method for quantifying differences between AD patients and controls compared to gold‐standard methodology. Regional increases in neuroinflammation are more reliable for SUVR than V
T in AD‐related regions. Ongoing work includes a larger sample size to further validate noninvasive PET quantification.
Physical function characteristics among older adults at high risk of developing cognitive decline
Authors: Reparaz‐Escudero Imanol , Altuna Miren , Ecay Mirian , Ros Naia , Saldias Jon , Garcia‐Sebastian Maite , Capetillo‐Zarate Estibaliz , Lopez Carolina , Clerigue Montserrat , Estanga Ainara , Etxeberria Usune , Mateo‐Abad Maider , de Asteasu MIkel Lopez‐Saez , Izquierdo Mikel , Tainta Mikel , Martinez‐Lage Pablo
Published: December 2023

Background

Physical function profiles of older adults (≥ 60years) cognitively unimpaired but at high risk of dementia (CAIDE dementia risk score ≥6) have not been well described. The CAIDE index evaluates both modifiable, cardiovascular (CVRF), and non‐modifiable risk factors such as age, sex and educational level. The association of these factors with physical function has not been thoroughly studied.

Method

We present preliminary cross‐sectional data from the first 2 (out of 4) recruitment waves of the CITA Go‐On study, a FINGER‐like multimodal intervention prevention trial. Inclusion criteria were based on age (≥60 and ≤85) and CAIDE score (≥6). Participants were categorized according to their cognitive status. Physical function assessment included gait speed, handgrip strength and maximum leg strength measured as 1 repetition maximum (1RM). We explored physical function by CAIDE scale, regarding hypertension (i.e. systolic >140mmHg or diastolic >90mmHg), hypercholesterolemia (i.e >250 mg/dL) and body mass index (BMI) as modifiable risk factors, and accounting for age, sex and educational level as non‐modifiable ones. Analysis was performed with SPSS v.29.

Result

Sample of 380 subjects aged 68.4 ± 5.6 years (mean, SD), 50% women, Mini‐Mental State Examination (MMSE) mean of 28.4 ±1.7 and CAIDE index mean was 7.4 ± 1.3. Of these, 91.6% were cognitively preserved, 5.5% had subjective complaints and 2.9% mild cognitive impairment. Dyslipidemia was present in 23.4%, hypertension in 46.9% and 63.1% showed BMI of overweight or obese. Univariate regression analysis showed that CAIDE index was significantly associated to maximum leg strength (1RM) (η2
= 0.05, p = 0.008), after adjusting for non‐modifiable risk factors (age η2
= 0.054, p = 0.001; sex η2
= 0.453, p = 0.001; and educational level η2
= 0.003, p = 0.333) and BMI (η2
= 0.156, p = 0.001). Handgrip strength and gait speed were not explained by modifiable factors in our sample (p = 0.12 and p = 0.53).

Conclusion

Physical function as measured by maximum leg strength is associated with CAIDE dementia risk index, and most significantly with sex and BMI component, with age displaying a moderate effect. Together with vascular risk factor control, interventions on physical function are important for prevention.
Gut microbiome‐related metabolites in plasma are associated with general cognition
Authors: Kastenmuller Gabi , Wu Tong , Arnold Matthias , Hankemeier Thomas , Ghanbari Mohsen , Uitterlinden André G. , Kraaij Robert , Van Duijn Cornelia M , Kaddurah‐Daouk Rima F. , Ikram M. Arfan
Published: December 2023

Background

Increasing evidence suggests a role of metabolism in neurological disorders including Alzheimer’s disease (AD). The human metabolome is determined by genes and modifiable factors such as gut microbiota, diet, medication, and other lifestyle choices. We hypothesized that metabolites related to endophenotypes of brain health maybe derived or influenced by these modifiable factors. Identifying the determinants of metabolites associated with AD‐related endophenotypes may help to discover new targets for drugs and prevention.

Method

We profiled plasma samples of 1082 participants of the Rotterdam study for 1387 metabolites using a non‐targeted metabolomics platform. After preprocessing and quality control, plasma levels of 991 metabolites were available for analysis of 1068 cognitively normal participants. We assessed the role of metabolites in general cognition (G‐factor) and magnetic resonance imaging (MRI) markers using linear regression. Replication analysis was performed for general cognition in an independent dataset. To identify the source of brain health‐associated metabolites, we estimated the explained variance (EV) of metabolites by genes, gut‐microbiome, medication use, and clinical features using gradient boosting decision tree (GBDT). Multiple testing correction was performed based on the false discovery rate (FDR) by Benjamini Hochberg (FDR<0.05).

Result

Among the 991 analyzed metabolites, 14 showed significant associations with general cognition, 21 metabolites with total brain volume, and one with total white matter lesions. In the replication analysis of metabolites associated with cognition, 9 metabolites showed consistent association with G‐factor. While genetics explained more than 5% of the variance of all associated metabolites, for three cognition‐associated metabolites (ergothioneine, 3‐hydroxy‐2‐methylpyridine sulfate, 4‐vinylguaiacol sulfate), modifiable lifestyle factors, medication and microbiota additionally explained up to 15% of their variance, with lifestyle factors showing the largest influence. Among the metabolites associated with brain imaging phenotypes, clinical factors and medication explained more than 5% of the variance of four metabolites (3‐hydroxysebacate, 3‐hydroxybutyrylcarnitine, sphingomyelin (d18:2/24:2), unnamed metabolite).

Conclusion

Our study provides evidence for the association between circulating metabolites and cognition or brain imaging phenotypes in participants without cognitive impairment. The levels of these metabolites are influenced by genetics and in part by modifiable factors. Further, studies are warranted to elucidate the complex relationship between gut microbiota, diet, genome, metabolome, and cognition.
Impact of Mid‐ and Late‐Life Diabetes in the Trajectories of Cognitive Aging in a Bi‐ethnic Cohort of Mexican Americans and Non‐Hispanic White Older Adults
Authors: Vazquez Janette , Wang Chen‐Pin , Bernal Rebecca , Seshadri Sudha , Hazuda Helen , Satizabal Claudia L.
Published: December 2023

Background

Midlife vascular risk factors, including diabetes, have been associated with an increased risk of Alzheimer’s disease (AD) and related dementias (ADRD). Hispanics experience both a higher burden of cardiometabolic diseases and AD/ADRD compared with non‐Hispanic White older adults. However, there is a lack of diversity in AD/ADRD research, and additional investigations are needed to understand the impact of cardiometabolic diseases in AD/ADRD disparities. We aimed to investigate the association of mid‐ and late‐life diabetes with cognitive decline in Mexican American (MA) and Non‐Hispanic White (NHW) adults.

Method

We included participants from the San Antonio Heart Study (SAHS), initiated in 1979 to examine ethnic differences in diabetes and cardiovascular disease between MA and NHW. In 1992, SAHS participants were invited to the San Antonio Longitudinal Study of Aging (SALSA), in which cognitive function was assessed using the MMSE at four time points. The latent variable mixture model implemented in Mplus was used to identify statistically distinct classes in cognitive trajectories based on repeated MMSE scores. The Bolck‐Croon‐Hagenaars method was used to test covariate differences across classes. Participants with missing data in 2 or more MMSE scores or covariates were excluded from the analysis.

Result

Our analytical sample included 337 participants (52.2% MA, 60.8% women, Table 1). Two distinct classes were identified (Shannon’s entropy = 0.813). Participants within class 1 had a steeper cognitive decline (0.53‐point drop per follow‐up), whereas those in class 2 appeared more stable (0.17‐point drop per follow‐up). Compared to class 2, participants in class 1were 2.1 and 2.5 times more likely to have diabetes during midlife (p = 0.019) and late‐life (p = 0.002) respectively. In contrast, ethnic‐stratified analysis revealed significant findings only among MA (Table 2), where participants in class 1 were 2.4 times more likely to have diabetes in midlife (p = 0.023) and 1.8 times in late life (p = 0.005) compared to class 2.

Conclusion

Diabetes was related to a steeper cognitive decline, particularly among MAs with prevalent diabetes in midlife. These findings provide new insights into the role of vascular burden in cognitive decline disparities among MAs. Further analysis exploring additional vascular factors are underway in this unique population.
Deciphering the components of Amyloid‐beta (Aβ)‐driven dementia using a novel peptide‐focused global proteomics platform
Authors: Saxena Satya , Ye Yuanqing , Devanarayan Viswanath , Reyderman Larisa , Koyama Akihiko , Sachdev Pallavi
Published: December 2023

Background

The overlap of Alzheimer’s disease (AD) symptomology and pathology with other dementia types is a significant challenge to treatment, patient care, and new drug development. Amyloid‐beta (Aβ) peptides begin to accumulate in AD subjects over a decade prior to clinical symptoms and impair multiple cellular pathways during disease continuum. However, how the brain proteome is remodeled by Aβ burden remains an enigma. Here we compared the cerebrospinal fluid (CSF) proteomes of demented subjects with or without Aβ pathology to unveil alterations specific to Aβ‐driven dementia.

Method

Mass spectrometry data (PRIDE archive PXD016278) from CSF of cognitively impaired Sweden cohort subjects was reanalyzed using our de novo‐assisted workflow. Peptide raw peak area intensities were quantile normalized and log2 transformed to reduce technical variation and ensure distribution symmetry. Differentially expressed peptides were identified via analysis of covariance after adjusting for age and gender. Multiscale Embedded Gene Co‐expression Network Analysis (MEGENA) was used to explore the dysregulated network from Aβ‐driven brain proteome remodeling.

Result

The de novo‐assisted workflow significantly increased the CSF proteome depth ‐ 4,572 CSF protein groups vs 1542 protein groups reported in PXD016278 analysis. Comparison of peptide‐level CSF proteomes of demented subjects with or without Aβ pathology identified 2,014 differentially regulated peptides (q<0.2). These alterations may reflect the Aβ‐driven brain proteome remodeling in CSF. MEGENA network analysis identified several hubs and network modules. The most significantly altered ALDO‐A peptide represented a hub, a highly connected node within a network module, and exhibited high correlation with AD‐linked neurosecretory protein VGF and MAPT. The top pathways enriched in MEGENA network modules, e.g. extracellular matrix organization, cell adhesion, and neurogenesis, are consistent with other pathway enrichment analyses across other cross‐sectional studies in AD and non‐AD dementias.

Conclusion

This is the first study capturing the peptide‐level alterations in CSF to reflect brain proteome remodeling by Aβ burden. This data will serve as an important resource for biomarkers demarcating AD from non‐AD.
Coronary Heart Disease, Cognitive Impairment and Patient‐Physician‐Communication: Data from the MenDis‐CHD study
Authors: Sannemann Lena , Leikert Charlotte , Müller Hendrik , Nordmeyer Laura , Peltzer Samia , Schulz‐Nieswandt Frank , Albus Christian , Jessen Frank
Published: December 2023

Background

Coronary heart disease (CHD) and dementia often co‐occur in the aging population. In addition, CHD seems to increase the risk for subsequent cognitive decline, which may in turn negatively affect the prognosis of CHD. Current CHD guidelines therefore recommend appropriate diagnosis and management of comorbid cognitive impairment. Here, we present the progression and characteristics of cognitive impairment in a group of patients with CHD and their perception of care in the patient‐physician‐relationship.

Method

For the MenDis‐CHD study, n = 364 patients with CHD were recruited from cardiologic hospital departments, rehabilitation clinics and cardiologist practices in Cologne, Germany. Medical records were used to assess severity of CHD and comorbidities. The New York Heart Association (NYHA) Functional Classification was applied for estimation of heart failure‐related symptom severity. Each patient was screened for cognitive impairment (DemTect) and depressive or anxiety symptoms (HADS questionnaire) as well as for subjective cognitive deficits. Patients were asked whether cognitive impairment was discussed with the treating physician. A follow‐up was carried out after M = 3.19 [2.2‐4.2] years in n = 118 patients. We compared patients whose cognition declined based on DemTect score to those who remained stable using t‐tests/Mann‐Whitney‐U‐tests and X²‐tests.

Result

At baseline, 10.2% of patients were screened positive for cognitive impairment, while 18.4% reported subjective cognitive deficits. Patients with a decline in cognition between study visits were significantly older (M = 67.9 vs. M = 63.1, t(115) = ‐2.7, p = .009) and showed more depressive symptoms (M = 5.0 vs. M = 3.8, t(115) = ‐2.1, p = .039). They also had more severe NYHA grades (M = 2.1 vs. M = 1.7, U(102) = 2044.5, p = .011) and a concomitant cerebrovascular diagnosis was more frequent compared to patients who did not decline (20.0% vs. 4.1%, X²(1) = 5.2, p = .048). Out of those who experienced either subjective or objective impairment at baseline (n = 88), 38.6% indicated that cognitive symptoms had previously been addressed during visits with their primary attending physician and 9.1% had been actively approached by their physician in this regard.

Conclusion

A relevant proportion of CHD patients displayed cognitive symptoms at baseline with progression at follow‐up. Conversations about cognitive symptoms with the physician occurred only in a minority. Our data supports the importance of raising awareness about the link between CHD and cognitive impairment in physicians.
Altered Resting‐state fMRI BOLD Signal Fluctuations in the Spectrum of Alzheimer’s Dementia and in Patients with White Matter Hyperintensities
Authors: Behrenbruch Niklas , Incesoy Enise I , Bernal Jose , Menze Inga , Vockert Niklas , Kleineidam Luca , Buerger Katharina , Wolfsgruber Steffen , Spottke Annika , Fließbach Klaus , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schneider Anja , Heneka Michael T. , Wagner Michael , Tipel Stefan , Wiltfang Jens , Speck Oliver , Perosa Valentina , Yakupov Renat , Jessen Frank , Düzel Emrah , Mattern Hendrik , Schreiber Stefanie , Ziegler Gabriel , Maass Anne
Published: December 2023

Background

Altered fluctuations in blood oxygen level dependent (BOLD) signal during resting‐state functional magnetic resonance imaging (rs‐fMRI) have been considered indicative of decreased cerebrovascular health. Previous studies reported changes in BOLD fluctuations associated with Alzheimer’s dementia (AD) and white matter hyperintensities (WMH). However, to date, there has been no large‐scale study involving patients with AD, mild cognitive impairment (MCI), subjective cognitive decline (SCD), and control subjects (CON) that has explored local AD‐ and WMH‐related effects in BOLD fluctuations.

Method

We calculated the voxel‐based coefficient of variation (CV: standard deviation divided by the mean) and the relative CV (rCV: CV divided by the mean CV of the whole‐brain) of the rs‐fMRI BOLD signal in the large multicentric DZNE DELCODE cohort. After spatial preprocessing, regression of movement parameters, movement spikes, and scanner drift, low‐pass filtering and exclusion of subjects with high motion, CV and rCV maps were obtained and compared with respect to (A) clinical diagnosis (AD: n = 79; MCI: n = 113; SCD: n = 314; CON: n = 192) and cerebrospinal fluid Aβ42/40 (AD: n = 41; MCI: n = 64; SCD: n = 139; CON: n = 77); and (B) effects of vascular‐related lesions, here WMH.

Result

The CV and rCV of the precuneus and middle cingulum indicated increasingly reduced BOLD fluctuation across the clinical groups towards AD. Interestingly, we observed increases in rCV in the basal ganglia and frontal white matter in AD compared with CON. Of note, lower CSF Aβ42/40 (more pathological) was associated to reduced CV and rCV in the precuneus and with lower rCV in the right angular gyrus. Subjects with higher WMH volume showed widespread reductions of CV in white matter near the left angular gyrus and reduced rCV in large portions of white matter and subcortical gray matter.

Conclusion

The AD spectrum exhibits altered BOLD fluctuations that are at least partially tied to actual amyloid differences. Larger WMH are associated with reduced BOLD signal fluctuations consistent with widespread white matter pathology ‐ beyond the effects of diagnosis. We argue that rCV is a useful complement to CV to detect these changes that might reflect cerebrovascular impairment.
Prevalence of dementia risk factors in the first 150 patients of the Oxford Brain Health Clinic
Authors: Blane Jasmine , Gillis Grace , Griffanti Ludovica , O'Donoghue M Clare , Mitchell Robert , Fossey Jane , Martos Lola , Raymont Vanessa , Mackay Clare
Published: December 2023

Background

Personalised risk reduction is a key driver for the nascent UK Brain Health Clinic (BHC) network, with increasing evidence that modifying dementia risk could delay or prevent disease progression. Livingston et al. (2020) demonstrated a number of risk factors for dementia, including less formal education (identified as no secondary education), excessive alcohol consumption (>21 units/week), obesity (BMI >30), depression and presence of an ApoE Ɛ4 allele; whilst increased physical activity has been associated with reduced risk and sleep duration is suggested to have a U‐shaped association with dementia risk. The aim of this study was to understand the prevalence of these risk factors within a typical UK memory clinic population.

Method

The Oxford BHC is a joint clinical and research assessment service for Oxford Health NHS Foundation Trust memory clinic patients (O’Donoghue et al., 2022). It aims to provide detailed clinical assessment and equal access to research opportunities. Between August 2020 and May 2022, 152 BHC patients (93.2%) consented to their clinical data, including subsequent diagnosis, being used for research purposes (mean age = 78.2 years, range 65‐101 years; 52.6% female). Self‐reported questionnaires collected education (N = 124), alcohol consumption (M SASQ, N = 150), depressive symptoms (PHQ9, N = 148), physical activity (IPAQ, N = 152) and sleep (PSQI, N = 152). BMI was calculated from height and weight measured at BHC appointment (N = 146) and ApoE Ɛ genotyping from saliva sampling (N = 76).

Result

Preliminary results show 7% of patients reported no formal qualifications, 1% consumed 6 or more units of alcohol daily/almost daily, 15.7% had a BMI >30 and 45% showed mild‐severe symptoms of depression. Inappropriate sleep was reported by 13%, 71% engaged in less than 150 minutes of physical activity a week and 41% had an ApoE Ɛ4 allele (see Figure 1).

Conclusion

In this population, we found a relatively small prevalence of low education and alcohol consumption, but a large proportion of patients could benefit from interventions focused on improving mood and physical activity. Ongoing analysis aims to create a weighted composite risk score for this population and explore relationships with primary diagnosis, cognition and measures of brain health including hippocampal volume and white matter hyperintensities.
A new de novo‐assisted mass spectrometry method for novel antimicrobial peptide expression profiling in cerebrospinal fluid (CSF) of demented subjects
Authors: Saxena Satya , Ye Yuanqing , Devanarayan Viswanath , Reyderman Larisa , Koyama Akihiko , Sachdev Pallavi
Published: December 2023

Background

Activation of innate immunity is a pathological hallmark of Alzheimer’s disease (AD). Antimicrobial peptides (AMPs), small (12‐50 amino acid) peptides, are essential components of the innate immune system and provide the first line of defense against microbial infections in immune‐privileged tissues, like brain. Many proteins with antimicrobial activity have been shown to be involved in AD. We developed a new mass spectrometry (MS)‐based method to profile known and novel AMPs in CSF. Here we report differentially expressed AMPs in CSF of Ab+ (AD) and Ab‐ (non‐AD) dementia.

Method

We created a custom (Swiss‐Prot + human AMP) database for our de novo‐assisted proteomics platform. MS data (PRIDE archive PXD016278) from CSF of cognitively impaired subjects with or without amyloid positivity were analyzed. Peptide raw peak area intensities were quantile normalized and log2 transformed to reduce technical variation and ensure distribution symmetry. Differentially expressed peptides were identified via analysis of covariance after adjusting for age and gender, with the significant criteria based on 20% false discovery rate. Multiscale Embedded Gene Co‐expression Network Analysis (MEGENA) was used to identify AMPs with the potential to regulate the molecular changes in AD.

Result

We identified 24 differentially expressed AMPs in CSF of Ab‐driven dementia mapping to 6 proteins. These include the AMPs released by the chromaffin cells of the adrenal medulla (Chromogranin A and B, Ubiquitin), Beta‐2 macroglobulin, Amyloid‐beta A4, and Clustrin proteins. The antimicrobial activity containing sequence from Chromogranin A was represented in top two modules identified by MEGENA network analysis. These modules exhibited high correlation with peptides from a dementia‐linked neurosecretory protein VGF. The top 5 pathways enriched in MEGENA modules include cell adhesion, system development, nervous system development, regulation of nervous system development, and neurogenesis.

Conclusion

This study reports the first unbiased analysis of dementia‐linked AMP diversity that can be monitored in CSF. Contribution of these AMPs and the associated pathways in the AD pathophysiology warrants further investigation.
Regulation of extracellular progranulin in the medial prefrontal cortex
Authors: Hall Justin A , Kaplelach Azariah K , Davis Skylar E. , Arrant Andrew E.
Published: December 2023

Background

Loss‐of‐function mutations in progranulin (GRN) are a major genetic cause of frontotemporal dementia (FTD). Progranulin is a secreted protein that is trafficked to lysosomes, where it promotes lysosomal function. Progranulin also exerts neurotrophic and anti‐inflammatory effects, some of which may be mediated by extracellular signaling. Neurons and microglia express progranulin and loss of progranulin from either cell type induces FTD‐like deficits in mice. Both cell types secrete progranulin in culture, but their contribution to extracellular progranulin in the brain is unclear, as are the mechanisms regulating progranulin secretion from each cell type. In this study, we used microdialysis to gain insight into the contribution of neurons and microglia to extracellular progranulin in the medial prefrontal cortex (mPFC), a region that degenerates in FTD and develops impaired dendritic arborization in progranulin‐insufficient mice.

Method

Polyethylene probes (2 mm, 1000 kDa cut‐off) were implanted in mouse mPFC and perfused with artificial cerebrospinal fluid containing 4% BSA using a push‐pull pump system (Atmos LM, Amuza). Progranulin levels in interstitial fluid (ISF) were measured by ELISA (Adipogen).

Result

Grn+/– mice exhibited a roughly 50% decrease in ISF progranulin versus wild‐type, which was similar to the reduction of progranulin in mPFC tissue. In wild‐type mice, inducing cellular depolarization with KCl (100 mM) increased ISF progranulin, but stimulating synaptic activity with picrotoxin (100 μM) or NMDA (50 μM) did not. Inducing systemic inflammation with LPS (10 mg/kg i.p.) increased ISF progranulin to around 200% of baseline at eight hours after injection. Analysis of ISF progranulin from microglial progranulin knockout mice (Cx3Cr1‐Cre‐ER:Grnfl/fl) revealed a nearly 50% reduction in ISF progranulin compared to Cre– littermates, which was a larger reduction than observed in mPFC tissue. Ongoing studies are analyzing ISF progranulin in neuronal progranulin knockout mice (CamKII‐Cre:Grnfl/fl).

Conclusion

Our findings indicate that inflammation increases ISF progranulin in the mPFC and that nearly half of the extracellular progranulin in the mPFC may originate from microglia. In contrast, synaptic activity does not significantly increase ISF progranulin in the mPFC. Ongoing studies will investigate the contribution of neurons to extracellular progranulin in the mPFC.
The use of therapeutic lying in dementia care from the perspective of Brazilian caregivers
Authors: Alves Emily Viega , Beber Bárbara Costa
Published: December 2023

Background

Therapeutic lying (TL) is a strategy that aims at the safety and well‐being of people with dementia (PwD), especially when they present behavioral changes. James et al. (2006) developed a protocol of guidelines on how to use the technique, demonstrating that its use requires trained professionals and caregivers. Considering that caregivers are the primary stakeholders in the daily life of PwD, it is critical to obtain their views on the use of TL in care practice. This study is part of a sequence of investigations into different public views on the use of TL with PwD, having already published the study with speech‐language pathologists. Thus, the purpose of this study was to verify the use and knowledge of TL among caregivers of PwD.

Method

This is a cross‐sectional study carried out through an online questionnaire. This is a cross‐sectional study carried out through an online questionnaire. The questionnaire was spread on social networks and collected sociodemographic data and information on knowledge, use and opinion regarding TL among PwD caregivers. The results were presented descriptively and the association between the frequency of the answers and the category of caregivers (formal or informal) was verified using the Chi‐square test with 5% significance.

Results

Twenty caregivers (17 informal and 3 formal), with a mean age of 48.6 years (±14.6), were included in the study. 90% of them had lied to PwD to benefit the patients and 25% had lied to benefit themselves. 20% had heard about TL, only 10% learned about the strategy in their training, and 75% would like to learn more about it. Also, 70.6% of caregivers think it is very valid to use TL, but 50% think it is very ethical. There was no significant difference for the responses when compared between formal or informal caregivers.

Conclusion

The use of TL is widespread among caregivers, even without appropriate training to use this technique. Many caregivers question how ethical it can be to lie to PwD, even if it is to benefit them. Clearly, there is a need for education and training on TL in this population.
Baseline neuropsychological intra‐individual variability predicts cognitive impairment 8 years later in the Brazilian Longitudinal Study of Adult Health (ELSA‐Brasil)
Authors: Bertola Laiss , Gonçalves Natalia G , Bensenor Isabela M , Lotufo Paulo A , Suemoto Claudia Kimie
Published: December 2023

Background

Neuropsychological assessment is still vastly based on a nomothetic approach. However, middle‐aged and older adults might start to reveal higher intra‐individual cognitive variability (IICV) as an early sign of cognitive impairment, even when still cognitively normal. IICV refers to inconsistency in function and has been related to an increased risk for dementia. Therefore, we aimed to verify if baseline IICV predicts the occurrence of cognitive impairment after eight years.

Method

We included 10,783 participants from the ELSA‐Brasil study, a multicenter, prospective cohort study with three waves, approximately four years apart each, starting in 2008. The ELSA‐Brasil baseline exclusion criteria included the presence of clinically observed severe cognitive or communication impairment. Participants' health status and cognitive performance were evaluated at baseline (W1) and Wave 3 (W3). Baseline neuropsychological assessment comprised measures of memory and executive function. We used regression corrected‐based norms, from a robust normative subsample, to generate the presence of baseline cognitive deficit (< ‐1.5 SD) (BCD) and the mean standard deviation across baseline cognitive scores (IICV). Mini‐Mental State Exam at W3 was corrected according to education‐based cutoff to verify the presence of cognitive impairment. Logistic regression, adjusted for sociodemographic (age, sex/gender, education, race/ethnicity) and clinical confounders (depressive symptoms, hypertension, diabetes, and alcohol consumption), was used to predict the odds ratios (OR) of being cognitively impaired after eight years of follow‐up when considering IICV, BCD and both.

Result

Participants had a mean age of 59.0±8.7 years old, 56% were women, 7% had less than high school level, and 42% were Black/Brown (Table 1). IICV within tasks ranged from 0.7 to 7.9 standard deviations, and only 1% of the sample had BCD. Higher IICV is associated with a higher occurrence of cognitive impairment after eight years, even after controlling for other risk factors (Table 2). IICV was associated with cognitive impairment even after controlling for BCD.

Conclusion

Higher cognitive intra‐individual variability among test scores at baseline was associated with a higher risk for cognitive impairment later in life. Cognitive heterogeneity should be considered during the neuropsychological assessment interpretation and can be a target for the detection of pre‐clinical cognitive impairment.
Longitudinal Quantification of Sub‐Regional Hippocampal Amyloid‐Beta Burden in Ex‐Vivo slices from the AppNL‐G‐F Mouse Model of Alzheimer’s Disease
Authors: Chen Yuqing , Turner Richard , Fuchsberger Tanja , Kelly Tommy L , Paulsen Ole
Published: December 2023

Background

Amyloid‐beta (Aβ) pathology is suggested to precede the onset of clinical Alzheimer’s disease symptoms by up to two decades. The humanised AppNL‐G‐F knock‐in model of amyloidopathy has accelerated pathogenesis and can be used to study AD progression. Here we used it to quantify the temporal and spatial characteristics of Aβ plaque accumulation as they first appear in the hippocampus, and as pathology continues to develop.

Method

AppNL‐G‐F knock‐in mice and wild‐type mice at 1, 3, 6, and 9 months of age were transcardially perfused with PBS followed by 4% paraformaldehyde (PFA), followed by preparation of coronal slices for immunohistochemistry analysis. Samples were stained with anti‐Aβ antibody (6E10) together with a neuronal marker, NeuN, and DAPI. Images were taken of sub‐hippocampal regions (CA1, CA3, DG), in left/right hemispheres, and ventral/dorsal segments using a confocal microscope (Leica SP8). Summation of intensity across Z‐stacks in Fiji was used to quantify Aβ plaques in regions of interest.

Result

We found age to be a statistically significant factor on determining area density, with hippocampal deposition observed by 3 months. Bin analysis showed a near‐exponential reduction in plaque number with increasing plaque size, increasing with age. Regionally, there was an increase in plaque density in CA3, with non‐linear regression analysis indicating area density for CA3 is most strongly correlated with age. Within the CA1 region, the densest plaque formation was in the pyramidal cell layer. Further analysis at the aged 9‐month time point suggested a differential pathology across the axial plane and greater left‐hemispheric lateralisation.

Conclusion

This data provides further evidence for the protracted timeline to which AppNL‐G‐F knock‐in mice recapitulate key AD neuropathologies including insoluble amyloidosis beginning before 3 months in the hippocampus. It also indicates potentially novel differential sub‐regional Aβ accumulation patterns, axial variations, and hemispheric asymmetries, offering mechanistic insights for plaque localisation and differential susceptibility to Aβ. This could aid advancement of Αβ‐targeting therapies.
Workforce training through massive open online courses: can education generate collective hope for better dementia care?
Authors: Canty Alison Jane
Published: December 2023

The personal care workforce is generally poorly paid, often unregulated, minimally trained and unprepared for the challenges of working with people with dementia. When it comes to accredited healthcare degrees, established programs have little space to accommodate emerging health priorities, such as dementia, in an already crowded curriculum. This creates the perfect storm of a significantly unprepared healthcare workforce as we look towards an expected 139 million cases of dementia worldwide by 2050 (www.alzint.org).

Could freely available, online, evidence‐based dementia care education be a solution, offering hope, knowledge and skills to carers across the globe? In 2013, the University of Tasmania launched an Understanding Dementia Massive Open Online Course (MOOC). Over 7 weeks participants increase their knowledge of dementia: its causes, symptoms and ways of responding to the needs of people living with the condition. This award‐winning MOOC has world‐leading completion rates, been rated amongst the top MOOCs of all time (Class Central), and reached over 330,000 people around the globe. As well as offering free MOOCS, there are low or no‐cost university level education options in a Diploma and Bachelor of Dementia Care. Targeted to the Australian Aged Care workforce, but open to any student, these fully online programs attract personal care workers, health professionals and family members of people living with dementia. Thousands of students have enrolled, primarily for professional and practice development reasons and to provide better care for family members or friends with dementia. These programs were created specifically for learners of all ages and from culturally and linguistically diverse backgrounds, and designed to facilitate success and progress. They are scalable and are being translated into a number of languages and cultures. With this approach, one click at a time, we offer hope through accessible education for those that need it most. In this sense, education is considered an intervention ‐ improving dementia care and awareness, decreasing stigma, and in driving a public health approach for dementia prevention.
Brain age gap, dementia risk factors and cognition in middle age
Authors: Stefaniak James D , Mak Elijah , Su Li , Carter Stephen F , Dounavi Maria‐Eleni , Muniz‐Terrera Graciela , Wells Katie , Ritchie Karen , Lawlor Brian , Naci Lorina , Koychev Ivan , Malhotra Paresh A , Ritchie Craig W , O'Brien John T
Published: December 2023

Background

Brain Age Gap (BAG) represents the difference between an individual’s predicted age, derived from machine learning models trained on neuroimaging data, and their chronological age. BAG has been associated with dementia and cognition in old age. Less is known relating BAG to dementia risk‐factors or cognitive performance in middle‐age.

Method

Cognitively healthy, middle‐aged (40‐59 years) subjects from PREVENT‐Dementia had an array of neuropsychological, neuroimaging and genetic assessments. Brain Ages were predicted from T1‐weighted 3T MRI scans. Cognition was assessed using COGNITO. Multiple linear robust regression models tested hypotheses that: (i) BAG is positively associated with dementia risk‐factors; (ii) increased BAG is associated with worse cognition; (iii) longitudinal BAG change is positively associated with longitudinal cognitive deterioration. A range of machine learning algorithms with nested cross‐validation was used to assess whether BAG and cognition could predict each other.

Result

552 middle‐aged participants (median age 52.8 years) had all baseline assessments; 68 had amyloid PET data and 138 had longitudinal data. Median BAG was ‐2.0 years with a range from ‐21.2 to 18.4 years (Figure 1). BAG in middle‐age was associated with hypertension (p = 0.007) and alcohol intake (p = 0.008) but not APOE4 carrier status (p = 0.14) or amyloid centiloids (p = 0.53). BAG was not associated with cognitive performance either cross‐sectionally (p = 0.74) or longitudinally (p = 0.30), and there was no added predictive value between BAG and cognition. More education was associated with better cognition (p = 4.7×10−11) but not with BAG (p = 0.32).

Conclusion

Even in midlife, substantial inter‐individual heterogeneity exists in the extent to which brains have aged. BAG in middle‐age is associated with modifiable dementia risk‐factors, suggesting that lifestyle risk‐factor modification needs to start at, or before, midlife to optimise brain health. BAG in middle‐age was not associated with risk‐factors for Alzheimer’s disease (APOE4, amyloid deposition) or cognitive performance, despite there being a plausible and expected association between more education and better cognitive performance. These results are important for understanding brain‐age in middle‐aged populations who might be the target of future dementia‐preventing therapies.