bluuebunny/crossref_metadata_2025 huggingface dataset:
Extremes of baseline cognitive function determine the severity and outcomes of delirium: findings from a prospective longitudinal cohort study
Authors: Tsui Alex
Published: December 2023

Background

Epidemiological studies have shown the bidirectional relationship between dementia and delirium to be complex and non‐linear. This has implications for mechanistic studies investigating the extent to which any pathophysiology might be specific to delirium, or shared with dementia. While delirium is associated with long‐term dementia risk and cognitive decline, this association may be independent of classical Alzheimer’s pathology in oldest‐old patients.

Method

The Delirium and Population Health informatics (DELPHIC) study prospectively followed a population‐representative sample of 1510 individuals aged ≥70 years living in London, UK. We performed cognitive assessments at baseline, two years, and ascertained delirium symptoms during incident hospitalisation in 209 participants across 371 episodes.

Result

Better baseline cognitive function was generally associated with a lower likelihood of delirium. However, during delirium episodes, there was a U‐shaped relationship between baseline cognition and delirium symptom severity; participants with the lowest and highest baseline cognition experienced the most severe delirium and arousal deficits (baseline z‐score ‐2: mean MDAS 15; baseline z‐score +2: mean MDAS 11). At follow‐up, we observed the largest cognitive decline in participants with better baseline cognition experiencing delirium (2.2SD decline vs 0.8SD without delirium).

Conclusion

These findings imply that delirium pathophysiology research should take into account differences in baseline cognition, for example by defining pre‐existing subclinical dementia pathology. We suggest the need for prospective, serial pathophysiological studies to consider the temporal sequence of delirium‐related neural damage. In this way, we could differentiate which mechanisms are unique to delirium, and which might interact with pre‐existing dementia pathophysiology to result in long‐term cognitive deficits.
Association between poor periodontal health and 15‐year risk of incident dementia
Authors: Asher Sam , Suominen Anna Liisa , Stephen Ruth , Ngandu Tiia , Koskinen Seppo , Solomon Alina
Published: December 2023

Background

Poor oral health, particularly tooth loss, has been highlighted as a potential modifiable risk factor for dementia. However, longitudinal evidence concerning the association of poor periodontal health with dementia is limited. This study examines the impact of poor periodontal health on 15‐year risk of incident dementia.

Method

This study included 4596 dementia‐free and dentate (i.e., having ≥1 teeth remaining) participants, aged 30‐93 years, from population‐based Finnish Health 2000 Survey. Periodontal health at baseline was evaluated through bleeding on probing (BOP), periodontal pocket depths (PPD), and alveolar bone loss (ABL). BOP for each sextant and PPD for each tooth (excluding third molars and residual roots) were recorded clinically during oral examination. Based on BOP, participants were dichotomized into having ≥1 sextant with BOP versus no BOP.

Tooth with PPD of ≥4mm was considered as having deepened periodontal pocket. Based on PPD, participants were dichotomized into having ≥1 teeth with deepened PPD versus no PPD. ABL for each tooth was examined through orthopantomographs and defined as vertical bone loss extending apically to at least the middle third of tooth root. Based on ABL, participants were dichotomized into having ≥1 teeth with ABL versus no ABL. Dementia diagnosis until 2015 was retrieved from national health registers.

Cox proportional regression was conducted and adjusted for age, gender, education, cardiovascular risk, socioeconomic status, depression, alcohol consumption, c‐reactive protein, and overall tooth count. Sensitivity analysis accounting for potential reverse causality bias was conducted by excluding incident dementia during the first five years of follow‐up.

Result

183 participants developed dementia over 15 years. Fully adjusted hazard ratio among participants with ≥1 sextant with BOP was 1.15 (CI:0.80‐1.65), with ≥1 teeth having deepened PPD was 0.94 (CI:0.67–1.31), and with ≥1 teeth having ABL was 0.97 (CI:0.64–1.49). Findings from sensitivity analysis for potential reverse causality bias corroborated with results for main analyses.

Conclusion

Preliminary findings indicate no association of BOP, PPD, or ABL with 15‐year dementia risk. However, further well‐designed longitudinal studies with more comprehensive periodontal assessment (e.g., clinically diagnosed periodontitis and severity of periodontitis) are warranted to conclusively assess its impact on dementia risk.
Time of the day at sampling affects amyloid‐beta levels in CSF and plasma
Authors: Orduña Dolado Anna , Stomrud Erik , Ashton Nicholas J. , Nilsson Johanna , Brinkmalm Ann , Zetterberg Henrik , Blennow Kaj , Janelidze Shorena , Hansson Oskar
Published: December 2023

Background

Studies suggest that cerebrospinal fluid (CSF) levels of Alzheimer’s disease (AD) biomarkers, amyloid‐β (Aβ) and tau, follow a circadian rhythm. However sustained sampling of CSF with indwelling intrathecal catheter used in most of these studies might have affected the observed fluctuations in the biomarker levels.

Methods

We included 38 individuals with either normal (N = 18) or abnormal (N = 20) CSF Aβ42/40 status. CSF and plasma were collected, at the same occasion, at two different visits separated by an average of 53 days with lumbar punctures and venepunctures performed either in the morning or evening. At the first visit, collection was performed in the morning for 17 participants and the order was reversed (evening collection first) for the remaining 21 participants. CSF and plasma samples were analyzed for Aβ42, Aβ40, GFAP, NfL, p‐tau181, p‐tau217 and p‐tau231. CSF samples were also tested for a battery of synaptic and lysosomal proteins.

Results

CSF Aβ42 (mean difference [MD] = 0.208ng/ml; p = 0.043), CSF Aβ40 (MD = 1.85ng/ml; p<0.001), plasma Aβ42 (MD = 1.65pg/ml; p = 0.002) and plasma Aβ40 (MD, 0.011ng/ml, p = 0.003) levels were increased in the evening samples compared with morning samples by 4.2%‐17.0% (Figures 1‐2). However, changes between morning and evening samples were not significant for either CSF or plasma Aβ42/40. Additional proteins in CSF, APP, STX1B, NPTXR and NPTX1, were also found increased in the evening samples (MDrange, 0.087–0.243; p<0.048) by 4.7%‐12.15% (Figure 3). No significant differences were found between morning and evening levels for any of the other biomarkers, including p‐tau’s, NfL and GFAP. There were no significant interactions between time of day at sample collection and either Aβ status or order in which samples were obtained.

Conclusion

Our findings provide further evidence for diurnal fluctuations in Aβ peptides, which is observed in both CSF and plasma. Additionally, CSF levels of some synaptic proteins followed circadian rhythm. Importantly, CSF and plasma Aβ42/40 ratios remained unaltered, suggesting that increased production or decreased clearance of Aβ peptides during daytime similarly affect the CSF and plasma levels of both Aβ42 and Aβ40. Thus, these ratios are more suitable for implementation as biomarkers of AD as they are not influenced by diurnal fluctuations.
Liver X receptor α suppresses SNAI2 ensuring blood‐brain barrier function
Authors: Vacondio Davide , Coenen Loet , Mulder Inge , Fontijn Ruud , Hof Bert , Fung Wing Ka , Kooij Gijs , Rozemuller Annemieke J.M. , Zelcer Noam , Vries Helga E , Wit Nienke M
Published: December 2023

Background

More than 48% of Alzheimer’s disease (AD) patients display amyloid beta (Aβ) accumulation around small brain vessels: capillary cerebral amyloid‐angiopathy (capCAA). The accumulation triggers reduction in the cerebral blood‐flow and localized hypoxia, possibly inducing dysfunction of the neuroprotective blood‐brain barrier (BBB). However, the molecular mechanism driving vascular changes and BBB impairment is largely unknown. Recently, a unique role for Liver x receptor α (LXRα) in securing BBB stability has been discovered. Nonetheless, the role of LXRα in BBB dysfunction remains elusive. This study investigates the activity of LXRα in the promotion of BBB functions evaluating how this is compromised in AD and capCAA.

Method

We use shRNA based gene‐editing to ablate LXRα in human brain endothelial cells (BECs) followed by RNA‐sequencing to identify differentially expressed genes. In addition, BECs are grown in hypoxia to mimic capCAA and study the role of LXRα. We further evaluate the angiogenic ability of LXRα KD cells and hypoxic cells. Finally, post‐mortem human brain tissue is used to validate promising candidates and recapitulate the molecular mechanism in pathological condition.

Result

The gene set enrichment analysis performed on LXRα knockdown (LXRα KD) cells revealed a downregulation of BEC markers including ABC transporters and tight junctions. The significantly upregulated genes suggested SNAI2 as the major player in the BECs dedifferentiation. In depth molecular studies revealed the indirect inhibitory role of LXRα on SNAI2 expression. We further implicate hypoxia as LXRα regulatory condition and substantiate the importance of LXRα in BECs identity. SNAI2 upregulation in LXRα KD and hypoxic BECs represses DLL4‐Notch1 signaling, thereby promoting aberrant angiogenesis. Ultimately, we provide evidence of SNAI2 upregulation in capillaries of AD and capCAA patients.

Conclusion

Our data suggests that LXRα helps preserving BECs identity and function via the constitutive inhibition of SNAI2. This mechanism is compromised in capCAA patients where Aβ deposition creates an hypoxic environment responsible for LXRα suppression. The resulting SNAI2 increase leads to BBB impairment and abnormal angiogenesis. These findings contribute to understand the microvascular dysfunction taking place in AD and capCAA, providing new insights on their pathophysiology.
Virtual brain network modeling in AD: from pathophysiology towards treatment
Authors: de Haan Willem
Published: December 2023

Background

While much is known about the pathology and clinical symptoms of AD, their mutual relationship to impaired brain function during the AD disease course is incompletely understood. For deriving a coherent, integrated multi‐scale disease mechanism, computational neurophysiology is a promising candidate. Virtual models of neurons, neuronal circuits and large‐scale networks are being used at different scales and for different purposes. Ranging from biologically plausible neural mass models to more abstract models of complex system behaviour or pathology spreading patterns, their diversity and versatility can help to address issues that are hard to tackle experimentally.

Method

In this presentation I will review several recent developments that illustrate how virtual models can help to translate local neuronal activity to brain‐wide network level data, probe the effects of AD pathology on brain network behaviour, and predict neurophysiological outcomes of different types of treatment. More specifically, I will show how amyloid‐induced hyperexcitability is compatible with large‐scale oscillatory slowing in AD, and how we can simulate counteracting activity‐targeting interventions such as non‐invasive brain stimulation using virtual models.

Result

AD‐like adaptations in neuronal excitability in neural mass model parameters led to the combination of high absolute power and large‐scale oscillatory slowing in nearly all tested scenarios. In contrast, the hypoexcitable neural mass scenarios did not produce AD‐like oscillatory changes. Furthermore, simulating various counteracting tDCS‐induced excitability changes led to highly variable ‘virtual treatment’ outcomes, supporting the idea that electrode location choice can play a substantial role in tDCS treatment success, and generating specific predictions to be falsified in patient studies.

Conclusion

Virtual models of altered brain activity can help to understand AD pathophysiology and facilitate treatment development.
Positron emission tomography (PET) imaging of neuroinflammation in healthy and Alzheimer disease participants using TSPO tracers
Authors: Fuh Jong‐Ling , Lin Yung‐Shuan , Yeh Skye Hsin‐Hsien , Lee Wei‐Ju , Chang Wen‐Yi , Chang Chi‐Wei , Yang Bang‐Hung , Peng Nan‐Jing , Huang Wen‐Sheng
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common type of dementia. In addition to the widely recognized accumulation of amyloid and tau protein being the core pathology of AD, neuroinflammation is another cause of brain dysfunction and structural change. Expression of translocator protein (TSPO) on the outer mitochondrial membrane of activated microglia is strongly associated with neuroinflammation. With the development of TSPO positron emission tomography (PET) tracer, we were able to evaluate neuroinflammation non‐invasively in a clinical cohort of AD spectrum.

Method

Cognitively impaired patients (including AD and mild cognitive impairment (MCI)) and cognitively normal controls (CN) were recruited from single dementia clinic. [18F]FEPPA, the second‐generation PET ligand specifically binds TSPO was synthesized fully automated. Structural brain MRI and functional PET imaging were performed simultaneously with a PET/MR scanner (SIGNA, GE Company, USA). Kinetic analyses were performed using PMOD 4.2 modeling software. Total distribution volume (VT) in each ROI, including frontal, temporal, inferiolateral parietal, occipital, hippocampus and cerebellum, were derived from a two‐tissue compartment model (2‐TCM). In addition, APOE and rs6971 polymorphism genotyping were conducted in all subjects. Mann‐Whitney U Tet, Kruskal‐Wallis Test and linear correlation were performed.

Result

A total of 39 participants (23 males and 16 females) participated, including 13 cognitively normal, 9 with MCI and 17 with Alzheimer’s disease. The rs6971 genotype had no significant effect on [18F]FEPPA binding to TSPO. The amount of TSPO expression was independent of age, gender, and APOE ε4 carrier status. The VT of each ROI did not differ significantly between cognitive groups. VT of frontal, temporal, inferiolateral parietal and occipital lobe were all negatively correlated with MMSE, Boston Naming Test and Trial Making A performance. However, such association was not observed between VT of hippocampus and cognitive tests.

Conclusion

Although there was no difference between TSPO expression in each ROI among cognitive groups, we still observed that higher TSPO expression in the cortex was associated with worse performance in certain cognitive tests. This implied that the increase in neuroinflammation was related to the decline of cognitive performance regardless of cognitive diagnosis.
The role of the biofilm of Porphyromonas gingivalis in driving amyloid beta secretion and aggregation
Authors: Dumoulin David , Fulop Tamas , Beauregard Pascale B.
Published: December 2023

Background

Over the past five years, the hypothesis linking periodontitis to Alzheimer’s disease (AD) has gained significant traction even though little is known about the underlying mechanisms driving this association. Periodontitis is caused by the dysbiosis of the dental biofilm, an extra‐cellular matrix produced by bacteria, which is mostly caused by the Gram‐negative bacterium Porphyromonas gingivalis. P. gingivalis has been found to infect the brain of AD patients and drive amyloid beta (Aβ) production while biofilm components can be identified interwoven with Aβ plaques1,2. We therefore hypothesize that P. gingivalis drives Aβ production in neural cells which co‐aggregates with bacterial biofilm to expedite plaque formation and downstream neuroinflammation.

Method

To assess if the biofilm of co‐aggregation of Aβ and the matrix was then analyzed by fluorescence microscopy, atomic force microscopy (AFM) and thioflavin T (ThT) fluorescence assays. To examine whether P. gingivalis stimulates Aβ production, we infected BE(2)‐M17 human neuroblastomas at a mean of infection of 1:100 before collecting cells and supernatant proteins to observe the cell response through protein and transcription assays.

Results

When co‐cultured, P. gingivalis and Aβ1‐42 co‐aggregated in plaque‐like structures, Interestingly, colocalization analysis revealed that Aβ1‐42 particularly associate with the extracellular component of biofilm (Figure 1). ThT assays and AFM imaging demonstrated faster aggregation of Aβ1‐42 when co‐incubated with fragments of P. gingivalis biofilm for 8 h, which suggests a significant cross‐seeding phenomenon between the two components (Figure 2). Furthermore, infection of human neuroblastomas resulted in a significant increase in Aβ production that could be detected by western blot, thus offering a workable model to study the link between AD and periodontitis (Figure 3).

Conclusion

Our project offers significant insights into the relationship between periodontitis and AD, allowing us to understand how P. gingivalis triggers Aβ production and how its biofilm drives plaque aggregation. This research greatly contributes to a better understanding of external AD risk factors and how to mediate their impacts on neurodegeneration.

1Dominy et al. Science Advances (2019)

2Mirzaei et al. Microbial Pathogenesis (2020)
Visual rating scales of atrophy to differentiate Frontotemporal dementia from Primary psychiatric disorder: results from DIPPA study
Authors: Fumagalli Giorgio G , Sorrentino Federica , de Boer Sterre C.M. , Riedl Lina , Landin‐Romero Ramon , Matis Sophie , Southwood Dean , Chatterton Zac , Diehl‐Schmid Janine , Halliday Glenda M , Ducharme Simon , Piguet Olivier , Pijnenburg Yolande A.L. , Galimberti Daniela
Published: December 2023

Background

Adult‐onset behavioral changes and altered executive functioning are frequently caused by behavioural variant of Frontotemporal dementia (bvFTD) or primary psychiatric disorders (PPD) which overlap in terms of clinical presentations but differ in terms of treatment and prognosis. The multi‐centre study DIPPA‐FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late‐onset PPD. Although atrophy on neuroimaging seems to be an appropriate discriminator between neurodegenerative and non‐neurodegenerative conditions, the sensitivity of frontotemporal atrophy for bvFTD is relatively low, whereas decreased brain volumes may be found in conditions like schizophrenia. The aim of the study is to identify a discriminative pattern of brain atrophy between bvFTD and PPD in a clinically applicable way.

Method

The DIPPA FTD consortium retrospectively collected patients with late onset behavioral disturbances after the age of 45 years, across 5 centers (Milan, Amsterdam, Munich, Sydney, Montreal). The subjects had been classified either as bvFTD or PPD according to current clinical criteria and the majority had clinical follow‐up. Among the patients collected in the project, only those with T1 MRI available were selected. A protocol of 9 visual rating scales of atrophy (orbitofrontal, anterior cingulate, anterior temporal, fronto‐insula, medial temporal, parietal, medial ventricular and axial ventricular) was applied by a rater blind for clinical and demographic infomation. The rater was asked to classify the subjects as bvFTD or PPD. A composite score of frontal, temporal and ventricular rating scales was also calculated.

Result

The MRIs of 323 subjects (211 bvFTD and 112 PPD) were analysed. Groupwise bvFTD cases showed significantly higher scores of atrophy for all the scales used. The rater accurately predicted 72% of the cases (Sens 0.70, Spec 0.76) while the composite score reached an accuracy of 76% (Sens 0.77 Spec 0.74). ROC curve analysis showed that fronto‐insula was the single most useful scale in the differentiation between bvFTD and PPD (AUC 0.80).

Conclusion

Brain atrophy has a significant role in the discrimination between bvFTD and PPD. The use of visual rating scales, and in particular the fronto‐insula one, could increase the diagnostic accuracy in the clinical setting.
Systematic review of strategies to justify validity of instrumental variables in observational studies of dementia and neurodegenerative disease
Authors: Hiu Shaun , Yong Tingting , Teare M Dawn , Taylor John‐Paul
Published: December 2023

Background

Instrumental variable (IV) analysis is a methodology used to study causal effects of treatments or exposures. If properly implemented, causal effects can be estimated even in the presence of unmeasured confounding. . Central to IV analysis is the identification of a valid instrument that satisfies three assumptions – one is empirically verifiable (Restriction) but the remainder require substantive knowledge and convincing argumentation (Exclusion restriction and Exchangeability). The objective of this study is to systematically review the strategies used to validate an IV in observational studies of dementia and neurodegenerative disease. This systematic review is pertinent given the increasing use of real‐world evidence to guide public health and regulatory decision‐making in lieu of randomised controlled trials.

Methods

We conducted our search using PubMed, PsycINFO, and Web of Science. We included published observational studies investigating the causal effect of some risk factor, exposure, or treatment using IV analysis and using either a sample of: i) adults without diagnosis of dementia or neurodegenerative disease and an outcome of incident diagnosis of dementia or neurodegenerative disease; or ii) adult patients diagnosed with dementia, major neurocognitive disorder, or neurodegenerative disease and a clinical outcome related to incident dementia, mortality, hospitalisation, institutionalisation, serious adverse outcomes, medication adherence, cognition, neuropsychiatric symptoms, and biomarkers of neurodegeneration. We will extract and categorise text information directly arguing for the assumptions of a valid IV and the type(s) of falsification tests used.

Results

927 unique articles were retrieved. Screening for eligibility and data extraction by two study authors are currently underway. Results will be presented at the conference.

Conclusions

Reviewing how variables have been reasoned to be valid IVs may help improve our understanding of the causal effects of treatments or exposures on dementia and neurodegenerative disease which may have relevance in shaping future therapeutic and management approaches.
Baseline plasma levels of ADAMTS13 predict cognitive decline and neurodegeneration among APOE‐ε4 carriers over a 7 year follow‐up period
Authors: Kresge Hailey A. , Khan Omair A. , Liu Dandan , Libby Julia B. , Robb W Hudson , Patterson Khiry L , Arul Albert B , Choi Min Ji , Oliver Nekesa , Whitaker Marsalas D , Houston Michelle L , Pechman Kimberly R. , Landman Bennett A. , Gifford Katherine A. , Robinson Renã AS , Hohman Timothy J. , Jefferson Angela L.
Published: December 2023

Background

Von Willebrand Factor (VWF), a multimeric glycoprotein involved in hemostasis, and ADAMTS13, a metalloproteinase that cleaves VWF, are associated with dementia risk. In in vitro studies endothelial cells expressing apolipoprotein E (APOE)‐ε4 overexpress VWF but no clinical studies have investigated interactions between VWF or ADAMTS13 with APOE‐ε4 status in predicting brain health. We assessed whether VWF and ADAMTS13 levels predict longitudinal cognitive decline and atrophy, especially in APOE‐ε4 carriers.

Methods

Vanderbilt Memory and Aging Project participants (n = 333, 73±7 years, 41% female) underwent blood draw, neuropsychological assessment, and brain magnetic resonance imaging (MRI) serially over a 7‐year period. Plasma abundance measures of VWF and ADAMTS13 at baseline were quantified using mass spectrometry. Linear mixed‐effects regressions related protein levels to longitudinal neuropsychological and brain MRI outcomes (including grey matter volume and an Alzheimer’s disease (AD) neuroimaging signature), adjusting for age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile score, cognitive status, intracranial volume, APOE‐ε4 status, and follow‐up time. Models were repeated with an APOE‐ε4 interaction.

Results

Lower baseline ADAMTS13 levels related to greater longitudinal decline in language, episodic memory, information processing speed, executive function, and visuospatial skills (p‐values<0.02) as well as temporal lobe, occipital lobe, and hippocampal atrophy (p‐values<0.02). APOE‐ε4 interacted with ADAMTS13, such that among APOE‐ε4 carriers, lower baseline ADAMTS13 related to greater decline in naming (p‐values< = 0.002), information processing speed (p = 0.006), executive function (p = 0.001), and visuospatial skills performances (p = 0.001) as well as greater occipital lobe atrophy (p = 0.002) and AD imaging signature thinning (p = 0.02). All results survive false discovery rate correction. By contrast, VWF did not relate to any outcomes (p‐values>0.08).

Conclusion

Lower ADAMTS13 levels related to greater cognitive decline and neurodegeneration over a 7‐year follow‐up period, with effects driven by APOE‐ε4 carriers. VWF was unrelated to outcomes, potentially suggesting that ADAMTS13 relates to brain health independent of its role cleaving in VWF. While VWF is the only known substrate of ADAMTS13, ADAMTS13 may be involved in diverse biologic processes (e.g., inflammation, angiogenesis). Replication is needed to fully elucidate the role of VWF. Additional research is also needed to characterize mechanisms underlying interactions between ADAMTS13 and APOE‐ε4 in predicting brain health.
Mortality and risk of dementia in individuals with serious mental illness: a population‐based study
Authors: Stevenson‐Hoare Joshua O , Owen Michael J , Kirov George , Escott‐Price Valentina
Published: December 2023

Background

Individuals with mental illness such as schizophrenia experience dementia at greater rates than the general population(1). These disorders are also associated with shorter lifespan(2). Consequently, a person with mental illness may be more likely to experience dementia but less likely to live long enough to reach dementia onset. By using deeply phenotyped data across a large portion of person’s lifespan it is possible to examine the causal structure that may lay behind this seeming contradiction.

Method

Using a longitudinal medical record database of 4.5 million individuals in Wales, UK, we were able to follow individuals over a period of two decades. We identified nearly 1 million living individuals aged at least 45 in 1999, of whom one third had diagnoses of psychosis, mania, depression, or anxiety. We tested whether the development of dementia is associated with premorbid mental illness, using Cox regression survival analyses accounting for hospitalisation, history of medication, sex, social deprivation, and cooccurrence between disorders, as compared to matched controls.

Result

Controlling for the age of onset of mental illness and the reduced lifespan of individuals with these serious mental health disorders, we found a strong relationship between all mental illness and higher risk of dementia. The dementia onset was earlier in individuals with mental illness. We also found a complex relationship with hospitalisation and number of prescriptions, two metrics often associated with disease severity, when explaining mental illness‐related mortality and dementia.

Conclusion

All studied mental illnesses are associated with the elevated risk of developing dementia, if individuals survive to a sufficient age. Of these illnesses, psychosis was the strongest risk factor for dementia development. Disease severity and treatment, defined by hospitalisation and medication, are also highly significant factors, with hospitalisation increasing risk of dementia and mortality.

References:

(1)Stroup et al. (2021) JAMA Psychiatry, https://doi.org/10.1001/jamapsychiatry.2021.0042

(2)Chang et al. (2010) BMC Psychiatry, https://doi.org/10.1186/1471‐244X‐10‐77
Altered Endogenous Expression of Alzheimer’s Risk Genes impacts Neural Morphology in a Large Cohort of Healthy study Participants
Authors: Bledsoe Xavier , Sale Rebecca L , Lin Phillip J , Gamazon Eric J
Published: December 2023

Background

Dysregulation of white matter tracts (WMTs) in the brain is a common feature of Alzheimer’s Disease (AD) and is associated with declining cognitive function. Two neuroimaging measures, Fractional Anisotropy (FA) and isometric volume fraction (ISOVF) represent WM integrity through quantifying organization of axon bundles and changes in extracellular fluid within the fiber tracts (as occurs in inflammation or degeneration) respectively. Previous work examining the genetic basis of WMT changes in AD largely focused on SNP‐level associations. Here, we leverage transcriptome wide association studies (TWAS) and Mendelian randomization (MR) to interrogate the expression‐mediated influence of AD genes on WMT integrity.

Method

We first perform a multi‐tissue TWAS for AD by applying JTI‐PrediXcan to summary statistics from the largest AD GWAS meta‐analysis (Bellenguez, 2022). This approach leverages tissue‐specific eQTL models trained on data from the Genotype‐Tissue Expression project and enriched via Joint Tissue imputation to identify associations between genetically regulated gene expression (GReX) and AD (Barbeira, 2018). We apply prediction performance thresholds and correct for multiple testing. We perform similar TWAS using JTI‐PrediXcan on neuroimaging data from 33,000 participants in the UK Biobank to identify tissue‐specific associations between GReX and WMTs (FA and ISOVF) (Smith, 2021). We integrate these studies to identify AD‐associated genes associated with changes in FA or ISOVF. We quantify the GReX causal effect on WMTs through the MR protocol, MR‐JTI, which assumes gene expression as the exposure (Zhou, 2020).

Result

Our AD TWAS identifies 59 genes. 14 occur at the APOE locus and we replicate 2 additional genes prioritized in the initial GWAS. FUMA analysis of our gene set implicates the brain as the primary tissue of downregulation (Watanabe, 2017). Neuroimaging analysis of these genes highlights 5 WMTs and 2 genes. GReX of CR1 is causally associated with ISOVF of the right acoustic radiation and superior longitudinal fasciculus. GReX of INO80E is causally associated with FA of the left inferior longitudinal fasciculus and the bilateral superior thalamic radiations.

Conclusion

By integrating TWAS of AD and neuroimaging data, we identify multiple significant, tissue‐specific, causal associations between AD‐associated GReX and the integrity of key WMTs associated with cognitive function.
Changing the trajectory of Alzheimer’s disease: What is a meaningful delay in disease progression?
Authors: Lanctôt Krista L. , Raket Lars Lau
Published: December 2023

Background

Recent trials of anti‐amyloid therapies have shown it is possible to change the course of early symptomatic Alzheimer’s disease (AD). However, the limited durations of these trials with the associated limited decline in the patient populations have left questions about the clinical meaningfulness of the observed treatment differences. Through progression analysis, one can quantify trial results in terms of time delay of progression. Compared to treatment differences on clinical scales, time delays are arguably more interpretable to patients and their families. However, it is yet to be established what constitutes a meaningful time delay in AD progression.

Method

Assess how different hypothetical delays in disease progression in early symptomatic AD translate into treatment differences on the Clinical Dementia Rating Sum of Boxes (CDR‐SB) based on published results placebo‐arm trajectories in recent anti‐amyloid trials. Estimates are compared to published estimates of minimal clinically important differences (MCIDs) in AD and meaningful delays in progression in other diseases.

Result

Based on placebo arms from six recent trials of anti‐amyloid antibodies, a 6‐month delay over 18 months (33% slowing) corresponded to treatment differences on CDR‐SB between ‐0.5 and ‐0.8, a 12‐month delay (67% slowing) corresponded to treatment differences between ‐1.0 and ‐1.7, and completely stopping progression (18‐month delay) corresponded to treatment differences between ‐1.6 and ‐2.3 (Figure 1, Table 1). Observed treatment effects in the EMERGE, CLARITY‐AD and TRAILBLAZER‐ALZ trials are consistent with approximately 4‐6 months delay of progression (22‐30% slowing, Figure 1). Established MCIDs in CDR‐SB in early AD range between 1.0 and 1.6, suggesting that a 12‐month delay or 67% slowing of disease progression in an 18‐month trial would be considered borderline in terms of clinical meaningfulness.

Conclusion

Quantifying treatment effects in progressive diseases such as AD in terms of time delays or slowing of progression may offer a more meaningful interpretation of the treatment effects. Based on the trajectories of placebo group in recent trials, we found that treatment effects matching conventionally used MCIDs in AD would correspond to a very substantial slowing of disease (>67%), suggesting that current MCIDs for CDR‐SB are likely inflated.
Predicting cognitive decline in a low‐dimensional representation of brain morphology
Authors: Lamontagne‐Caron Rémi , Desrosiers Patrick , Potvin Olivier , Duchesne Simon , Doyon Nicolas ,   the Alzheimer’s disease neuroimaging initiative, and the CIMA‐Q
Published: December 2023

Background

Identifying early signs of neurodegeneration due to Alzheimer’s disease (AD) is a necessary first step towards preventing cognitive decline. Individual cortical thickness measures, available after processing anatomical magnetic resonance imaging (MRI), are sensitive markers of neurodegeneration. However, cortical decline in aging and high inter‐individual variability complicates the determination of AD‐related neurodegeneration on trajectories. Further, the high‐dimensional nature of these trajectories necessitate the use of a transformation into lower‐dimensional spaces in order to perform comparative statistical analyses, model decline, and identify criteria differentiating pathological from normal trajectories.

Method

In this project, we computed trajectories in a 2D representation of a 62‐dimensional manifold of individual cortical thickness measures. To compute this representation, we used a nonlinear dimension reduction algorithm called Uniform Manifold Approximation and Projection (UMAP). We first created a UMAP embedding on measurements from 6,237 cognitively healthy participants (3,556 women) aged 18 to 100 years old from the NOMIS database. We then projected longitudinal data from 537 mild cognitively impaired (MCI) subjects and 340 AD subjects from ADNI into this embedding. Each participant had multiple visits (n ≥ 2), one year apart. Finally, differences in trajectories were analysed by clustering the reduced data and comparing the positional variations through time between MCI and AD subjects. The validity of the approach was verified through cross‐validation.

Result

First, the embedding was shown to be positively associated (r = 0.65) with participants' age (see figure 1) in the NOMIS data. When projected in this space, differences between ADNI’s MCI and AD distributions were found (see figure 2). Average trajectories between clusters were shown to be significantly different between MCI and AD subjects (see figure 3). Moreover, we showed that some clusters and trajectories between clusters were more prone to host AD subjects. Finally, cross‐validation showed an accuracy of up to 72% at predicting cognitive decline in MCI participants over 2,000 bootstrap iterations.

Conclusion

A 2D low‐dimensional cortical thickness representation embeds sufficient discriminatory information as to predict decline to AD in MCI participants with strong accuracy.
Blood biomarkers of Alzheimer’s disease as predictors of eligibility for disease‐modifying treatment
Authors: Rosenberg Anna , Solomon Alina , Matton Anna , Wistbacka Ulf Öhlund , Hall Anette , Bonnard Alexandre , Daniilidou Makrina , Hagman Göran , Rydén Marie , Ashton Nicholas J. , Zetterberg Henrik , Kivipelto Miia
Published: December 2023

Background

Blood biomarkers show promise in screening for Alzheimer’s disease (AD) brain pathology, but best predictors of eligibility for disease‐modifying treatment remain unclear. We have previously reported estimates for potential eligibility for anti‐amyloid treatment in a real‐life memory clinic setting (Rosenberg et al., Neurology 2022); the current study explored associations between AD blood biomarkers and treatment eligibility.

Method

Study population consisted of 224 patients from the Karolinska University Hospital Theme Aging Memory Clinic, with complete data (clinical, CSF, MRI, and plasma biomarkers Aβ40, Aβ42, NFL, GFAP, ptau181, ptau231). In total, 57% had subjective cognitive impairment, 21% mild cognitive impairment, and 22% dementia. Blood biomarkers were analysed using ultrasensitive Single molecule array (Simoa). Logistic regression models were used with zero‐skewness log‐transformed blood markers as predictors of treatment eligibility (defined based on the published use recommendations for anti‐amyloid treatment aducanumab). Areas under the curve (AUCs) were calculated for a pragmatic model including age, sex, and global cognition (MoCA) (base model), and for each model including blood biomarkers (alone and in combinations, with or without base model).

Result

Thirty‐two out of 224 patients (14%) were classified as potentially eligible for anti‐amyloid treatment. AUC for the base model was 0.65 (95% confidence interval 0.56–0.74). AUCs for models including only blood markers were 0.76 (0.69–0.83; Aβ42/40), 0.77 (0.70–0.84; NFL), 0.80 (0.73–0.88; GFAP), 0.81 (0.74–0.89; ptau181), 0.83 (0.76–0.90; ptau231), and 0.87 (0.82–0.93; all markers). AUC was 0.89 (0.83–0.94) for the full model (all data). In a scenario where the base model was combined with a single blood marker, highest AUCs were observed for models including ptau231 or GFAP (both 0.83, 0.75–0.90).

Conclusion

All blood biomarkers, individually and combined, outperformed the commonly available clinical variables in predicting potential eligibility for disease‐modifying treatment. Ptau markers, especially ptau231, and GFAP seem most promising in this context.
CSF Alzheimer’s Disease Biomarker Changes in Veterans with Mild Traumatic Brain Injury
Authors: Li Ge , Iliff Jeffrey J , Shofer Jane , Mayer Cynthia L , Meabon James , Zetterberg Henrik , Blennow Kaj , Peskind Elaine R
Published: December 2023

Background

Traumatic brain injury (TBI) has been reported to increase risk of Alzheimer’s dementia (AD). It remains unknown whether mild TBI (mTBI) caused by blast in Veterans confers a similar increase of risk. This study investigated early AD changes defined by cerebrospinal fluid (CSF) AD biomarkers in Veterans with blast mTBI.

Method

Fifty‐one Veterans with mTBI, 34 non‐mTBI Veterans, and 51 non‐mTBI civilians were recruited from Seattle, Washington. Age‐matched Veteran and civilian non‐mTBI participants had no lifetime history of TBI. All blast‐mTBI Veterans had experienced at least one war zone blast or combined blast/impact exposure, with acute symptoms meeting VA/Department of Defense criteria for mTBI. All participants underwent standardized clinical and neuropsychological assessments and lumbar puncture for collection of CSF. CSF biomarkers were measured at the Clinical Neurochemistry Lab in Mölndal, Sweden, using Meso Scale Discovery (MSD) assays for Aβ40 and Aβ42, and Innotest ELISAs for phosphorylated Tau181 (pTau181) and total Tau (tTau).

Result

Differences in all 4 CSF AD biomarkers between participants with and without mTBI were highly age‐dependent and most pronounced in older ages (Figure 1). Both CSF Aβ40 and Aβ42 became lower as age increasing in the mTBI group starting around age 40‐45 years, while they increased with age in the non‐mTBI participants. In contrast, CSF tTau and pTau181 mean levels remained relatively constant with age in participants with mTBI, but increased after age 45 in the non‐mTBI participants. Consequently, for participants aged 50+ years, Veterans with mTBI had lower mean AD biomarkers than the non‐mTBI participants. Similarly, the differences in cognitive performance were age‐dependent, i.e., poorer performance in older Veterans with mTBI than in the non‐mTBI participants. Furthermore, the relationships between CSF Aβ42 and cognitive performance were also age‐dependent; specifically, in participants aged 45+ years, lower CSF Aβ42 level was associated with poorer performance on tests of verbal fluency and memory.

Conclusion

The earliest AD biomarker, CSF Aβ42, started to decrease in middle‐aged Veterans with mTBI, more than a decade earlier than those without mTBI in our earlier study, suggesting mTBI may accelerate brain deposition of Aβ and increase risk for AD.
Viability of an EEG‐based Automatic System for Early Dementia Screening
Authors: Agatic Filip , Dreo Jurij , Jug Jan , Pavlovcic Tisa , Ogrin Ajda , Aljaz Barbara , Sakic David
Published: December 2023

Background

Based on recent demographic projections the worldwide number of people with dementia will triple by the year 2050, a socio‐economic burden that will disproportionally affect low‐ and middle‐income countries (Nandi et al., 2022). Therefore, a reliable, objective and cost‐effective screening methods are needed to be able to apply early interventions and slow down a decrease in quality of life for millions of patients. To address this issue, we explore viability of an EEG based system as an affordable solution for early dementia screening.

Method

The tested system includes a mobile amplifier (mBrainTrain) with 24 channel sponge EEG cap (Greentek) and a custom software (BDI) for EEG data acquisition and analysis (BrainTrip). The BDI software automatically detects and removes common EEG artifacts, calculates spectral EEG features known to be associated with cognitive decline (Sanchez‐Reyes et al., 2021), and uses density clustering and a multi‐layer perceptron classifier to predict the cognitive ability using a score between 0 and 100. We tested 448 senior participants who undertook five cognitive screening tests (MoCA, ADAS‐cog, ACE‐III, Eurotest, Phototest) and eight minutes resting state EEG recording on three separate sessions.

Result

Our previous analysis was performed on about 50% of the total included subjects, which we now expended to the full dataset. Additionally, more provisions were made to prevent potential overfitting in building the final predictive model. Setting the cut‐off value of the BDI at 50 points, the specificity was at 97% and sensitivity at 65% compared to a consensus of all other cognitive tests. Assuming a dementia prevalence of 10%, the BDI test achieved an accuracy of 94%.

Conclusion

Based on the high accuracy of the EEG‐based assessment in detecting cognitive decline and dementia, it could be a promising option for dementia screening. It is an efficient, low‐cost and non‐invasive option for early intervention, especially in a primary healthcare setting.
An Alzheimer’s disease blood test study in a diverse community‐based population: Preliminary results from SEABIRD
Authors: Li Melody , Li Yan , Schindler Suzanne E. , Yen Daniel , Sutcliffe Siobhan , Babulal Ganesh M. , Benzinger Tammie L.S. , Lenze Eric J. , Bateman Randall J.
Published: December 2023

Background

Alzheimer’s disease (AD) blood tests are needed to aid in the evaluation of dementia, but the performance of these tests should be evaluated in diverse groups and real‐world settings. The goals of the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD) were to enroll 1120 participants to determine the participant acceptability and validity (relative to amyloid PET) of a plasma amyloid‐β 42/40 test in a diverse, community‐based sample of older adults, and explore the impact of important factors (age, race, education, cognition, APOE genotype, and medical conditions) on the blood test’s performance.

Method

SEABIRD measured plasma amyloid‐β 42/40 in a diverse population of older adults in the Saint Louis, Missouri, USA area. Participants completed a blood collection, cognitive screening (AD8® dementia screening interview and Montreal Cognitive Assessment [MoCA]), and a survey about their study experience and perceptions of the blood test. A subset of participants completed additional blood collection for reproducibility, amyloid PET and MRI for validation of the blood test, and the Clinical Dementia Rating® (CDR) for validation of the cognitive screening measures.

Result

Of the 859 participants enrolled in this ongoing study, 20.6% self‐identified as Black or African American and the percentage of APOE ε4 carriers was 30.2% (Table 1). Compared to the general population, SEABIRD participants were more likely to be female, aged 70‐79 years, and highly educated. They were less likely to report high cholesterol, diabetes, kidney disease, and stroke, and more likely to report depression. The receiver operating characteristic area under the curve for distinguishing cognitively unimpaired (CDR = 0) from cognitively impaired (CDR>0) individuals was 0.72 for the informant‐rated AD8, 0.46 for the self‐rated AD8, 0.70 for the MoCA, and 0.79 for the AD8/MoCA composite (Table 2). Survey results indicated that the blood test was well accepted (Figure 1), but it was perceived more positively by white and highly educated individuals.

Conclusion

A study of an AD blood test achieved rapid enrollment, broader diversity than typical AD cohorts, and high rates of participation. These results suggest that an AD blood test could be used for screening in a diverse clinical population.
Physical Inactivity and Social Determinants of Health Among Older Adults with Mild Cognitive Impairment and Dementia
Authors: Bartley Mairead M. , Baer‐Benson Henry , Schroeder Darrell R. , St Sauver Jennifer , Khera Nandita , Griffin Joan M.
Published: December 2023

Background

Physical activity can improve the physical health of people living with mild cognitive impairment (MCI) and dementia and may have cognitive benefits. Identifying modifiable social factors inhibiting physical activity among this group is important. We examined the relationship between reported physical activity levels and social determinants of health (SDOH) in a population of older adults living with MCI or dementia.

Method

We included people with a diagnosis of MCI or dementia, age 55 years and older, who were empaneled to Community Internal Medicine at Mayo Clinic (Rochester, Minnesota), had a clinic visit between June 1, 2019 and June 30, 2021 and had completed a SDOH questionnaire. We focused on 8 SDOH domains: education, depression, alcohol use, stress, financial resource strain, social connections, food insecurity and transportation needs. Self‐reported activity levels were categorized as inactive (0 minutes of exercise per week), insufficiently active (10‐140 minutes per week) or sufficiently active (≥150 minutes per week). SDOH domains were compared according to physical activity level using χ2 tests and multinomial logistic regression.

Result

A total of 3224 persons with MCI (n = 1371) or dementia (n = 1853) who had completed questions on physical activity were included. Of these, 1936 (60%) were characterized as physically inactive and 837 (26%) insufficiently active. Characteristics associated with an increased likelihood of physical inactivity were older age, female sex, obesity, lower education, dementia diagnosis, depression risk and increased social isolation (all p<0.001).

Conclusion

Physical inactivity is common among people living with MCI and dementia. Physical activity levels may be influenced by many modifiable factors, highlighting potential areas for intervention in this population.