bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping High‐Frequency Conductivity Using MRI in the Brains of Alzheimer’s Disease Patients
Authors: Jahng Geon‐Ho , Park Soonchan , Lee Mun Bae , Rhee Hak Young , Ryu Chang‐Woo , Kwon Oh In
Published: December 2023

Background

Previous studies reported increased concentrations of metallic ions and imbalanced Na+ and K+ ions in patients with Alzheimer’s disease (AD) and the increased mobility of protons by microstructural disruptions in AD. The purposes of this study were: 1)to apply a high‐frequency conductivity (HFC) mapping technique using a clinical 3T MRI system and 2)to compare HFC values among participant groups.

Method

This prospective study included 74 participants (23 AD patients, 27 amnestic mild cognitive impairment (MCI) patients, and 24 cognitively normal (CN) elderly people) to explore the clinical application of HFC mapping in the brain. For the brain MREPT images, a multi‐echo turbo spin‐echo pulse sequence was used. A homemade software was used to map the HFC at the Larmor frequency of 128 MHz at 3T. We performed statistical analyses to 1) compare HFC maps between the three participant groups and 2) to evaluate the association of HFC maps with Mini‐Mental State Examination (MMSE) scores.

Result

The HFC value was higher in the AD group than in the CN and MCI groups. MMSE scores were negatively associated with HFC values, but age was positively associated with HFC values. The HFC value in the insula has a high area under the ROC curve (AUC) value to differentiate AD patients from the CN participants (Sensitivity (SE) = 82, Specificity (SP) = 97, AUC = 0.902, p < 0.0001), better than GMV in hippocampus (SE = 79, SP = 83, AUC = 0.880, p < 0.0001).

Conclusion

HFC values were significantly increased in the AD group compared to the CN group and increased with age and disease severity. HFC values of the insula along with the GMV of the hippocampus can be used as an imaging biomarker to improve the differentiation of AD from CN.
The European Prevention of Alzheimer’s Dementia Programme: Summary outputs post Innovative Medicines Initiative Funding
Authors: Ritchie Craig W , Collij Lyduine E. , Barkhof Frederik ,   the EPAD consortium
Published: December 2023

Background

The in 2015 initiated European Prevention of Alzheimer’s Dementia (EPAD) programme was funded by the Innovative Medicines Initiative (IMI), a European Union led programme that brought commercial, academic, and third sector organisations together. A key part of the project was the development of the EPAD Longitudinal Cohort Study (LCS) to test existing and develop new disease models regarding the pre‐dementia phases of Alzheimer’s disease (AD). After 2020, the maintenance of the EPAD Dataset and Biorepository was supported from multiple sources, including the Alzheimer’s Association and Gates Ventures. EPAD was the first dataset to be uploaded onto the AD Workbench, directly supporting the development of this key part of the Alzheimer’s Disease Data Initiative (ADDI).

Method

EPAD‐LCS data is openly available on the AD workbench, with access being split into 3 domains: Data Only, Biological Samples (CSF, Blood, Saliva, and Urine), and (advanced) MRI data. Access to these data sets is monitored and reported on closely via the AD Workbench. More recently the NTK App developed by Roche Diagnostics has been embedded on the AD Workbench as a free‐to‐use app to ease data analysis from EPAD and other cohorts on the AD Workbench.

Result

The total number of requests for data will be presented grouped by research question domain, geographic location, and academic/commercial split. The outputs from these data requests in terms of academic publications will be presented with a summary of where these findings are pointing towards in terms of new insights in our understanding of preclinical and prodromal AD. Operational aspects will also be presented with regards speed of access from initial enquiry, through application to provision of data and samples.

Conclusion

The EPAD‐LCS is a major pan‐European study which has generated vast amounts of data across a comprehensive range of biological, clinical, and epidemiological variables. Access to this data to generate new knowledge is free for anyone and we prioritised rapid access to a data environment that facilitates analysis. Combining the major programmes of EPAD, ADDI and the NTK App has been shown to achieve the core objective of knowledge generation which research participants expect.
Effects of hippocampal atrophy and white matter lesions on cognitive function in Alzheimer’s disease
Authors: Yamamoto Ryo , Shimizu Soichiro , Inagawa Yuta , Takenoshita Naoto , Ishii Kenji
Published: December 2023

Background

We investigated the effects of white matter lesions and hippocampal atrophy on head MRI on cognitive function in AD patients.

Method

We examined 47 patients who were diagnosed with Alzheimer’s disease according to the ATN classification at the geriatric department of Tokyo Medical University Hospital. We evaluated the severity of white matter damage by the sum of PVH and DWMH in the Fazekas classification on head MRI at the first visit, and hippocampal atrophy by VSRAD.

Result

There was a significant correlation between white matter impairment and cognitive changes (r = 0.292, p<0.05). And the correlation test for hippocampus atrophy and MMSE change was also performed with correlation coefficients r = 0.00926 and p = 0.951 (>0.05).

Conclusion

The sum of PVH and DWMH and the amount of change in MMSE were positively correlated in AD patients. Therefore, it was concluded that the more severe the white matter disorder, the slower the progression of cognitive decline. These results suggest that advanced white matter disorders may inhibit the progression of AD in AD patients.
Predicting Sojourn Times across Dementia Disease Stages, Institutionalization, and Mortality
Authors: Tate Ashley , Bouteloup Vincent , van Maurik Ingrid S. , Mank Arenda , Speh Andreja , Eriksdotter Maria , Wimo Anders , Dufouil Carole , van der Flier Wiesje M. , Jönsson Linus
Published: December 2023

Background

A common concern for patients with dementia is the time until severe stages and mortality. Current literature is sparce and often features small sample sizes. We aim to determine the time spent in mild cognitive impairment (MCI), mild‐, moderate‐, or severe dementia, institutionalization, and death.

Method

Multistate modeling was used to obtain the time in each state. Covariates were age at study baseline, sex, amyloid status, and Alzheimer’s disease (AD) diagnosis. The sample included a register (SveDem) and memory clinics (Amsterdam Dementia Center and Memento).

Result

Based on 80,972 patients, the full disease course from MCI to institutionalized‐severe dementia lasted between 7.91 (95% CI: 7.07‐9.02) years for males aged 87 at baseline and 11.70 (9.96–14.44) years for females aged 71.

Conclusion

Generally, rapid progression was associated with older age at baseline, males, and AD diagnosis. The results provide key estimates for researchers and clinicians to estimate prognosis.
The Memory Binding Test: a new tool to assess emerging episodic memory decline in asymptomatic at‐risk individuals to Alzheimer’s disease
Authors: Pereira Filipa Raposo , George Nathalie , Barba Gianfranco Dalla , Dubois Bruno , La Corte Valentina
Published: December 2023

Background

Episodic memory (EM) deficits are a hallmark of Alzheimer’s disease (AD). The Free and Cued Selective Reminding Test (FCSRT) is the most specific official diagnostic tool detecting AD‐linked EM alterations in advanced preclinical stages (Grober et al., 2021). However, new tools that anticipate diagnosis to the at‐risk phase are needed, to reach more meaningful therapies. Based on existing research, we aim to investigate the Memory Binding Test (MBT) promising capacity to detect the appearance of subtle AD‐linked EM alterations and anticipate AD‐diagnosis to an at‐risk phase (Bushcke ey al., 2017; Mowrey et al., 2018).

Methods

FCSRT and MBT scores were collected yearly during 5 years from the INSIGHT‐preAD cohort. We selected 3 groups controlled for age, education level, gender, beta‐amyloid burden (AB+), and neurodegeneration status based on 15 individuals who converted to prodromal‐AD during follow‐up, as follows: converters/AB+; non‐converters/AB+; controls/AB‐. Evaluation of both list‐learning tests is mainly based on free recall (FR) and total (cued) recall (TR) scores. The FCSRT uses 1‐list of words to remember while the MBT uses 2‐lists, introducing a binding component sensitive to subtle EM alterations. Data was analysed using mixed effect models including age, gender, and education as covariates.

Results

When compared with the FCSRT, the MBT anticipated the detection of AD‐linked EM alterations in the converters/AB+ versus the other groups. In the MBT decline started up to 5 years prior to diagnosis, in delayed FR (mainly associated to executive dysfunction), followed by decline in 4 binding‐associated scores 1 year later (linked to storage deficits associated with the amnesic hippocampal syndrome characteristic of AD). Therefore, at an at‐risk phase, MBT outperformed FCSRT, both in the year of diagnosis and in the number of scores confirming AD‐linked EM deficits.

Conclusion

We show the MBT capacity to detect the initial subtle EM alterations and to anticipate diagnosis to the at‐risk phase, while participants remain cognitively normal. We argue that the MBT (at‐risk phase detection) and the FCSRT (preclinical phase classification) could be complementary rather than concurrent tools, fostering meaningful innovative treatments to prolong quality of life in AD, a disease that remains without a cure.
A PROSPECTIVE STUDY OF ALZHEIMER’S DISEASE DIAGNOSIS AND PROGNOSIS (VALCODIS COHORT)
Authors: Cháfer‐Pericás Consuelo , Baquero Miguel , Álvarez Lourdes , Ferré‐González Laura , Peña‐Bautista Carmen , García‐Vallés Lorena , Ferrer Inés
Published: December 2023

Background

The Valencian Cognitive Diseases Study (VALCODIS) provides a large cohort of cases suffering from neurodegenerative diseases causing cognitive problems in their initial phases. This cohort is being obtained from admitted patients at Cognitive Disorders Unit Hospital Universitari i Politècnic La Fe (Valencia, Spain), as a basis to contribute on the Alzheimer’s disease (AD) diagnosis and prognosis research.

Method

Patients who come to the Cognitive Disorders Unit at Neurology Department of Hospital La Fe can be recruited to the VALCODIS cohort after their informed consent have been obtained. Patients with moderate and severe dementia are not proposed to participate. Included patients were studied with standard analytical and neuroimaging procedures, commonly brain MR, and CSF biomarkers determination (β‐amyloid‐42, β‐amyloid‐40, p‐Tau, t‐Tau, neurofilament light chain). Patients on anticoagulation, other contraindications or not suitable for LP can be included if an amyloid brain PET can be obtained. In some patients, brain PET with FDG is also obtained. After amyloid status is assured, a detailed neuropsychological evaluation is obtained in every patient using at least MMSE, CDR, RBANS and GDS scales. Finally, blood samples were taken to determine some potential biomarkers (lipid peroxidation, lipids, proteins, microRNAs) and stored simultaneously with CSF samples.

Result

A total of 1100 participants aged 50 to 80 years, who were on follow up from January 2017 to August 2022 have been included in the VALCODIS cohort. This cohort is composed by early AD patients (mild cognitive impairment (MCI), mild dementia), other dementias in their initial phases (frontotemporal dementia, Lewy body dementia, vascular dementia) and cognitively healthy persons. Also, some of MCI‐AD patients were followed‐up at 2 years to carry out a prognosis study, by means of neuropsychological evaluation and blood biomarkers.

Conclusion

The VALCODIS cohort represents a valuable infrastructure describing 6‐year experience about early and specific AD diagnosis, and prognosis. This cohort will provide a large number of patients, biologically diagnosed by CSF biomarkers, as well as their demographical, clinical and biochemical data. In addition, the biological samples (blood, plasma, urine, saliva, CSF) were stored to carry out further biomarkers studies.
Retinal microvasculature and risk of incident dementia over a 10‐year period: results from the 3C‐Alienor population‐based study
Authors: Rebouças Sara Cristina Lima , Cougnard‐Gregoire Audrey , Arnould Louis , Delyfer Marie‐Noëlle , Schweitzer Cédric , Korobelnik Jean‐François , Foubert‐Samier Alexandra , Cheung Carol Y , Wong Tien Yin , Delcourt Cécile , Helmer Catherine
Published: December 2023

Background

The retina and the brain microvasculatures share many anatomical and physiological similarities; thus, retinal microvasculature could represent a potential screening tool for cerebrovascular and neurodegenerative diseases. Changes in retinal microvasculature have been associated with dementia in previous studies. However, all the previous studies analyzing retinal vascular network features in relation to dementia or Alzheimer Disease (AD) were cross‐sectional. This study aimed to explore the longitudinal relationship between retinal microvascular features and dementia incidence over a 10‐year follow‐up period.

Method

We included 617 participants from the Three‐City (3C) population‐based cohort and its ancillary ophthalmological study, the Alienor study. Quantitative retinal vascular features (caliber, tortuosity, fractal dimension) were assessed at baseline in the Alienor study using the semi‐automated Singapore I Vessel Assessment (SIVA) software; dementia was actively screened and diagnosed over a 10‐year period. Cox proportional‐hazards models were used to estimate the risk of incident dementia and its main etiologies (i.e., probable or possible AD and mixed or vascular dementia) associated with retinal vascular features.

Result

The mean age of the participants was 79.5 years (SD 4.4) and 66.6% were women. During the follow‐up (median of 7.2 years), 134 participants developed dementia (87 probable or possible AD and 38 mixed or vascular dementia). In multivariate models adjusted for the main potential confounders (socio‐demographic factors, vascular co‐morbidities and Apolipoprotein ε4 allele), increased arteriolar tortuosity was associated with increased risk of dementia (HR per SD increase = 1.26, 95%CI: 1.07; 1.50). Despite some trends, retinal calibers were not significantly associated with dementia all‐cause. When considering the different etiologies of dementia, wider retinal venular calibers were associated with mixed or vascular dementia, but not with Alzheimer’s disease. Fractal dimensions were not associated with dementia.

Conclusion

Changes in retinal microvasculature were associated with risk of incident dementia. More works are needed to replicate and determine which features could help identifying persons at risk of future dementia at an early stage, and to examine the specific processes that might be involved according to dementia etiology.
Vascular and extravascular localization of Aβ in Alzheimer’s retina
Authors: Lee Sieun , Whitney Dylan , Liu Alice , Schwab Katerina , Jiang Kailun , Hirsch‐Reinshagen Veronica , MacKenzie Ian R , Hsiung Ging‐Yuek Robin , Sarunic Marinko , Beg Mirza Faisal , To Eleanor , Cui Jing , Pham Wellington , Matsubara Joanne A
Published: December 2023

Background

Recent in vivo and ex vivo studies have demonstrated retinal vasculopathy may be associated with Alzheimer’s disease (AD). We investigated amyloid beta (Ab) localization relative to vessels in wholemount retinas from AD and control donors. We specifically tested whether extravascular retinal Ab aggregated toward vessels and whether the Ab localization pattern differed between the AD and control retinas.

Method

From 15 AD donors and 10 age‐matched controls, free‐floating punches were taken in the foveal, peri‐foveal, and mid‐peripheral temporal, superior, and inferior neuro‐retina. Immunohistochemistry was performed for Ab (6F/3D, 12F4) with secondary antibodies tagged with Cy3. The punches were imaged at 543‐nm using Zeiss LSM 510 confocal microscope focused at the ganglion cell layer in four non‐overlapping 450mm x 450mm images. Blind raters segmented the images into intravascular and extravascular regions excluding cell bodies and artefacts. Quantitative analysis was performed as follows: Ab reactivity was detected pixel‐wise by intensity thresholding, and the total vessel area, raw and normalized intra‐ and extravascular Ab load, and vessel proximity of extravascular Ab were computed.

Result

Out of 452 images 272 contained visible vessels. Total vessel area was lower in the AD retinas in the superior region (p = 0.004). There was no group difference in Ab load except in the temporal intravascular region (p = 0.007); however, intravascular Ab signal may be due to blood artefacts and requires caution in interpretation. Aggregation of Ab near vessels was tested by comparing the vessel proximity of extravascular Ab‐positive pixels against that of all other pixels in the extravascular region. Extravascular Ab were located significantly closer to the vessels than the background in the control retinas in the peri‐fovea (p = 0.0023) and temporal (p = 0.001) regions, but this was not observed in AD retinas.

Conclusion

With our previous study on intracellular retinal Ab, the current study suggests that Ab deposition pattern in the retina is specific in spatial regions (eg. temporal, superior) and anatomical regions (eg. intracellular, intravascular). The non‐specificity of Ab localization relative to the vessels in AD may indicate compromised Ab clearance via retinal vasculature.
ABOARD Cohort; a national initiative to involve citizens in AD research
Authors: Rhodius‐Meester Hanneke F.M. , de Boer Casper , Handgraaf Dédé , Claassen Jurgen A.H.R. , de Haan Romy , Hempenius Liesbeth , van Munster Barbara C. , van Strien Astrid M , de Vugt Marjolein , Arts Derk , Kooistra Minke , de Rijke Tanja J. , Beusink Miriam , Pijnenburg Yolande A.L. , van der Flier Wiesje M.
Published: December 2023

Background

Many research cohorts consist of selected research populations, and their outcomes may not translate directly to daily life. Patient Reported Outcomes (PROs) provide this information, but data across the entire disease trajectory, from ‘at risk’ to dementia, are lacking. To address this gap, paving the way for value‐based health care, we have set up a Dutch national data collection infrastructure. This initiative called the ABOARD Cohort aims to (i) study the AD disease trajectory using both PROs and medical data, (ii) link to available registry data, and (iii) serve as central platform to initiate additional studies.

Method

The ABOARD Cohort (www.aboard‐cohort.nl) is part of the ABOARD project, a national public‐private partnership with >30 partners. The cohort is an ongoing, participant‐centered data‐collection, focused on PROs, a minimal CRF with relevant medical data, and linkage to existing data sources. Eligible participants with or at‐risk of AD and their care‐partners are recruited directly‐to‐participant, via (social) media and leaflets. Informed consent and annual collection of PROs through questionnaires are facilitated online, on separate platforms. Governance is based on the principle of data‐portability, the participant being owner of their own data. Participants optionally consent for their study data to be linked to e.g. health insurance and medical record data. We ensure active public‐involvement through a dedicated participant panel.

Result

In September 2022, the ABOARD Cohort was launched. In the first 4 months, n = 82participants (mean age 56±16, female 53(65%)) signed up via the study portal. 60(73%) gave consent to link their data to registries. The ABOARD Cohort Panel, consisting of 57 participants recruited via social media, provided input on the (consent) procedure, via surveys and panel discussions. The early phase experiences are now used to optimize procedures prior to a large social media campaign inviting participants in Spring 2023. The narrative of this campaign is that participants can contribute an hour of their time to help Alzheimer’s research (Figure).

Conclusion

The ABOARD Cohort lays the foundation for a future with personalized medicine for AD. With this large scale societal initiative, we attempt to involve a large number of Dutch citizens in Alzheimer’s research.
Assessing posttraumatic stress disorder with patients suffering from neurocognitive disorder: development of the PTSD with NCD Inventory (PNI)
Authors: Coeur Estelle , Derreumaux Alexandre , Robert Philippe , Corveleyn Xavier
Published: December 2023

Background

PTSD and NCD have common symptoms such as mood disorders (depressive symptoms, aggressivity, etc.) or cognitive disorders (executive dysfunctionning, amnesia, etc.). Due to these similarities, and because existing tools are not suitable for this population specificities, PTSD diagnosis may be difficult. Based on the existing literature, a new screening tool was created, allowing a hetero assessment of PTSD for this population. This study consists in explaining the development and the pre‐testing of our new tool, following specific scale development guidelines.

Method

A research was conducted to analyze the inventory construct which allowed us to analyze over 50 tools and create our items. An expert panel assessed the first version, which was used in a protocol conducted with 44 participants suffering from NCD.

Result

First, the tool was modified consequently to the expert panel’s review, for a total of 15 domains with 4 at 8 items. Cronbach’s alpha and Pearson’s correlation enlightened good reliability when tested with the 44 participants (inventory’s Cronbach’s alpha = 0.75). By the end of the pilot testing, 13 domains composed of 70 items were kept.

Conclusion

The different validation steps lead to the creation of a new hetero‐assessing tool with specific PTSD items and suitable to a population with NCD. Domains will gauge both the symptoms frequency and impact. According to literature, this tool will focus on DSM‐5 criteria A, B and E. The next step will be to analyze the PTSD with NCD Inventory’s psychometric properties.
Longitudinal age effects in microstructures of the hippocampal subfields.
Authors: Zia Ghina , Shahid Syed Salman , Risacher Shannon L , Saykin Andrew J. , Wu Yu‐Chien
Published: December 2023

Background

The human brain undergoes considerable morphologic change with age, which is one of the primary risk‐factors for Alzheimer’s disease (AD). Age‐related microstructural changes in the brain may be quantified by advanced diffusion MRI (dMRI) with compartment modeling. In this longitudinal study, we aimed to investigate the effects of age on the hippocampal subfields, one of the brain regions vulnerable to the early stages of AD.

Method

Thirty‐seven cognitively normal older adults (70.6 ± 6.7 years) were recruited from the Indiana ADRC. Participants received a baseline and a follow‐up MRI scan over 24 ± 11.7 months with a Siemens 3T Prisma scanner using a 64‐channel head coil. We applied grey‐matter‐specific multi‐compartment diffusion model (cortical‐neurite orientation dispersion and density imaging) to derive diffusion microstructural metrics, namely orientation dispersion index (ODI), volume fractions of fast isotropic diffusion (VFISO), and intracellular‐space (VFIC) in the hippocampal‐subfields (CA1‐3, CA4 and dentate gyrus (CA4‐DG), and subiculum) [1]. To study the longitudinal age effects, we investigated the rate of change in the diffusion metrics and the association between the rate of change and age. Linear regression analysis was performed using SPSS software and adjusted for sex, education, APoE e4 status, and subfield volumes (Table 1).

Result

All subjects had normal cognition (i.e., MoCA and MMSE, Table 1). The volumes of CA1‐3 and subiculum significantly decreased between the baseline and follow‐up MRI scans, (p<0.05, Table 1). During this period, while significantly increased ODI within subject was observed in CA4‐DG, significantly decreased VFISO in all the subfields and increased VFIC in the subiculum were noted (Figure 1). The decreasing rate of VFISO in CA4‐DG was significantly associated with age (Table 2), suggesting the reduction in VFISO accelerated over age.

Conclusion

We demonstrated that diffusion metrics are sensitive to microstructural alterations in the hippocampal subfields of cognitively normal older adults. The cornu ammonis region 4 and dentate gyrus is the most vulnerable region affected by aging with increased tissue dispersion and age‐accelerated reduction in fast isotropic diffusion. Future studies will focus on the effects of the initial microstructural condition to its rate of change with aging.

References: 1. Shahid, et al., Brain,2022
Use of plasma P‐tau217 for enrichment in the Phase 2 PROSPECT‐ALZ study of LY3372689 in early symptomatic Alzheimer’s disease: Cohort selection and baseline characteristics
Authors: Munsie Leanne M , Fleisher Adam S , Cheng Yun‐Ju , Stauffer Marianne L , Schade Andrew E. , Page Todd J , Mergott Dustin J. , Brys Mirek
Published: December 2023

Background

Inhibition of O‐linked N‐acetyl glucosaminidase (OGA) is hypothesized to impede the formation of hyperphosphorylated, insoluble tau aggregates and neurofibrillary tangles. LY3372689 is an orally available, potent inhibitor of OGA being tested in the ongoing PROSPECT‐ALZ study. This is the first study assessing the safety and efficacy of an OGA inhibitor in individuals with early symptomatic Alzheimer’s Disease (AD). To improve efficiencies in identifying individuals with desired levels of tau pathology, PROSPECT‐ALZ implemented a gated screening approach using plasma P‐tau217 as an enrichment step prior to tau PET. We present the study design, findings from the screening process, and baseline characteristics of the PROSPECT‐ALZ study cohort.

Method

With 68 sites across Australia, Canada, Japan, Poland, and the US, PROSPECT‐ALZ is an ongoing multicenter, double‐blind, placebo‐controlled Phase 2 study with 1:1:1 randomization of daily LY3372689 low dose, LY3372689 high dose, or placebo. The primary objective is to evaluate the effect of LY3372689 on AD clinical progression, as assessed by the change from baseline to endpoint (76‐124 weeks with common close design) on the integrated AD Ratings Scale (iADRS).

Pre‐screening procedures include the Mini‐Mental State Examination (MMSE, scores of 22‐30) and a plasma P‐tau217 test to determine eligibility for further screening. Subsequent key inclusion requirements to meet were age 60‐85 years, a CDR global score of 0.5 or 1 with a memory box score of ≥ 0.5, and a PET (18F‐flortaucipir) scan demonstrating an intermediate or high level of aggregated brain tau by combined visual and quantitative assessment.

Result

After consent, 2180 participants entered screening. The top reason for screen failure was a P‐tau217 result below the eligibility threshold. Performance of the P‐tau217 test for pre‐screening patient selection as well as characteristics and demographics of the screening and randomized cohorts will be presented.

Conclusion

As blood‐based biomarkers become more accessible, their use in selecting participants for clinical research is desirable. The PROSPECT‐ALZ study successfully implemented plasma P‐tau217 in sequence with tau PET to improve efficiency in identifying trial participants. This study of LY3372689, the first orally administered OGA inhibitor to be investigated in AD, has topline trial results anticipated in 2024.
Suicide ideation, attempts and deaths in people living with dementia (PLWD): A systematic review and meta‐analysis of prevalence and risk factors
Authors: Stott Joshua , Tsipa Anastasia , Fearn Caroline , Baou Celine El , Charlesworth Georgina , Flanagan Katie , Brotherhood Emilie V , Crutch Sebastian J , John Amber , Desai Roopal
Published: December 2023

Background

Suicide is a major public health concern. However, little is known about whether dementia is associated with suicide outcomes, and if so what the risk factors for suicide are in this group. This study aimed to conduct meta‐analyses to examine pooled associations between dementia and suicide outcomes (ideation, attempts, death by suicide) as well as pooled associations between risk factors (sex, dementia subtype) and suicidality in people living with dementia (PLWD).

Method

Systematic searches were conducted in Medline, Embase, Psycinfo, Cinahl Plus, and Web of Science for keywords related to dementia and suicide. Quantitative studies with a sample of PLWD and suicidality as an outcome and that were available in English were included. Experimental studies, case reports and studies with a focus on euthanasia/assisted suicide, or self‐harm without suicidal intentionality were excluded. Relevant effect sizes were extracted and inverse variance weighted meta‐analyses were run using a random‐effects model.

Result

55 studies were included. Meta analyses showed that compared to people without dementia, having dementia was significantly associated with death by suicide (OR = 2.48, 95% CI:1.82;3.38), and suicidal ideation (OR = 2.29, 95% CI:1.75‐2.99), but not suicide attempts. Men with dementia were more at risk of attempting (OR = 1.28, 95% CI:1.25;1.31) and death by suicide (OR = 2.84, 95% CI:1.51;5.37) than women with dementia, but there was no difference in suicidal ideation. Compared with Alzheimer’s disease, people with vascular dementia (VaD), frontotemporal dementia (FTD), and other dementia (OD) types were significantly more likely to attempt suicide. People with Lewy body dementia (LBD) were significantly more likely to report suicidal ideation.

Conclusion

PLWD are at higher risk of suicidal ideation and death by suicide than those without dementia, but not suicide attempts. This could suggest that PLWD are not more likely to attempt suicide but are more likely to be successful when an attempt is made. Key risk factors for suicide attempts amongst PLWD are being male, sub‐type of dementia diagnosis (VaD, FTD and OD), while having a diagnosis of LBD is a risk factor for suicidal ideation. These results are important for understanding and managing risk in PLWD.
White matter hyperintensity volume changes are associated with progressive hippocampal atrophy in Insight 46: the neuroscience sub‐study of the MRC National Survey of Health and Development, the British 1946 birth cohort
Authors: Brown Thomas M. , Sudre Carole H , Keuss Sarah E , Coath William , Prosser Lloyd , Nicholas Jennifer M , Malone Ian B , James Sarah‐Naomi , Murray‐Smith Heidi , Cash David M , Richards Marcus , Barnes Jo , Schott Jonathan M
Published: December 2023

Background

White matter hyperintensity volume (WMHV) is a presumed marker of cerebrovascular disease associated with ageing, Alzheimer’s disease (AD) and vascular dementia. Higher baseline WMHV is associated with increased brain atrophy rate, with disproportionate effects in the hippocampus – a region affected early in AD. Understanding the relationships between longitudinal change in WMHV and hippocampal atrophy, while accounting for AD and cardiovascular risk factors, will increase our understanding of the multifactorial disease processes occurring during the early stages of AD.

Method

Rate of change in WMHV was calculated using Bayesian Model Selection (BaMoS) and total hippocampal atrophy rate was calculated using the Boundary Shift Integral (BSI), measured concurrently between two time‐points. Participants with major neurological disorders were excluded. Linear regression was used to test whether rates of WMHV change predicted rates of hippocampal atrophy while adjusting for total intracranial volume (TIV), sex and age. Further models adjusted for baseline PET amyloid‐β (Aβ) standard uptake value ratio (SUVR), ApoE‐e4 carrier status, and Framingham heart study cardiovascular risk (FHS‐CVS) aged 69, and tested for interactions with rate of WMHV change.

Result

308 individuals with high‐resolution isotropic MRI data at two time‐points were analysed in this study (Table 1). For every 1ml/year increase in WMHV there was an associated 0.013ml/year decrease in total hippocampal volume (Table 2, Model 1). This association remained when adjusting for Aβ SUVR (Table 2, Model 2), ApoE‐e4 status (Table 2, Model 3), and FHS‐CVS (Table 2, Model 4). A separate semi‐partial correlation analysis showed 4.6% of variance in rate of hippocampal atrophy was uniquely explained by rate of WMHV change when accounting for TIV, sex and age. There were no significant interactions between rate of WMHV change and Aβ, ApoE‐e4 or FHS‐CVS in relation to hippocampal atrophy rate.

Conclusion

Increases in WMHV were significantly associated with progressive hippocampal atrophy accounting for head size, age and sex. These associations were not materially changed when adjusting for amyloid deposition, ApoE‐e4 or cardiovascular risk factors. These results suggest systemic processes that contribute to WMH development also contribute to hippocampal atrophy. Further work is required to determine the processes that drive this relationship.
The interactive impact of sex and APOE genotype on post‐mortem brain fatty acids profile in Alzheimer’s Disease, Results from the UK BrainBank.
Authors: Saleh Rasha , Minihane Anne‐Marie
Published: December 2023

Background

Two‐thirds of Alzheimer’s Disease (AD) patients are women, with the risk becoming higher if carrying the APOE4 genotype. Omega‐3 fatty acids status is associated with reduced risk of AD. Little is known about the interactive impact of sex and APOE genotype on brain fatty acids status. In this study, fatty acids were measured in post‐mortem brain tissue of AD patients and stratified according to sex and APOE genotype.

Method

Fatty acids were extracted from the hippocampus and frontal cortex of AD cases (n = 25, 11 are women) and controls (n = 25, 12 are women) using Folch method (from total lipids). Fatty acids were analysed using gas chromatography and flame ionization detection (GC‐FID). Samples were requested and granted from the UK Brain Bank. Adjustment for age and post‐mortem delay was done.

Result

Arachidonic acid (ARA) and n‐6DPA were higher in APOE4 women with AD compared to control (P‐Disease*sex*APOE = 0.01 and <0.001 respectively).These results were more evident in the hippocampus than the frontal cortex. n‐3DPA/ARA ratio (indicator of inflammatory status) was significantly higher in APOE4 women control compared to AD in both the hippocampus and frontal cortex (P‐disease*sex*APOE = 0.028 and <0.001 respectively). Similar trends were observed for EPA/ARA ratio. There was no impact of sex or APOE on BRAAK stage.

Conclusion

APOE4 women with AD show a pro‐inflammatory brain fatty acid profile compared to controls, with increased n‐6 PUFAs (ARA and DPA) and reduced n‐3DPA/ARA ratios. Further extraction and analysis of fatty acids‐derived oxylipins and SPMs will be carried out.
High cholesterol levels promotes TNF‐α‐dependent necroptosis in Alzheimer’s disease
Authors: Calaf Xenia Abadin , Dios Cristina , Roca Vicente , Trullas Ramon , Colell Anna
Published: December 2023

Background

Necroptosis has been reported in post‐mortem Alzheimer’s disease (AD) brains, but still, the events that trigger or regulate this type of inflammatory cell death in AD are not fully known. Oxidative stress may be determinant as to whether a cell initiates necroptosis; Therefore, it is, likely that mitochondrial dysfunction, observed in the early stages of AD, might favor cells to undergo necroptosis. Previous studies from our group have shown that high intracellular cholesterol levels deplete the mitochondrial pool of GSH, thus sensitizing neurons against amyloid‐beta (Ab)‐induced mitochondrial oxidative stress. The present study is aimed to evaluate whether cholesterol can regulate the necroptotic pathway using both APP‐PSEN1 mice that overexpress the cholesterol‐related transcription factor SREBF2 and cholesterol‐enriched SH‐SY5Y cells.

Method

Cholesterol enrichment was assessed by incubating the cells with soluble cholesterol:methyl‐cyclodextrin complex (50 mg/ml) for 1 h followed by 4 h recovery. To induce necroptosis, cells were treated with TLQ [TNFa (10 ng/ml) plus the SMAC mimetic (LCL‐161, 10 mM) and the pan‐caspase inhibitor qVD‐OPH (10 mM)] for 24 h.

Results

Brains from APP‐PSEN1‐SREBF2 mice show up‐regulated expression of the necroptosis‐related proteins RIPK3 and MLKL, which together with RIPK1 accumulated in the urea‐soluble protein fraction, indicative of necrosome assembly. Moreover, western blot analyses of brain extracts from triple transgenic mice also showed high levels of c‐FLIP, the natural inhibitor of caspase‐8, further pointing to a cholesterol‐regulated engagement of the necroptotic pathway. In SH‐SY5Y cells, cholesterol enrichment resulted in enhanced cell death after exposure to TLQ, which was prevented by RIPK1 and RIPK3 inhibitors (Necrostatin and GSK’872, respectively). Similar protection against TLQ‐induced necroptosis was achieved when mitochondrial GSH levels were recovered by GSH ethyl ester. Intriguingly, cholesterol also regulated the intracellular localization of RIPK3 and MLKL. Confocal microscopy showed an increased presence of nuclear RIPK3 and MLKL in cholesterol‐enriched cells, recently described as a requirement for the subsequent necrosome formation in the cytosol.

Conclusion

Overall, these findings indicate that high intracellular cholesterol levels compromise neuronal viability, promoting oxidative stress and subsequent necroptosis, a pro‐inflammatory type of cell death, which ultimately may contribute to chronic neuroinflammation in AD.
Lower serum carotenoid levels are associated with incident cognitive decline independent of traditional risk factors in a prospective study of older men from Northern Ireland
Authors: McKay Gareth J , Linden Gerry , Patterson Christopher , Passmore Anthony Peter , McEvoy Claire T , Woodside Jayne V , Holmes Clive , McGuinness Bernadette
Published: December 2023

Background

Nutritional influences, and antioxidant status in particular, have been implicated in the aetiology of cognitive decline. This study investigated the neuroprotective effects of serum antioxidants in a prospective cohort of older men to identify associations with cognitive outcomes, independent of traditional risk factors.

Method

This cohort study included 873 Northern Irish men nested within PRIME (Prospective Epidemiological Study of Myocardial Infarction) who were followed‐up for at least 15 years. Mini Mental State Examination (MMSE) was carried out at baseline. The Addenbrooke’s Cognitive Examination‐R and MMSE were carried out at follow‐up. A consensus diagnosis of normal cognition for age, mild cognitive impairment (MCI) or dementia was made using accepted clinical criteria. Serum concentrations of retinol, two forms of vitamin E (α‐ and ϒ‐tocopherol) and six carotenoids measured from baseline samples were quantified by high‐performance liquid chromatography and assessed by multiple logistic regression analyses.

Result

The case definition included the 163 men characterised with MCI and 46 men with dementia; 664 participants were considered cognitively normal controls (Table 1). In unadjusted analyses, serum levels of the carotenoids α‐carotene, β‐carotene, lycopene and β‐cryptoxanthin were significantly lower in MCI/dementia cases than controls, in contrast to ϒ‐tocopherol, which was significantly higher (Table 2). Following adjustment for traditional risk factors including height, APOε4 genotype, diastolic blood pressure, smoking status and the presence of (pre)diabetes or depression, the effect size of those carotenoids significant in the unadjusted analysis was attenuated somewhat; only α‐carotene remained significantly associated with MCI/dementia (odds ratio = 0.55; confidence interval: 0.31‐0.99; Table 2).

Conclusion

Our data implicates lower levels of serum carotenoids as potential early biomarkers of MCI/ dementia before overt manifestation of symptoms, independent of traditional risk factors. These findings are consistent with hypotheses supportive of a neuroprotective role of dietary antioxidants and corroborate previous associations of higher serum carotenoid levels with better cognition in aging subjects. There is emerging evidence that carotenoids, through their potent antioxidant and anti‐inflammatory properties, may positively impact cognitive function. Limiting cognitive decline through lifestyle, exercise, and a higher carotenoid intake, may prove beneficial.
Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR‐1707 in healthy adult subjects: two randomized, double‐blind, phase 1 studies
Authors: Hu Wei , Shakib Sepehr , Williams Jasmine , Fan Yuru , Zhang Qin , Qin Huiling , Wu Juan , Zhang Xuan , Liu Yueyue , Zhou Renpeng , Yang Yaru , Zhang Qian , Ye Zi , Qiu Hongyan , Ma Jingyue , Zhu Mengyuan , Feng Sheng , Fei Yue , Li Na , Cui Xiaojing , Dong Fangli , Wang Tao
Published: December 2023

Background

SHR‐1707 is a novel humanized anti‐Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques and to promote the microglial phagocytosis of Aβ. Preclinical studies in 5xFAD transgenic mice showed that SHR‐1707 reduced brain Aβ deposition and ameliorated memory deficits. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR‐1707 in healthy adult subjects.

Method

Two randomized, double‐blind, single‐ascending‐dose, phase 1 studies were conducted in China (Study CHN; NCT04973189) and Australia (Study AUS; NCT04745104). Study CHN consisted of 2 parts. In part 1, eligible healthy young adults (18‐45 years) were sequentially randomized 8:2 to receive SHR‐1707 (5 cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in part 2, elderly subjects (55‐80 years) were randomized 8:4 to receive SHR‐1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across 3 dosing cohorts (2, 20, and 60 mg/kg).

Result

62 (part 1/2, n = 50/12; mean age, 27.0/57.2 years) and 30 subjects (mean age, 26.1 years) were treated in Study CHN and Study AUS respectively. In Study CHN, across all dose levels, all TRAEs were mild in severity, with the most common being laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR‐1707/placebo); the most common TRAEs with SHR‐1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR‐1707 increased in a slightly greater than dose‐proportional manner over the dose range of 2‐60 mg/kg in young adults; there was a dose‐dependent increase in plasma Aβ42 concentration following SHR‐1707 administration compared with the placebo group. The safety and PK/PD profiles of SHR‐1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety and PK/PD of SHR‐1707 was observed.

Conclusion

A single intravenous dose of SHR‐1707 at 2‐60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK/PD profiles are supportive of further clinical development.
An OMICS‐based analytical framework to identify metabolic predictors of the cognitive response to a multimodal intervention: preliminary findings from the PENSA Study
Authors: Soldevila‐Domenech Natalia , Wada Rin , Ruiz‐Colom Anna , Turrisi Federica , Forcano Laura , Bodinier Barbara , Grau‐Rivera Oriol , Pizarro Nieves , Chadeau‐Hyam Marc , Molinuevo Jose Luis , Torre Rafael ,   PENSA Study Group
Published: December 2023

Background

Not all individuals may respond to a cognitive decline preventive intervention. However, the low frequency of cognitive assessments during short‐lasting interventions hampers the study of the heterogeneity of treatment effects (HTE). We have recently developed and validated an innovative method for remote monthly monitoring of executive functions, which leverages the performance indicators from cognitive training games (CTG) (Figure 1). Here, we aimed to examine the HTE to a multimodal intervention using this CTG measure and to identify which baseline glycaemic, lipidic, and inflammatory factors are associated with the cognitive response profiles.

Methods

We included N = 98 individuals (65.3% females; 67.2 ±4.6 years) APOE‐ɛ4 carriers with Subjective Cognitive Decline who had completed eight months of the PENSA Study multimodal intervention on January 2023. We analysed P = 62 baseline exposures that included: anthropometric factors, biochemical parameters, endocannabinoids, and plasma metabolites of the tryptophan and glutamine metabolism. First, we examined the HTE with the CTG measure as the outcome (6 repeated measures/subject) using growth mixture models. Second, we assessed the partial correlations between exposures using graphical LASSO with stability selection. Finally, we identified the most contributing predictors to the cognitive response profiles using stability selection‐based LASSO multinomial regression, fit on 500 random 80% subsamples of the data using the R package ‘sharp’.

Results

We identified and labelled three different cognitive response trajectories: ‘average respondents’ (75.6%), ‘super respondents’ (16.3%), and ‘non‐respondents’ (8.2%) (Figure 2A). The network of exposures showed higher intra‐family than inter‐family correlations (Figure 2B). Finally, four out of 62 exposures were identified as stable predictors of the cognitive response profiles (Figure 2C). Compared to ‘average respondents’ the ‘super‐respondents’ and ‘non‐respondents’ presented higher carnitine and serotonin concentrations. However, fasting plasma glucose and total cholesterol were lower in ‘super‐respondents’ (OR = 0.63 and OR = 0.69) and higher in ‘non‐respondents’ (OR = 6.07 and OR = 2.40).

Conclusions

This study shows that not all individuals at high risk of Alzheimer’s disease respond to an intensive lifestyle‐based multimodal intervention, and that baseline cholesterol and glycaemic homeostasis could determine the success of preventive interventions for cognitive decline. Further cholesterol‐ and glycaemic‐related metabolites should be analysed to better understand the underlying mechanisms of these findings.