bluuebunny/crossref_metadata_2025 huggingface dataset:
The detrimental effects of apathy on cognition, frailty and quality of life
Authors: Soo See Ann , Leow Yi Jin , Lee Faith Phemie Hui En , Ghildiyal Smriti , Koh Chen Ling , Kandiah Nagaendran
Published: December 2023

Background

Apathy is defined as the lack of motivation and has been found to be associated with incident dementia in western populations (Dalen, 2018). Little is known about the impact of apathy in Asians. Apathy is a prevalent behavioural symptom of pre dementia and current literature shows that apathy increases the risk of dementia (Bock, 2020). Apathy is also linked to an increased risk of frailty(Ayers, 2018) and found to impair executive function and processing speed(Lohner, 2017). We aim to evaluate the association of apathy with cognitive function, frailty and lifestyle factors in a pre‐dementia community population in Singapore.

Method

We recruited 534 participants from the community who completed a detailed neuropsychological assessment. Apathy was measured using the mild behavioural impairment checklist (MBI‐C). To test for the association of apathy with the different variables, we performed a multiple generalized linear model controlling for covariates age, sex and education.

Result

The study population included 186 participants with subjective cognitive decline and 348 mild cognitive impairment participants from Dementia Research Centre (Singapore). Mean age of the cohort was 62.55, SD = 9.55, mean education years was 13.97, SD = 3.45 and majority were women (57.1%). The prevalence of apathy among our cohort was 23.5%. Compared to participants without apathy, those with apathy had poorer cognitive scores in processing speed (test of coding) (β = ‐4.60, p<0.001), executive function (colour trails 2) (β = 9.71, p = 0.020), episodic memory on the RAVLT Delayed (β = ‐0.738, p = 0.026), RCFT Delayed (β = ‐1.941, p = 0.009) and FCSRT delayed (β = ‐0.616, p = 0.030). Participants with apathy were also more frail (β = 0.316, p<0.001) on the Fried Phenotype frailty assessment test and had poorer quality of life (β = ‐12.49, p<0.001), had lower levels of physical activity (β = 0.163, p = 0.017), and had poorer sleep (β = 2.25, p<0.001).

Conclusion

Apathy is associated with worse cognitive performance, higher frailty, lower physical performance and poorer sleep in an Asian pre‐dementia community cohort. Screening for apathy and appropriate early intervention could reduce incidence of dementia and frailty.
What do elevated cerebrospinal fluid p‐tau levels signify in the absence of beta‐amyloid pathology?
Authors: Wisse Laura , Binette Alexa Pichet , Strandberg Olof , Palmqvist Sebastian , Stomrud Erik , Janelidze Shorena , Mattsson‐Carlgren Niklas , Blennow Kaj , Hansson Oskar
Published: December 2023

Background

The introduction of the A/T/(N) (β‐amyloid/tau/neurodegeneration) framework has revealed an A‐T+ (β‐amyloid‐negative/tau‐positive) group which has been named suspected non‐Alzheimer’s pathophysiology. Cerebrospinal fluid (CSF) markers are often utilized to divide individuals in the A and T categories, but it is unclear what elevated CSF p‐tau levels signify in the absence of β‐amyloid. We aim to better understand A‐T+ as defined by CSF markers in two independent samples of cognitively unimpaired and impaired individuals by assessing baseline and longitudinal change in CSF, magnetic resonance (MRI), positron emission tomography (PET) and cognition measures.

Method

Cognitively normal (CN) and Mild Cognitive Impairment subjects from BioFINDER‐1 and 2 were included. A status was based on two CSF measures of β‐amyloid 42/40 (Aβ42/40) where A‐ individuals had to be negative on both measures using previously established cut offs. T status was determined by the 75th, 80th and 85th percentile of A‐ CN subjects for Roche Elecsys p‐tau181 (Table 1). Analyses of covariance and linear mixed models were performed to assess baseline and change differences in CSF (p‐tau181, Aβ42/40 ratio, neurofilament light (NFL)), MRI (hippocampal volume, entorhinal cortex and temporal meta‐region of interest thickness), cognition (modified Preclinical Alzheimer’s Cognitive Composite and delayed recall), and PET measures (entorhinal cortex Tau‐PET and early and global Alzheimer’s Disease composite β‐amyloid‐PET uptake) over 8 years (10 for cognition) for BioFINDER‐1 and 4 years for BioFINDER‐2.

Result

In A‐T+ versus A‐T‐, higher baseline NFL levels were found. No other baseline differences were found except for p‐tau181 and Aβ42/40 ratio by design. A‐T+ did not show significant change compared to A‐T‐ on any measure. Using different cut offs for p‐tau181 did not notably change the results. Comparisons with the A+ groups are shown in Figures 1‐2.

Conclusion

Our results indicate that A‐T+ as determined by p‐tau181 does not seem to be clinically meaningful as this group shows no decline on any of the biomarkers or cognitive measures over several years. The high NFL levels in the A‐T+ group suggest the presence of a latent factor that affects both NFL and p‐tau levels. Analyses will be repeated with other p‐tau isotopes and assays.
Utilization and future of biomarkers in biofluid as outcome measures in clinical trials for Alzheimer’s disease: a systematic review
Authors: Oosthoek Marlies , Vermunt Lisa , de Wilde Arno , Bongers Bram , Antwi‐Berko Daniel , Scheltens Philip , Van Bokhoven Pieter , Vijverberg Everard G.B. , Teunissen Charlotte E.
Published: December 2023

Background

In recent years, the availability of biofluid markers in Alzheimer’s disease (AD) has increased substantially, but it is unclear to what extend these are applied to support drug development. Therefore, we provide an overview of biofluid biomarker use within trials.

Method

To identify how fluid biomarkers are used in clinical trials, we performed a search (8‐FEB‐2022) on www.clinicaltrials.gov, using the search term ‘Alzheimer’s disease’, and selected trials aimed at disease modification starting from 1‐JAN‐2017 to 1‐JAN‐2022. Biofluid markers and their purpose in each trial were described. Results are summarized by trial phase, target class, and endpoint information.

Result

We identified 186 trials of which 44% used biofluid markers. 15% of phase 1 trials, 15% of phase 2 trials, and 6% of phase 3 and 4 trials employ fluid biomarkers as primary outcome (Figure 1). Blood and CSF biomarkers were used equally frequent. CSF biomarkers for Aβ, Tau, and other biomarkers were employed in 21%, 25%, and 16% of the 186 trials, respectively. Blood biomarkers for Aβ, Tau, and other biomarkers were used in 14%, 13%, and 23% of the trials, respectively. Moving further in the drug development phases, contribution of classic AD biomarkers increased, especially in CSF. Overall, a combination of Aβ, Tau and other biomarkers was used most frequent. 25% of the trials use biofluid target engagement markers. Target engagement marker use is most prominent in amyloid and tau targeting drugs. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis, gut‐brain axis targeting drugs.

Conclusion

There exists a need for new fluid biomarkers, to reflect pathology which can be used in certain target classes where there currently is a lack of fluid biomarkers. To support future use biofluid markers as surrogate outcomes, research into the specific pathological processes they reflect and their correlation with cognition is warranted. This can pave the way into implementation of surrogacy biomarkers in AD clinical trials.
Investigation of inflammation in Lewy body dementia: a scoping review
Authors: Loveland Paula M , Yu Jenny , Churilov Leonid , Yassi Nawaf , Watson Rosie
Published: December 2023

Background

Inflammatory mechanisms are increasingly recognized as part of the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Advances in analytical techniques using in vivo and postmortem samples have been applied to address questions of key mechanisms and relevance to clinical manifestations. Our primary objective was to review methods used to investigate inflammation in LBD (dementia with Lewy bodies and Parkinson’s disease dementia), and how these are applied to conceptualise inflammation. Our secondary objective was to identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease, and compared to related neurodegenerative disease, in particular AD and PD.

Method

A scoping review was performed by identifying relevant human studies that investigated inflammation in LBD. The major electronic databases MEDLINE, Embase, Web of Science, and PSYCHInfo were searched. Two authors performed abstract screening and full text review.

Result

Of 1970 results screened, 65 studies were included. Twenty‐nine studies analysed postmortem brain tissue and 35 included living subjects. Largely cross‐sectional data were available, although 2 longitudinal clinical studies of prodromal Lewy body disease were noted. Analysis of biofluid (blood and cerebrospinal fluid) was the most common in vivo method used (n = 31) and 3 studies investigated LBD genetics. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, lymphocytes), and molecules linked to inflammation (e.g., cytokines). Results of included studies supported innate and adaptive immune system contribution to inflammation associated with Lewy body pathology and clinical features of the disease. Different signals in early and late‐stage disease, with possible late immune senescence including dystrophic microglia and altered adaptive immunity, were distinct from Alzheimer’s disease. The strength of these associations is limited by the varying methodologies, small study sizes and cross‐sectional nature of data.

Conclusion

Current investigation of inflammation in LBD utilises substrate collected from early to late‐stage disease. Strengths and limitations of the range of analytical techniques used must be considered when forming conclusions. Longitudinal data that informs associations with clinical and other biomarker outcomes is needed to improve understanding of inflammatory activity over the disease course of LBD. This could identify markers of disease activity and therapeutic targets.
Sex‐specific effects of Ceramides on White Matter Hyperintensities in the Rhineland Study
Authors: Landstra Elvire Nadieh , Lohner Valerie , Breteler Monique M.B.
Published: December 2023

Background

The frequency of white matter hyperintensities (WMH), which are considered to reflect cerebral small vessel disease, shows substantial sex differences. The biology underlying this remains unknown. Ceramides (CERs) are important sphingolipids, have been associated with WMH, and might play a key role in WMH pathogenesis. Of note, their plasma levels reportedly differ between men and women. Here, we examined sex‐specific effects of CER concentrations, CER ratios and the CER score on WMH load.

Method

The analysis is based on the first 3,284 participants aged 30‐95 years of the community‐based Rhineland Study with brain MRI and sphingolipid data available. Twelve CERs were measured in plasma on the Metabolon Complex Lipids Platform, while WMH were automatically segmented on T1, T2 and FLAIR images. Using multivariable linear regression, we examined the association of scaled absolute (nmol) and relative (mol%) CER concentrations, 6 CER ratios and a CER score with logit‐transformed WMH load. In model 1, we adjusted for age, sex and age‐squared, while model 2 was additionally adjusted for body mass index (BMI), smoking and use of lipid‐lowering medication. Additionally, we included a sex‐interaction term and performed a sex‐stratified analysis where it was significant. P‐values were FDR adjusted.

Result

Mean age of participants was 54±14 years, 57% were women. Multiple CERs (CER18:0, CER20:0, %CER18:0), CER ratios (CER18:0/16:0, CER18:0/24:0, CER20:0/24:0, CER22:0/24:0), and the CER score were associated with increased WMH load independent of sex and age. The absolute concentration of almost all CERs and some ratios were more strongly associated with WMH in women compared to men (Figure 1). Associations were largely independent of body‐mass index, use of lipid‐lowering medication and smoking.

Conclusion

We showed novel associations of CERs, CER ratios and the CER score with WMH, and found a significant sex‐interaction for the majority of these associations. Thus, our results suggest that CERs could be important in understanding sex‐specific mechanisms of WMH and possibly explain the higher WMH burden in women.
Clinical Characteristics of a PSEN1 Variant in the Argentine Cohort of the Dominantly Inherited Alzheimer Network
Authors: Clarens Maria Florencia , Mendez Patricio Chrem , Tapajoz Fernanda , Martinez Carlos , Helou Belén , Surace Ezequiel , Crivelli Lucía , Romero Daniela , Vigo Gabriela , Allegri Ricardo Francisco
Published: December 2023

Background

In recent years, there has been an increase in the number of case reports of families with autosomal dominant Alzheimer’s disease (ADAD) in Latin America (LA). Nevertheless, little is known about the clinical phenotypes and demographic characteristics of mutations in each country. Past literature has proved that variants in LA have different and unique characteristics than those reported in Asia, North America, and Europe. Clinical heterogeneity in ADAD supports the need to study clinical phenotypes, especially in preclinical stages, to develop cognitive and clinical markers of the disease.

We aimed to describe clinical and cognitive characteristics at baseline assessment of an Argentina PSEN1 p.M146L family enrolled at DIAN.

Method

Fifteen Dian Participants living in Buenos Aires and its suburbs and in Taco Pozo, a rural and isolated community from the Province of Salta, positive for the PSEN1 p.M146L mutation, were recruited. DNA was obtained from peripheral blood leukocytes according to standard protocols. In addition, exon 5 of the PSEN1 gene was PCR‐amplified, and Sanger sequencing was performed. NACC Uniform Data Set clinical assessment, including the 2.0 UDS Neuropsychological Battery, was administered. Two groups were used to compare cognitive data: Patients with CDR:0 (n:10) and patients with CDR>0 (n:5).

Result

The mean age at symptom onset reported in this cohort was 42,90 (SD: 4,62). Significant differences were found in several cognitive measures: Logical Memory Immediate, TMT B and Digit Backward (<0,001); MMSE, Category Fluency Animals, TMT A and Digit Symbol(<0,05). In neurological signs, paraplegia was reported in one of the patients.

Conclusion

As expected, differences in neuropsychological tests showed a prevalence of memory deficits, however, dysexecutive symptoms were also present for this mutation. Paraplegia in PSEN1 p.M146L has not been reported in the literature so far. Ongoing longitudinal work will be important in tracking changes in this cohort. Other characteristics, proper of underrepresented groups, such as socioeconomic status, education, race, and ethnicity, deserve appropriate follow‐up. Future studies are planned, comparing urban and rural populations in this cohort with the same mutation.
Neurofilament Light Chain modifies the association of olfactory dysfunction with cognitive decline: a 12‐year follow‐up of the Shanghai Aging Study
Authors: Xiao Zhenxu , Wu Wanqing , Ma Xiaoxi , Wu Jie , Liang Xiaoniu , Zhao Qianhua , Ding Ding
Published: December 2023

Background

Olfactory dysfunction has been reported for its association with cognitive impairment and incident dementia. However, the underlying role of neurodegeneration in this relationship is not fully understood.

Method

This prospective cohort study included participants from the Shanghai Aging Study (SAS) who were 60 years or older and diagnosed as dementia‐free at baseline and completed at least one follow‐up interview between 2010 and 2022. At baseline, olfactory identification function was assessed by the 12‐item Sniffin’ Sticks Smell test (SSST‐12). Olfactory dysfunction was defined as SSST‐12 < 7, 6, and 5 in three age groups of participants with (age < 70, 70 ≤ age < 80, and age ≥ 80), respectively, according to previously reported normative data of olfaction in the SAS. Baseline blood Neurofilament Light Chain (NfL) was quantified using the ultra‐sensitive Single Molecular Array technology (Quanterix), and dichotomized into low and high levels according to the median concentration. Multiple cognitive function assessments were administered by the Mini‐mental State Examination (MMSE) at baseline and follow‐ups. We used the linear mixed‐effect model to fit the MMSE trajectories in participants with and without olfactory dysfunction adjusting for baseline age, sex, education year, smoking, and APOE ε4, with person‐specific MMSE intercept and slope. Stratified analysis was conducted in participants with low and high NfL.

Result

Among 1125 participants included in this study, 296 were defined as having olfactory dysfunction at baseline. Less education, higher proportion of APOE ε4 allele, and lower baseline and follow‐up MMSE scores were observed in participants with olfactory dysfunction (Table 1). During the median 9.4 years follow‐up, participants with olfactory dysfunction at baseline evidenced a faster MMSE decline compared with those without olfactory dysfunction (b [95% CI]: ‐0.08 [‐0.15, ‐0.02], P = 0.02) (Figure 1). Such association remained statistically significant (‐0.18 [‐0.31, ‐0.06], P = 0.005) in the subgroup with high NfL, but not in the subgroup with low NfL (0.004 [‐0.07, 0.07], P = 0.92) (Figure 2).

Conclusion

Blood NfL may modify the association of olfactory dysfunction with long‐term cognitive decline in community‐dwelling older adults. In individuals with high potential neurodegeneration, olfactory dysfunction may be an independent indicator of future cognitive deterioration.
Comparison of brain volume estimation via cerebral computed tomography and magnetic resonance imaging
Authors: Schmieschek Maximilian H. T. , Richter Nils , Gramespacher Hannes , Dronse Julian , Onur Oezguer A.
Published: December 2023

Background

In clinical routine, cerebral computed tomography (cCT) is easily accessible and more commonly used than brain magnetic resonance imaging (cMRI). However, to the best of our knowledge a fully automated, validated regional specific volume estimation tool is lacking. Therefore, the aim of this study was to investigate the association between tissue classification for gray matter of both modalities.

Method

Brain imaging segmentations of cCT and structural MRI of 37 healthy controls and 20 patients with mild cognitive impairment due to Alzheimer’s disease were performed. The intensity and voxel count of normalized gray matter maps (MNI) in regions of interest using the Automated Anatomical Labelling Atlas (AAL3) were computed and compared between cCT and cMRI in both cohorts.

Result

Brain Volume, measured by intensity and voxel count of gray matter, is associated between cortical regions acquired by cCT and cMRI. Although correlation coefficients varied between different brain areas, cortical compared to subcortical regions showed a relatively strong correlation.

Conclusion

The evaluation of brain atrophy using segmented brain images acquired by cCT may be a simple, cost‐effective, and valuable addition to the clinical workflow, particularly in the context of socioeconomic and health disparities.
Education as Risk Factor of Mild Cognitive Impairment ‐ the Role of the Gut Microbiome
Authors: Klee Matthias , Aho Velma T. E. , May Patrick , Krüger Rejko , Wilmes Paul , Leist Anja K.
Published: December 2023

Background

Research on social determinants of health has identified modifiable risk factors that contribute to an individual’s risk of developing dementia [1]. Individuals with mild cognitive impairment (MCI) present a group with highest potential of lifestyle interventions due to the risk of progressing to dementia [2]. The pathways from identified modifiable risk factors for dementia such as education have not been clarified, however understanding the relationships between risk factors and MCI could help identify mechanisms for intervention and reducing risk of progressing to dementia. Previous findings found taxonomic differences in dementia and MCI patients, and further education linked to indicators of gut dysbiosis [3–5]. We sought to test the possibly mediating role of gut dysbiosis and taxonomic differences in the relationship between modifiable risk factors and MCI, independent of genetic risk for developing dementia.

Method

Gut microbiome composition was ascertained with 16S rRNA gene amplicon sequencing. MCI classification was based on MoCA performance. Educational attainment in years was grouped. Mediation analysis [6] was conducted decomposing direct and indirect effects of educational attainment on MCI mediated by markers of dysbiosis (Chao1, Inverse Simpson, Shannon) while controlling for polygenic risk of Alzheimer’s Disease, Lewy Body Dementia and Parkinson’s Disease to account for different etiologic neurodegenerative pathways manifesting as MCI. Taxonomic differences across education groups were further tested (ANCOM‐BC, DESeq2) and PAM clustering based on relative abundance at Genus level was conducted to explore underlying signatures.

Result

After exclusion of participants below age 50, or with missing data, n = 256 participants (n = 58 with MCI) of the Luxembourg Parkinson’s Study without Parkinson’s disease were eligible for analysis (M[SD] Age = 64.7[8.3] years). Higher vs lower educational attainment had a controlled direct effect (CDE) = 0.35 (P<.01) on MCI, Chao1 included as mediator. We did not find significant indirect effects via any indicator of dysbiosis. Clusters with lower abundance of Bacteroides relative to Prevotella and Ruminococcus were at higher risk of MCI.

Conclusion

Our findings indicate direct effects of education not mediated by markers of dysbiosis. Taxonomic analysis suggests a signature linked to lower risk of dementia in higher educated individuals.
Grey matter alterations associated with the phenomenology of visual hallucinations in Lewy Body Disease
Authors: D'Antonio Fabrizia , Teghil Alice , Boccia Maddalena , Suppa Antonio , Fabbrini Andrea , Canevelli Marco , Fiorelli Marco , Caramia Francesca , Bruno Giuseppe , Ferracuti Stefano , Guariglia Cecilia , Aarsland Dag , Ffytche Dominic H
Published: December 2023

Background

Visual hallucinations (VH) phenomenology in Lewy Body Disease (LBD) is heterogenous, including minor phenomena (passage, presence, illusions) and complex hallucinations. Neural substrates and mechanisms involved are still unclear. Here we investigated grey matter (GM) alterations associated with minor (MVH) and complex VH (CVH).

Method

LBD patients (n = 28) with VH and Healthy controls (HC‐n = 20) underwent MRI. We administered the North East Visual Hallucinations Interview (NEVHI), a semi‐structured interview assessing the phenomenology of VH, their duration and frequency. VH were clustered in MVH and CVH and treated as a patient’s trait. First we compared GM volume of LBD and HC. Then, multiple regressions were performed to disclose alterations associated with the duration, frequency and severity of MVH and CVH, including the opposite VH domain, total intracranial volume (TIV) and MMSE as nuisance regressors.

Result

We found a decreased GM volume in the bilateral fusiform gyrus (FG), in the left posterior cingulate and in the right inferior frontal gyrus in LBD compared to HC. We also found that CVH duration was negatively associated with GM volume in the left FG. We did not find any association with MVH phenomenology.

Conclusion

LBD patients showed GM alterations in ventral‐visual‐stream, default‐mode‐network and inhibitory regions compared to HC. Although the LBD versus HC comparison is not specific to VH, the regions identified have been implicated in VH in previous studies suggesting they may represent structural hallmarks of functional alterations in networks contributing to VH. When the association with VH phenomenology was tested, we did not find GM alterations associated with MVH. It is likely that these phenomena might be not associated with structural alterations but with functional alterations within visual networks. CVH were instead associated with decreased GM in FG. The atrophy in the FG may lead to a spontaneous activation of this region that sustain CVH duration, accounting for VH content (D’Antonio et al., 2022). These alterations may represent the predisposing condition to VH in LBD. According to the hodotopic model, VH phenomenology may help identify brain regions implicated and might reveal the substrates for cortical region/network dysfunctions occurring during VH state (ffytche et al., 2008).
Brain dynamics during mnemonic discrimination in preclinical and prodromal Alzheimer’s disease
Authors: Gellersen Helena M , Baumeister Hannah , Heneka Michael T. , Schneider Anja , Fliessbach Klaus , Spottke Annika , Teipel Stefan , Wiltfang Jens , Jessen Frank , Düzel Emrah , Berron David
Published: December 2023

Background

Mnemonic discrimination of similar lures and targets is emerging as a promising marker of subtle memory decline in early Alzheimer’s disease (AD) due to its reliance on regions most affected by AD pathology. Tau pathology initially targets medial temporal lobe (MTL) regions in an anterior‐temporal (AT) brain network, which is preferentially involved in object processing, before it can be found in the posterior‐medial (PM) network associated with scene processing. Tests of object and scene mnemonic discrimination may therefore serve as behavioural indicators of the functional integrity of AT and PM regions, respectively. We investigated behavioural and neural changes in mnemonic discrimination across the AD spectrum.

Method

201 DELCODE cohort participants underwent fMRI scanning during an object‐scene mnemonic discrimination task at four time points from baseline to three‐year follow‐up. At baseline, participants were split by diagnostic group (cognitively unimpaired = CU, subjective cognitive decline = SCD, mild cognitive impairment = MCI, dementia of the Alzheimer’s type = DAT; Table 1). We identified brain regions showing lower activity to repeated targets but not similar lures, indicative of successful pattern separation of overlapping memory representations.

Result

These findings present cross‐sectional baseline data. Behavioural data showed a main effect of group but no group by category (objects, scenes) interaction. CUs and SCDs outperformed patients across domains and CUs scored higher than SCDs only in scene discrimination. Amyloid positive and negative CUs and SCDs did not differ in performance. Successful mnemonic discrimination engaged hippocampus, parahippocampal cortex, precuneus, angular gyrus, and inferior frontal regions for both objects and scenes. Correct object discrimination was additionally associated with amygdala and transentorhinal cortical activity. Reduced brain activation in regions of the anterior‐temporal and posterior‐medial network during successful object and scene mnemonic discrimination, respectively, was found in patient groups (MCI+DAT) compared to cognitively normal (CU+SCD) older adults.

Conclusion

Our findings lend further support to the utility of mnemonic discrimination as indicator of memory impairment in early AD. Object and scene tasks engage partially dissociable brain networks and individuals with cognitive impairment show reduced neural pattern separation effects. These findings lay the groundwork for future longitudinal analyses to track these changes based on clinical and biomarker status.
Virtual Cognitive Stimulation Therapy for dementia: The development, feasibility and initial outcomes of a global framework
Authors: Spector Aimee E , Perkins Luke , Fisher Emily , Felstead Cerne , Wong Gloria HY , Dai Ruizhi , Vaitheswaran Sridhar , Natarajan Nirupama , Venkatesan Shreenila , Mograbi Daniel C. , Ferri Cleusa P , Santos Raquel L , Stott Joshua
Published: December 2023

Background

Group Cognitive Stimulation Therapy (CST) is the most widely implemented post‐diagnostic intervention for dementia in the UK (Perkins et al, 2022). This presentation describes the development and initial testing of a virtual group Cognitive Stimulation Therapy (vCST) programme for people with dementia, developed as a result of services moving online during the COVID‐19 pandemic and a general increase in teletherapies.

Method

The vCST protocol was developed using the existing group CST manual, through stakeholder consultation with people living with dementia, caregivers, CST group facilitators and dementia service managers. This protocol was then field‐tested with ten groups of people living with dementia in the Brazil, China (Hong Kong), India, Ireland and the UK, and feedback on the protocol was gathered from 14 facilitators. Finally, the vCST programme was delivered to people with dementia in India (n = 15), Brazil (n = 44) and the UK (n = 24).

Results

Field testing in five countries indicated acceptability to group facilitators and participants. Feedback from these groups was used to refine the developed protocol. Initial qualitative findings from the UK study and quantitative findings from India, Brazil and the UK will be presented, demonstrating the feasibility, acceptability and perceived benefits of these virtual groups.

Conclusion

The final vCST protocol is proposed, including session materials for delivery of CST over video conferencing and a framework for offering CST virtually in global settings. vCST is an acceptable online intervention for many people living with dementia globally. We recommend that it is offered to those unable to access traditional in‐person CST, for example for health reasons and lack of transport or COVID‐19 restrictions. Many services have indicated plans to continue vCST long‐term, hence further research is needed to explore if participant outcomes are comparable to in‐person CST groups.

Reference: Perkins, L., Fisher, E., Felstead, C., Rooney, C., Wong, G. H., Dai, R., … & Spector, A. (2022). Delivering Cognitive Stimulation Therapy (CST) Virtually: Developing and Field‐Testing a New Framework. Clinical Interventions in Aging, 17, 97.
Brain‐age prediction and its associations with glial and synaptic CSF markers
Authors: Cumplido‐Mayoral Irene , Milà‐Alomà Marta , Falcon Carles , Cacciaglia Raffaele , Minguillon Carolina , Fauria Karine , Molinuevo Jose Luis , Kollmorgen Gwendlyn , Suridjan Ivonne , Wild Norbert , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Vilaplana Verónica , Gispert Juan Domingo
Published: December 2023

Background

MRI‐derived brain‐age prediction is a promising biomarker of biological brain aging. Accelerated brain aging has been found in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, no previous studies have investigated the relationship between specific pathophysiological pathways in AD and biological brain aging. Here, we studied whether glial activation and synaptic dysfunction are associated with biological brain aging in the earliest stages of the Alzheimer’s continuum.

Method

We included 418 cognitively unimpaired individuals (CU) from the ALFA+ study with available structural MRI, and CSF biomarkers of amyloid‐β (Aβ42/40) and tau pathology (p‐tau181), synaptic dysfunction (neurogranin, GAP43, SYT1, SNAP25), glial activation (sTREM2, YKL40, GFAP, interleukin‐6 and S100b) and α‐synuclein (Table 1). Aβ42/40, neurogranin and the glial activation biomarkers were measured using the Roche NeuroToolKit. We computed brain‐age delta as the difference between chronological and predicted brain‐age. The latter was estimated using a previously pretrained machine learning algorithm on cerebral morphological measurements on individuals from the UKBioBank cohort (N = 22.000). General linear modeling was used to test the associations between CSF biomarkers and brain‐age delta, adjusting by p‐tau, age, APOE status and sex. For the biomarkers whose associations were significant, we evaluated the interaction term “biomarker” × AT status while adjusting by age, APOE status and sex. AT staging was performed using pre‐established cut‐off values. We then used hippocampal volume as a marker of AD‐related neurodegeneration and repeated the same association studies with CSF biomarkers, adjusting by p‐tau, age, APOE status, sex and TIV.

Result

Brain‐age delta was negatively associated with CSF sTREM2 (Padjusted<0.001), meaning that younger‐appearing brains showed higher levels of this biomarker (Table 1). None of the other biomarkers survived multiple comparisons. Hippocampal volume was not significantly associated with any of the CSF biomarkers (Table 2). There was no significant interaction between AT status and CSF sTREM2 for brain‐age delta, nor for hippocampal volume.

Conclusion

These results showed that higher levels of CSF sTREM2 were associated with younger‐appearing brains in CU individuals independently of AT status, which might indicate a protective effect of this microglial phenotype in brain aging. This effect might not be AD‐related.
Relationship between white matter lesion coalescence and plasma cystatin C in an ethnically diverse population.
Authors: Sudre Carole H , James Sarah‐Naomi , Barnes Jo , Huang Felicia , Direk Kenan , Barkhof Frederik , Rolf Jäger H. , Chaturvedi Nishi , Hughes Alun D
Published: December 2023

Background

: Brain and kidney share anatomical similarities in terms of the small vessels serving their irrigation. Previous work have shown associations between markers of cerebral small vessel disease (CSVD) e.g. white matter hyperintensities (WMH) and markers of renal function e.g. cystatin C. Few studies have however investigated the relationship between renal function and more detailed descriptions of lesion shape and distribution

Method

768 individuals from the tri‐ethnic SABRE cohort underwent brain MRI including T1w and FLAIR sequences. WMH were automatically segmented and an overall measure of coalescence was derived from the lesion map ranging from 0 (only punctuate lesions) to 4 (high level of coalescence). Regional coalescence measures according to distance from the ventricles were further derived in 4 equidistant layers. Clinic blood samples were available for 731 individuals (45% female, mean age 71.3 (SD 6.4) years) including from 311 European; 172 African Caribbean; and 248 South Asian ethnicity. Blood measures include plasma cystatin C, a marker of glomerular filtration rate, white blood cell count (WBC) and HbA1c. Associations between cystatin C and coalescence score or lesion volume expressed as percentage of total intracranial volume were investigated using robust linear regression adjusting for age, ethnicity, sex, HbA1c and WBC; all factors known to be associated with cystatin C levels and WMH.

Result

Cystatin C was positively associated with male sex, WBC and HbA1c, and differed across ethnicities being highest in South Asians and lowest in African Caribbeans. After adjusting for potential confounders, cystatin C was positively associated with overall coalescence score (b = 0.026 [0.004;0.047], p = 0.018) despite unconvincing evidence of an association with overall lesion volume (b = 0.003 [‐0.0003; 0.007], p = 0.066). Associations between cystatin C and coalescence score were stronger in the South Asian group (b = 0.066 [0.027;0.105], p interaction = 0.001). Associations between cystatin C and coalescence score were similar across different layers.

Conclusion

Shape patterns of WMH, rather than overall WMH volume, may provide a more sensitive measure to assess the relationship with markers of small vessel disease in the kidneys.
Brain‐age mediates the association between modifiable risk factors and cognitive decline early in the AD continuum
Authors: Cumplido‐Mayoral Irene , Brugulat‐Serrat Anna , Sánchez‐Benavides Gonzalo , Escalante Armand González , Anastasi Federica , Milà‐Alomà Marta , Falcon Carles , Shekari Mahnaz , Cacciaglia Raffaele , Minguillon Carolina , Fauria Karine , Molinuevo Jose Luis , Suarez‐Calvet Marc , Vilaplana Verónica , Gispert Juan Domingo ,   for the ALFA study
Published: December 2023

Background

Neuroimaging‐derived brain‐age is a useful biomarker to study the brain’s biological aging process. Brain‐age has shown cross‐sectional associations with cognitive function and modifiable risk factors for dementia. We aimed to study, in cognitively unimpaired (CU) individuals, the mediating role of brain‐age in the association between modifiable risk factors and cognitive changes, and the impact of AD pathology on this role.

Method

We included 416 CU individuals from the ALFA+ study with available structural MRI, measurements of the global cognitive Preclinical Alzheimer’s Cognitive Composite (PACC) (370 individuals had a follow‐up PACC assessment 3.28±0.27 years later), and lifestyle and cardiovascular risk factors assessments. We computed brain‐age delta as the difference between chronological and predicted brain‐age using a previously pre‐trained machine learning algorithm on structural MRI data. Partial Least Squares Path Modeling (PLS‐PM) was employed to investigate the mediation effect of brain‐age delta between a computed latent variable from modifiable risk factors (cardiovascular, mental health and mood, metabolic/endocrine disease history, and alcohol consumption factors; Table 1) and a latent variable from longitudinal PACC. Statistical bias adjustment was performed to control for the confounding effects of age and sex by using multiple linear regression. The analysis was performed on the whole sample (ALL) and after stratification by amyloid‐β (Aβ) status. Participants were classified as amyloid‐β positive (Aβ+) if CSF Aβ42/40<0.071 (Milà‐Alomà et al, 2020). Significance of mediation was examined by 95% confidence interval bootstrap.

Result

The effect of risk factors (latent risk) on longitudinal cognition (latent cognition) was partially mediated by brain‐age delta only in Aβ+ individuals (57.286%) (Figure 1C). Higher latent risk was associated with older brain‐age delta (p = 0.003) and older brain‐age delta was associated with worse latent cognition (p = 0.007). Conversely, the indirect effect was not significant in ALL nor in Aβ‐ individuals, where brain‐age delta was not significantly associated with latent cognition (Figure 1A‐B). Still, higher latent risk was associated with older brain‐age delta (ALL: p<0.001; Aβ‐: p = 0.004) and associated with worse latent cognition (ALL: p = 0.012, Aβ‐: p = 0.001).

Conclusion

In CU individuals in the AD continuum, biological brain aging mediates the association between modifiable risk factors and cognitive decline.
Sleep disturbances, cortisol, and neuroimaging correlates among memory clinic patients
Authors: Sørensen Charlotte , Kåreholt Ingemar , Kalpouzos Grégoria , Udeh‐Momoh Chi T. , Holleman Jasper , Aspö Malin , Hagman Göran , Kivipelto Miia , Solomon Alina , Sindi Shireen
Published: December 2023

Background

Sleep disturbances are increasingly acknowledged as a preclinical marker for Alzheimer’s disease (AD), however, the mechanisms underlying the association between sleep disturbances and dementia remain unclear. Sleep disturbances may affect AD through brain morphology changes and vascular damage, as sleep disturbances are known to be linked with altered grey‐ and white‐matter integrity. Moreover, sleep and brain changes may be linked with cortisol levels. Sleep disturbances have been proposed to parallel cortisol dysregulation, and older individuals with preclinical AD have altered awakening cortisol, a feature that is intensified among people also suffering from sleep disturbances.

Method

The study is based on 146 memory clinic patients from the Karolinska University Hospital memory clinic (Sweden). Participants are in the age range 47‐86 years and diagnosed with either subjective cognitive impairment or mild cognitive impairment. Self‐reported sleep disturbances are measured by the Karolinska Sleep Questionnaire. Brain imaging (MRI or CT) was used to semi‐quantify brain atrophy using four visual rating scales: Medial Temporal Atrophy, Global Cortical Atrophy, Koedam (posterior brain atrophy) and Fazekas (white‐matter lesions) scales. Lastly, saliva cortisol has been sampled 6 times daily to measure diurnal cortisol patterns.

Result

Ordinal logistic regressions show significant associations between sleep disturbances and brain parameters. Insufficient sleep (OR = 1.30, p = 0.048) is associated with greater odds of white‐matter lesions, and apnea (OR = 1.26, p = 0.036) and snoring (OR = 1.38, p = 0.045) are associated with greater odds of posterior brain atrophy. Increased daytime sleepiness is associated with both reduced awakening cortisol (β = ‐0.03, p = 0.025) and a flattened cortisol curve (β = ‐0.04, p = 0.019). Apnea is associated with reduced awakening cortisol (β = ‐0.06, p = 0.013). However, cortisol was not found to significantly interact with sleep in predicting brain outcomes.

Conclusion

These results show that various sleep disturbance parameters (short sleep duration, apnea, and snoring) are associated with neuroimaging correlates, while daytime sleepiness and apnea are associated with markers of dysregulated cortisol patterns. The results suggest that neuroimaging correlates and cortisol measures may clarify the mechanisms underlying the associations between sleep disturbance and cognitive impairment, and the combination of objective sleep measures and neuroimaging markers in future studies may further reveal the mechanisms.
Implementation of MIND at Home Program for People Living with Dementia in Primary Care
Authors: Ciemins Elizabeth , Samus Quincy M
Published: December 2023

Background

As the U.S. population ages, the numbers of people living with dementia (PLWD) continues to grow. One way to improve care for PLWD is to work with their primary care practices to provide patient‐ and care partner‐centered, better quality of care at lower costs for their patients.

Method

We collaboratively implemented the MIND at Home Dementia Care Coordination Program into two large primary care clinics in two states, Iowa and California. The program pilot expanded the skills of existing primary care staff members to the level of Memory Care Coordinators (MCCs), who worked with larger primary care teams on combining the benefits of clinic‐based with home‐based services that support PLWD, their families, and care partners. The program targeted 150 PLWD for a 3‐month program implementation period. Program delivery included one home visit per month, a comprehensive needs assessment, and the subsequent development and implementation of an individualized care plan.

Result

We demonstrated the feasibility of implementing the MIND at Home program into primary care in a racially, ethnically, and geographically diverse population of PLWD to prepare for a larger study and provide qualitative and quantitative data on patient and provider acceptability of the program and early learnings about the program’s impact and barriers to implementation from the primary care practice perspective.

Conclusion

This pilot study provides important information by determining the specific needs of patients in community‐based primary care and how creating tailored dementia‐focused care plans might improve communication and collaboration with primary care providers and their teams thereby reducing unnecessary hospitalizations and ER visits, reducing polypharmacy while increasing appropriate medication use, and improving care partners’ ability to provide needed support to PLWD.
Toward optimizing measurement of self‐perceived cognitive function ‐ a global expert survey on behalf of the SCD‐I Working Group
Authors: Butterbrod Elke , Rabin Laura , Tommet Douglas , Jones Richard N , Dubbelman Mark A. , Crane Paul K , Sikkes Sietske A.M.
Published: December 2023

Background

Assessment of self‐perceived cognitive decline (SCD) is relevant in the context of Alzheimer’s disease and related disorders, but heterogeneity in measurement limits its interpretability and usability. Selection of optimal content for a questionnaire measuring SCD requires statistical information and expert opinion to ensure reliability as well as acceptability and feasibility. This study aims to survey experts about their perspectives on essential features of SCD measurement.

Method

The survey was distributed through the ISTAART Subjective Cognitive Decline PIA, International Neuropsychological Society’s Dementia Special Interest Group, and authors’ professional networks. Targeted experts included professionals working with older adults with SCD through research and/or clinical practice. Main topics were item content, item format, and questionnaire features. Topics were evaluated with multiple choice questions and open‐ended questions. Furthermore, experts were shown items from existing SCD questionnaires with relatively high information value as identified in a previous statistical harmonization effort using Item Response Theory analyses (see Rabin et al., 2021), and asked to select items they viewed as most relevant. Frequency analyses were performed.

Result

Ninety‐one experts (66% female) across four continents completed the questionnaire (Table 1). Thirty‐nine experts (43%) indicated routinely using an instrument to assess SCD (17 different instruments were mentioned). Seventy‐nine experts (87%) perceived a need for a harmonized SCD instrument. Whereas most experts (72%) responded that a questionnaire should measure both current ability and change in ability, views on the most relevant timeframe varied substantially (top choices: past year (33%) and past six months (25%)). Figure 1a and 1b show that items with the highest statistical information value were not necessarily selected as most relevant by experts. Preferred practical features of a questionnaire were availability of an informant version and coverage of multiple cognitive domains (chosen by 13% and 14% respectively). Preferred validation approaches were distinguishing psychiatric illness from neurodegenerative disorders and the correlation with neuropsychological test performance (both chosen by 20%).

Conclusion

Despite agreeing on the need for a harmonized SCD instrument, experts express varying views on optimal content, format, and validation approaches. The complementary information derived from statistical results and expert opinion can facilitate more comprehensive measurement of SCD.