bluuebunny/crossref_metadata_2025 huggingface dataset:
Healthcare 3.0: How to Transform Machine Learning Prototypes into Functional Healthcare Applications for Diagnostic Assistance?
Authors: Dyrba Martin , Singh Devesh , Weber Marc‐André , Teipel Stefan
Published: December 2023

Background

As the number of elderly people is rapidly increasing, we are faced with the challenge that diagnostic services are demanded more frequently. At the same time, the number of medical centers and available experts remains almost constant. Tools for diagnostic assistance are urgently needed to improve the effectiveness of healthcare. In four externally funded projects, we will investigate aspects and strategies of how machine learning prototype systems can be translated into functional healthcare applications.

Method

In the ongoing project “ExplAInation” funded by the German research foundation (DFG), we are developing an artificial neural network framework to generate visual and textual explanations to improve the comprehensibility and interpretability of deep learning models. This effort includes participatory research with clinical users. In the complementary project “TESIComp” funded by the Federal Ministry of Education and Research (BMBF), we will investigate ethical and social aspects of the emerging field of computational psychiatry. Patients, caregivers, and medical doctors will be interviewed, which will be qualitatively analyzed. Within the German Medical Informatics Initiative, we will contribute to the project “Open Medical Inference” (OMI), which will develop a network of distributed machine learning evaluation services. We also participate in the international “Clinical AI‐based Diagnostics” (CAIDX) consortium, which receives funding from the European Interreg Baltic Sea Region program.

Result

We developed a deep learning application for the detection of dementia atrophy patterns in brain MRI scans. Derived relevance maps highlight diagnostically important brain areas for further evaluation by the radiologists. Interviews with clinicians will provide information on expectations, key requirements and the functional utility of machine learning‐based assistance. Interviews with patients and caregivers will elucidate future changes and challenges in the doctor’s role and responsibilities. The OMI network will allow hospitals to use distributed machine learning evaluation services remotely, without the need of operating all the tools locally. In CAIDX, we will develop best‐practice guidelines for the overarching process of integrating machine learning prototypes and commercial tools into the hospital.

Conclusion

In “Healthcare 3.0”, the digital transformation will change current diagnostic procedures and roles. Our activities focus on the involved stakeholders, regulatory aspects and implementation strategies to better steer this process.
The limbic‐predominant hypometabolic subtype of AD is not enriched for comorbid TDP‐43 pathology or hippocampal sclerosis
Authors: Levin Fedor , Grothe Michel J. , Dyrba Martin , Teipel Stefan
Published: December 2023

Background

Previous research has identified distinct subtypes of AD that differed with respect to the distribution of neurofibrillary tangles (NFT). One of them, a limbic‐predominant subtype, was enriched for comorbid TDP‐43 pathology. Our previous data‐driven analysis used FDG‐PET to identify a limbic‐predominant subtype of AD that may correspond to the limbic‐predominant NFT subtype. In the current study, we tested the expected associations between measures of neuropathology such as TDP‐43 pathology, hippocampal sclerosis, and Braak stages of NFT accumulation, and the limbic‐predominant hypometabolic subtype.

Method

We analyzed ante‐mortem FDG‐PET and neuropathological data of 74 individuals from the autopsy cohort of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 7 cognitively normal participants, 12 participants with MCI, and 55 with dementia (as assessed at the last available clinical evaluation). Severity of TDP‐43 pathology was operationalized as the number of brain areas with TDP‐43 immunoreactive inclusions (including amygdala, hippocampus, entorhinal/inferior temporal cortex and neocortex). Hippocampal sclerosis was operationalized as a binary variable. We measured similarity of individual FDG‐PET profiles to the limbic‐predominant subtype. For that, we used Euclidean distances from each individual profile to the mean profile of the limbic‐predominant AD subtype identified previously in a larger ADNI sample using a data‐driven hierarchical clustering approach (Fig.1). Lower Euclidean distances indicated higher similarity to the subtype. Bayesian linear regressions in JASP were used to assess associations between neuropathological markers and similarity to the limbic‐predominant FDG‐PET pattern, controlling for Thal phase of amyloid accumulation, age, sex, and time delay between the FDG‐PET scan and death in the null model. We assessed Bayes factors representing evidence for a given model in comparison to the null model (BF10).

Result

Our results suggest that similarity of individual FDG‐PET profiles to the limbic‐predominant FDG‐PET pattern was not related to severity of TDP‐43 pathology (BF10 = 0.449), presence of hippocampal sclerosis (BF10 = 0.544), or Braak NFT stages (BF10 = 0.525).

Conclusion

Contrary to the expected effects, our current analysis indicates a lack of reliable associations between neuropathological markers such as TDP‐43 pathology, hippocampal sclerosis, or global NFT accumulation and the limbic‐predominant hypometabolic subtype. Future analyses will assess potential alternative contributors, such as region‐specific patterns of NFT distribution.
The association between early diagnosis of dementia and health care utilization in psychiatric hospitalization for behavioral and psychological symptoms
Authors: Liu Chien‐Liang , Chueh Chen‐Han , Tsai Yi‐Wen , Yang Szu‐Nian
Published: December 2023

Background

Early diagnosis of dementia has been considered an effective strategy to reduce the healthcare cost for dementia but not conclusive. Our aim is to examine the association between early diagnosis of dementia and healthcare utilization in the first psychiatric hospitalization for behavioral and psychological symptoms.

Methods

This retrospective cohort study examined whether the diagnosis of dementia before index hospitalization affected healthcare management after the index hospitalization for 1972 elderly individuals between 2005 and 2015, using National Health Insurance claims data in Taiwan. Propensity scores, inverse probability of treatment weighting (IPTW), and regression analyses were used to adjust for confounding and examine the effect of early dementia diagnosis. The outcomes were chemical restraints, physical restraints, and healthcare utilization.

Results

Among the 1,972 patients, 89.6% had an early diagnosis, and 10.4% had a delayed dementia diagnosis. The delayed dementia diagnosis group was younger and had less comorbidity. IPTW showed that the delayed diagnosis group received more chemical and physical restraints. The length of stay of index hospitalization in the delayed diagnosis group was 8 days longer than the early diagnosis group. Additionally, the delayed diagnosis group had significantly higher total medical expenses by NT$27,344 and higher total drug expenses by NT$1,912 than the early diagnosis group.

Conclusion

An early diagnosis of dementia was associated with decreased use of physical and chemical restraints, shortened length of stay of acute hospitalization, and decreased overall healthcare costs in psychiatric hospital admissions compared with a delayed diagnosis.
RNAi knockdown of microtubule‐associated protein Tau prevents axonal damage and clears pre‐existing Tau aggregates in P301S transgenic tauopathy model mice
Authors: Haines Jeffery D , Farley Jonathan , Gannon Sean , Schlegel Mark , Castoreno Adam , Bisbe Anna , Zlatev Ivan , Rollins Jeff , Bostwick Bret , Avbersek Andreja , Brown Kirk , Macdonald Lynn , Gao Min , Anderson Matthew
Published: December 2023

Background

The hyperphosphorylation and subsequent aggregation of the microtubule‐associated protein Tau (encoded by the MAPT gene) is one of the major histopathological hallmarks of numerous tauopathies, including Alzheimer’s disease and progressive supranuclear palsy. The intracellular accumulation of aggregated Tau is associated with neuronal loss and disease progression in tauopathies. There is a high‐unmet need to identify strategies to target the intracellular accumulation of Tau aggregates with the aim of slowing tauopathy progression.

Method

To model this, we used mice carrying multiple copies of a transgene with a prion promoter driving human MAPT with human tauopathy‐inducing mutation P301S. P301S‐Tau transgenic mice progressively accumulate neuroglial Tau aggregates associated with axonal damage, gliosis, body weight loss, and ambulatory dysfunction.

Result

P301S mice treated with a single intracerebroventricular injection of Tau siRNA at eight months of age, had a sustainable decrease in MAPT mRNA and soluble Tau protein for three months following siRNA treatment (reduced ∼83% and ∼59%, respectively). siRNA treatment also prevented the progressive decrease in body weight and abrogated axonal damage, evidenced by decreased neurofilament light (NFL) chain in plasma and cerebrospinal fluid of eleven‐month‐old mice. Importantly, immunohistochemical analysis of misfolded Tau in vivo and HEK293‐4RD‐CFP/YFP Tau aggregate biosensor assay testing in vitro revealed a ∼97% decrease of Tau aggregates in the eleven‐month‐old mice, suggesting there exists a yet‐to‐be identified mechanism of Tau fibril clearance.

Conclusion

Together, these results suggest an RNAi therapeutics approach targeting of MAPT mRNA may be sufficient to improve multiple parameters of tauopathy disease progression and a provide a compelling rationale for further development of Tau‐lowering strategies.
Examining the validity of sleep diaries using a patient‐caregiver dyadic model of dementia
Authors: Youngkin Anna E , Manning Carol A , Quigg Mark S
Published: December 2023

Background

Developing successful sleep interventions for both people with dementia (PWD) and their caregivers (CGS) is critical to alleviate a strong difficulty associated with dementia. In the majority of current studies, sleep diaries are used to quantify the sleep quality of participants. However, whether or not sleep diaries can accurately describe sleep statistics is unclear and the completion of daily diaries can be tedious for caregivers, leading to gaps and inaccuracies in data. The current study aimed to compare sleep diaries of both patients and caregivers with gold standard diagnostic polysomnography to determine the validity of sleep diaries for future research methodology.

Method

Participants: Six caregiver‐patient dyads. Polysomnography (PSG): recorded and scored for 1 night for each dyad member separately. Sleep Diaries (SDs): logged over the course of 14 days by the primary caregiver on behalf of themselves and their care recipient. Variables: Total sleep time (TST), Sleep onset latency (SOL) and number of awakenings.

Result

Of the three variables assessed, TST was the only measure with meaningful correlations between SDs and PSG (CG r = 0.4315, PWD r = 0.7645). While those who reported greater sleep time in SDs also tended to have higher TST on PSG reports, SDs consistently overestimated the amount of sleep both PWD and CGS received compared to their sleep studies. SOL was inconsistent across SDs, with no clear pattern correlating SDs to PSG reports. However, data from both methods indicate significantly increased SOL in CGS compared to PWD (PSG p = 0.015, SDs p = 0.044). SDs additionally grossly underestimate the number of awakenings in both CGS and PWD.

Conclusion

Sleep diaries can be helpful tools for identifying broad trends or differences between groups, however, our data suggest that they should not be used as surrogate markers for quantitative sleep statistics. Studies aiming to study sleep or sleep interventions should not rely on subjective sleep measurements provided by SDs alone, but should consider the addition of PSG in order to best understand the sleep architecture of their participants.
Pathophysiological mechanisms of grey matter morphometry changes in preclinical Alzheimer’s disease
Authors: Pelkmans Wiesje , Cacciaglia Raffaele , Salvadó Gemma , Falcon Carles , Minguillón Carolina , Fauria Karine , Kollmorgen Gwendlyn , Carboni Margherita , Molinuevo Jose Luis , Grau‐Rivera Oriol , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   ALFA study
Published: December 2023

Background

The biological mechanisms underlying structural brain changes in early Alzheimer’s disease (AD) are not well understood. Combining a wide selection of biomarkers of AD pathology, synaptic dysfunction, neuroaxonal injury, and neuroinflammation, and examining their effects on grey matter (GM) changes may provide a deeper understanding of the multifactorial nature of AD. We aimed to identify biological components of key fluid biomarkers predictive of longitudinal GM changes in cognitively unimpaired adults.

Method

We studied 322 cognitively unimpaired individuals from the ALFA+ cohort (Table1) with available longitudinal MRI and cerebrospinal fluid (CSF) biomarkers of β‐amyloid (Aβ42/40), phospho‐tau (p‐tau181), neurogranin, neurofilament light chain (NfL), total‐tau, α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein‐1 (YKL‐40), soluble triggering receptor expressed on myeloid cells‐2 (sTREM2), S100 calcium‐binding protein B (S100B), and interleukin‐6 measured using the Roche NeuroToolKit immunoassays. Pairwise longitudinal registration analysis was performed using SPM12 to calculate Jacobian determinant maps. Next, we performed partial least‐squares analysis to determine the optimal number of CSF biomarker components and tested their association with GM volume changes by AT (Amyloid‐Tau) stage.

Result

Four distinct biomarker components (C1‐4) were identified (Figure1). C1 was driven by moderate contributions from several biomarkers, particularly markers of core AD pathology and neurodegeneration, which were strongly associated with temporal lobe atrophy in A+T‐ individuals. C2 represented mainly Aβ pathology and, to a lesser extent, axonal damage and astrogliosis that contributed to a decrease in GM volume, especially in the hippocampus in A‐T‐ participants, while showing strong correlations with volume increases in medial frontal regions in A+T+ participants. C3 loading was associated with greater frontoparietal atrophy, especially in A+T+ individuals, and consisted of microglial activation together with Aβ pathology but in the absence of reactive astrogliosis. Lastly, C4, reflecting mostly microglial activation alone, was also strongly associated with frontoparietal atrophy, particularly in A+T+ participants.

Conclusion

Our results suggest important contributions of Aβ pathology, neuroaxonal damage, and microglial activation to GM morphometry changes in the earliest stages of the AD continuum. Atrophy patterns differed depending on the underlying pathological drivers and on A and T positivity, showing stronger correlations with increasing disease severity; however, volumetric increases were also observed.
Diagnostic Paradigms and Prevalence Estimates
Authors: Hogervorst Eef
Published: December 2023

Background

Most consensus based international clinical criteria for dementia or neuro‐cognitive disorders require valid and reliable cognitive tests to assess objective impairment. However, cognitive assessments can be affected by educational attainment, cultural background, test exposure and literacy of those tested. These cognitive tests may not always transfer to low and middle‐income countries (LMIC) or to participants with different cultural‐ethnic and/or socioeconomic backgrounds.

Method

We compared data from Indonesian and UK surveys which had included different cognitive assessments and objective dementia diagnoses as a gold standard. Previous work had shown that the Hopkins Verbal Learning Test (HVLT, Brandt, 1991) was cross‐culturally applicable for dementia diagnostics, in different cohorts in Indonesia (Hogervorst et al., 2011), as well as in the UK (Hogervorst, 2002) independent of age, gender and education. Similar results were found for diagnoses of early dementia in Singapore, China,and other LMIC (Xin, 2014). We also included a visual sensitivity test previously found to be sensitive to early dementia (Bandelow, 2008) and various other gold standard assessments (e.g. MMSE, CERAD word list etc) commonly used for dementia diagnostics, as well as confounds such as age, gender and education in regression analyses using the ROC established optimal cut‐off scores.

Result

In the two cohort studies in Indonesia and the UK, lower sensitivity and specificity for dementia was shown for the HVLT and visual sensitivity using ROC analyses than expected. However, the HVLT and in particular our in house developed visual sensitivity test were still able to identify important risk and protective factors for dementia in these cohorts. We also reviewed several other Indonesian cohorts using different cognitive screening methods which had very high dementia prevalence (e.g. 29‐32% > 60 years of age).

Conclusion

Different cognitive assessments can provide varying data on dementia prevalence. Attention should be given to potential overestimates of dementia prevalence and this can possibly be prevented by using culturally and educationally sensitive test. Training of testers should be consistently reviewed and supervised to reduce inter‐tester variability. Cheap, easy to use by non medical but trained staff and good culturally appropriate cognitive tests need to be developed for cross culturally dementia screening studies.
High‐throughput CRISPRi screening to investigate mechanisms underlying Alzheimer’s risk loci
Authors: Gallagher Michael D , Hazel Katheryn EA , Du Wenjuan , Aydin Zeynep , Cheng Yiran , Bell George W , Jaenisch Rudolf , Corradin Olivia
Published: December 2023

Background

Alzheimer’s disease (AD) is a highly (60‐80%) heritable disease with 75 known genetic risk loci. Interestingly, preliminary data from human tissues suggests that these risk loci predominantly act through myeloid cells, implicating microglia, the brain’s resident immune cell, as playing a critical role in AD risk. However, whether the mechanisms underlying these risk loci can be studied in induced pluripotent stem cell (iPSC)‐derived systems, which are currently the only physiologically relevant human model system, remains unknown.

Method

We generated neural progenitors, excitatory neurons, astrocytes and microglia from two human iPSC lines, and performed RNA‐seq to identify all expressed genes and ChIP‐seq for H3K27ac to identify all active gene promoters and enhancers. We compared these data to ChIP‐seq data from primary uncultured (ex vivo) adult human microglia to compare the enrichment of AD risk loci polymorphisms in active promoters and enhancers, as well as a larger panel of neuropsychiatric and neurodegenerative conditions.

Result

iPSC‐derived microglia‐like cells (iMGLs) recapitulated an enrichment of AD risk loci polymorphisms in microglial promoters and enhancers previously seen in ex vivo primary human microglia. Furthermore, the enrichments of polymorphisms conferring risk for other neurological and neurodegenerative conditions were similar in iMGLs and ex vivo microglia, suggesting that the epigenome of iMGLs is similar to that of in vivo human microglia.

Conclusion

iMGLs will serve as a useful cell‐based model for studying AD risk loci, and we are currently developing high‐throughput CRISPR‐based genome and epigenome editing systems to dissect the molecular and cellular mechanisms at these loci, which will nominate novel genes and pathways for therapeutic development.
Closing the sex/gender gap in dementia: honing in on the vasculature (clinical/epidemiology)
Authors: Liu‐Ambrose Teresa
Published: December 2023

Vascular cognitive impairment is the second most frequent form of dementia after Alzheimer’s Disease (AD). Cerebral small vessel disease accounts for the majority of covert cerebrovascular damage and development of the most common form of VCI. Individuals with cerebral small vessel disease predominantly exhibit white matter hyperintensities (WMHs) and lacunes of presumed vascular origin. These pathologies exacerbate other dementias, including AD.

There are sex differences in the incidence and severity of cerebral small vessel disease. Females have greater WMH burden and progression, as well as incident lacunes vs. males. Preliminary evidence also suggest biological sex moderates the effect of aerobic exercise on WMH progression and cognitive function in adults with cerebral small vessel disease. Whether there is a sex difference in the effect of other types of exercise, such as resistance training, on WMH progression is currently unknown. Futures cohort and intervention studies need to include both sexes to examine sex differences in risk factors for cerebral small vessel disease as well as intervention effects. Understanding sex differences will allow precise recommendations that are sex specific for reducing the burden of VCI as well as AD.
Relational, Community Dementia Care for All: Observations and Lessons from On‐Reservation Providers, Administrators, and Formal Caregivers in the US and Canada
Authors: Ketcher Dana , Jacklin Kristen , Warry Wayne , Lewis Jordan P. , Blind Melissa J , Dertinger Melinda , Arredondo Brandylyn , Pederson Collette , Johnson January , Trudeau Rhonda , Pitawanakwat Karen , Strong Lois , Summers Marlene , Martin Wesley , Lambrou Nickolas H. , Zuelsdorff Megan , Gleason Carey E.
Published: December 2023

Background

Research with Indigenous populations in North America has consistently demonstrated divergent views on caregiving for people living with dementia (PLWD) compared to Western biomedical approaches. Few studies to date have applied strengths‐based approaches and, as a result, an Indigenous caregiving framework appropriate for on‐reserve/reservation populations has yet to be created. In this paper we share research findings that can be used to initiate strategies for culturally appropriate, sustainable, and supported care strategies for Indigenous PLWD.

Method

We used a community‐based participatory approach to conduct ethnographic research in a culturally safe way among four Indigenous communities in the US and Canada. Community‐based researchers conducted key informant interviews with dementia administrators and providers (n = 35), and sequential focus groups with local health care staff/formal caregivers that work with Indigenous older adults (14 sessions, n = 17). Data were coded in QSR NVivo and analyzed using a phenomenological framework.

Result

Participants described numerous assets available to Indigenous communities that can help PLWD age in place, based in a wholistic orientation. Main qualitative themes emerging from the analysis include: the need for wholistic models of care; the value and importance of family caregiving; the role of social/community support; the value of caring for the PLWD in the home for as long as possible; and the need for community services to support caregivers. Indigenous values, past experiences with health systems/colonization, and lived experiences of dementia were important underlying factors informing an Indigenous caregiving framework appropriate for on‐reserve/reservation populations.

Conclusion

Western models of caregiving for PLWD, especially the eventual placement of PLWD in care facilities, do not fit with Indigenous value systems and teachings. Relational, family, and community‐based care is a culturally appropriate form of care for most elders in Indigenous communities. This model will be most effective when culturally appropriate community support services such as personal support and home care nursing services, as well as adequate respite, are included. Further research with family caregivers and PLWD will be necessary to further our understanding of this Indigenous care model and together with this study will form the basis for a community‐based caregiving intervention.
Screening tyrosine kinases for their involvement in synaptotoxicity induced by tau microtubule‐binding region fibrils
Authors: Hodonou Kelly , Siedlecki‐Wullich Dolores , Vreulx Anais‐Camille , Lambert Jean‐Charles , Kilinc Devrim
Published: December 2023

Background

Synapse loss is an early event in Alzheimer’s disease (AD); yet, mechanisms of synaptotoxicity induced by amyloid‐β and tau –hallmarks of AD pathology– remain unclear. We have recently developed a lab‐on‐a‐chip device that fluidically isolates synapses of primary neurons from their cell bodies, thereby enabling us to exclusively access synaptic, as well as pre‐ and postsynaptic compartments. Our aim is to identify molecular mechanisms of synaptotoxicity related to AD.

Method

Using the said in vitro model, we assessed the impact of exogenously applied monomeric and fibrillar forms of tau microtubule‐binding region (tau‐MTBR), as well as of full‐length tau isoforms, on synaptic connectivity, quantified through distance‐based assignment of postsynaptic puncta to presynaptic puncta. After confirming that the fibrillar form of tau‐MTBR induces a detrimental effect on mature synapses, we conducted a medium‐throughput compound screening, in which we tested small molecule inhibitors of 25 tyrosine kinases for their capacity to block tau‐MTBR‐induced synaptotoxicity.

Result

Five compounds that protected synapses from the detrimental effect of tau‐MTBR were considered potentially protective. Dose‐response analysis conducted on these five compounds highlighted FIIN‐2, a highly specific inhibitor of FGF receptor (FGFR) family. We are currently validating this finding with an alternative compound against FGFR and assessing whether tau interacts with cell surface FGFR. In parallel, we are functionally validating the observed toxic and protective effects using electrophysiological recordings in microfluidic devices integrated with microelectrode arrays.

Conclusion

Deciphering downstream signaling mechanisms in tau‐induced synaptotoxicity will improve our understanding of AD pathophysiology and allow us to identify potential therapeutic targets.
Clinical Trial Targets Miss the Mark for Endophenotypes Associated with Elevated Disease Risk Metrics
Authors: Cary Gregory A. , Wiley Jesse C , Greenwood Anna K , Carter Gregory W , Center The Emory‐Sage‐SGC TREAT‐AD
Published: December 2023

Background

Most of the candidate disease modifying agents in clinical trials for Alzheimer’s Disease (AD) have been unsuccessful in providing significant relief to patients. While there are myriad possible reasons for the poor success rate of these trials, one potential explanation is that the targeted proteins and pathways are not the causal mechanisms of disease. The TREAT‐AD Consortium has recently developed tools to score the entire genome across several dimensions of disease risk, as well as organize genes into AD relevant biological domains of gene function. In this work we examine the historical data of AD clinical trials through the lens of AD risk and biological domains.

Method

Clinical trial data was obtained from the OpenTargets and clinicaltrials.gov platforms. For the target(s) identified for each trialed agent, we obtained the TREAT‐AD Target Risk Scores (TRS) and AD biological domain annotations. The results of gene ontology (GO) term over‐representation tests for the 253 genes targeted by agents in clinical trials were compared to the results from the top scoring genes ranked by the TRS.

Result

We find that genes targeted by agents that have entered phase IV trials tend to have a higher genetics risk score compared with genes targeted by therapeutic agents that are earlier in the clinical trial pipeline (i.e. phase I‐III). There is a mismatch between the biological domain annotations of genes targeted by clinical trials and those with the top TRS. Genes targeted by clinical trials tend to have a relatively higher fraction of annotations and are strongly enriched for terms in the Synapse, Vasculature, and APP Metabolism biological domains. Genes with elevated measures of disease risk tend to have relatively higher fraction of annotations and term enrichments in the Mitochondrial Metabolism, Proteostasis, and Endolysosome biological domains.

Conclusion

We find evidence of mismatches between the biological domains that are elevated for AD risk and those that are targeted by therapeutic agents in clinical trials. Our unbiased, genome‐scale analysis suggests that therapeutic development efforts should increase focus on the intersections of Mitochondrial Metabolism and Proteostasis, and Endolysosomal function.
Health‐related quality of life in full spectrum of Alzheimer’s disease: a longitudinal analysis
Authors: Aye Sandar , Bouteloup Vincent , Jean Delphine , Jönsson Linus
Published: December 2023

Background

Understanding the health‐related quality of life (HR‐QoL) in subjective cognitive decline (SCD), mild cognitive impairment (MCI) and demented patients is essential from the health economic perspective for evaluating new disease‐modifying treatments and preventive interventions. This study aims to assess HR‐QoL and the factors associated with longitudinal change in HR‐QoL in the full spectrum of Alzheimer’s disease.

Method

Longitudinal data from 918 SCD and 1,346 MCI patients from the MEMENTO cohort were included in the study. MCI was defined as performing one standard deviation (SD) worse than the age, sex and education‐level thresholds in one or more cognitive domains identified within six months of the study enrollment. SCD was defined as having isolated subjective cognitive complaints but without any objective cognitive deficit and aged 60 years or older. HR‐QoL was measured by EuroQol EQ‐5D‐3L patient‐reported version. Linear mixed‐effect models with disease stage as a time‐varying covariate were used to (1) assess the utility changes over time across the dementia spectrum and (2) compare the utility changes between amyloid positive and negative SCD and MCI patients.

Result

At baseline, mean utilities were 0.84 ± 0.16 and 0.81 ± 0.18 in SCD and MCI patients. Linear mixed effect models estimated that the utilities were ‐0.016 (SE 0.003), ‐0.07 (SE 0.009), ‐0.18 (SE 0.014) and ‐0.36 (SE 0.034) lower than SCD in patients with MCI, mild, moderate and severe dementia over the study period. Time is associated with a significant decrease in utility with ‐0.008 (SE 0.001) per year. Baseline age, BMI, female, diabetes, cardiovascular history, neuropsychiatric symptoms and inability to perform Instrumental activity of daily living (IADL) were negatively associated with utilities. Amyloid‐positive SCD patients showed a faster decline in utility than amyloid‐negative SCD patients (p < 0.05). The decrease was not statistically significant in amyloid‐positive MCI patients compared to amyloid‐negative MCI.

Conclusion

Health utilities decrease over time in all stages of dementia, and the decline is steeper in moderate and severe stages. Positive amyloid accelerates health utility decline in SCD but not MCI individuals. The ability to perform IADL is the major factor affecting HR‐QoL in all phases of dementia.
Chronic nSMase2 Inhibition Suppresses Neuronal Exosome Spreading In Vivo & Induces Sex‐Specific Attenuation of AD Pathology in APPNL‐F/NL‐F Knock‐In Mice
Authors: Mowry Francesca , Jin Shijie , Quadri Zainuddin , Bieberich Erhard , Yang Yongjie , Yang Yongjie
Published: December 2023

Background

Altered ceramide metabolism is implicated in Alzheimer’s disease (AD) progression. Although prior work shows that inhibition of neutral sphingomyelinase (nSMase) 2, a key enzyme responsible for hydrolysis of sphingomyelin to ceramide, reduces exosome secretion, attenuates Aβ pathology, and improves cognitive function, these studies have been limited to in vitro application or short‐term treatments in fast‐progressing models.

Method

We employed the slow‐progressing APPNL‐F/NL‐F knock‐in (APP KI) AD mouse model and cell type‐specific exosome reporter CD63‐GFPf/f mice to investigate the impact of chronic long‐term nSmase2 inhibition on in vivo neuron‐derived exosome dynamics, region‐specific Aβ plaque load, and cognitive function. Male and female APPNL‐F/NL‐F‐CD63‐GFPf/+ (APP KI‐CD63) mice were treated daily with the nSmase2 inhibitor, GW4869 (GW; 1.25mg/kg BW; i.p.), or vehicle (VEH, DMSO in saline), from 8 months old (mo.) to 13mo. and from 10 mo. to 18mo. We also analyzed ceramide levels in both APP KI and WT mice. Brain‐derived exosomes of 14mo. APP KI females versus males and age‐ and sex‐matched WT mice were also isolated and quantified.

Result

We found significant elevations in multiple ceramide species from somatosensory cortex (SC) samples of 14mo. APP KI mice compared to age‐ and sex‐matched WT controls. We also found a sex‐specific increase in total exosomes in 14mo. APP KI females versus males that was absent in WT mice. Chronic inhibition of nSMase2 by GW4869 leads to significantly suppression of neuronal exosome spreading. Non‐linear regression analyses of size distribution curves showed consistent shifts to smaller plaque sizes in GW‐treated APP KI females, which were accompanied by decreased plaque numbers in each region examined. Conversely, plaque load was largely unaffected by GW treatment in APP KI males. T maze trials to examine spatial working memory revealed a female‐specific reduction in spontaneous alternation rate in APP KI vs. WT mice, which was significantly reversed with GW treatment.

Conclusion

Our results demonstrate that chronic nSMase2 inhibition suppresses neuronal exosome spreading in APPNL‐F/NL‐F knock‐in mice and preferentially attenuates Aβ pathology and cognitive dysfunction in females, pointing to a strong contribution of sex‐specific alterations in ceramide metabolism and exosome dynamics to the progression of AD‐like pathology in this model.
Impact of Low‐value Medications in Dementia on Patient‐reported Health‐related Quality of Life, Hospitalizations, and Direct Health Care Costs
Authors: Platen Moritz , Flessa Steffen , Teipel Stefan , Raedke Anika , Scharf Annelie , Mohr Wiebke , Buchholz Maresa , Hoffmann Wolfgang , Michalowsky Bernhard
Published: December 2023

Background

Persons living with dementia (PwD) are commonly affected by low‐value medications (Lvm), i.e., medications unlikely to benefit patients but to cause harm. Lvm in PwD have been associated with negative physical, psychological, and financial outcomes. However, longitudinal effects have not yet been evaluated. Therefore, we aimed to analyze the impact of Lvm on patient‐centered outcomes among PwD over 24 months.

Method

This longitudinal analysis was based on 352 community‐dwelling PwD. Data were assessed at baseline and after 12 and 24 months. Medications that were explicitly not recommended were used to identify Lvm dichotomously (yes/no) and cumulatively (once, over one or two years). The 12‐Item Short‐Form Health Survey assessed patients' health‐related quality of life (HRQoL). Hospitalizations were assessed retrospectively for 12 months. Health care costs were monetarized by standardized unit costs. Multiple panel‐specific regression models were applied to analyze the impact of Lvm on HRQoL, hospitalizations and costs.

Result

Over 24 months, 182 PwD (52%) received Lvm at least once and 56 (16%) continuously. The Lvm prevalence decreased from 36% (CI95% 30.8% – 40.8%) at baseline to 29% (CI95% 24.2% – 33.7%) two years later. Treating PwD with Lvm significantly increased the risk of hospitalization by 58% (CI95% 1.14 OR – 2.19 OR; p = 0.006), increased health care costs by €5,359 (CI95% ‐790€ – 11,508€; p = 0.088), and reduced patients' HRQoL (b = ‐1.81; CI95% ‐3.00 – ‐0.63; p = 0.003). HRQoL declined more strongly the longer that Lvm was received, whereas hospitalizations and health care costs were substantially affected by short‐term Lvm use, indicated by an increased hospitalization risk due to receiving Lvm over one year of 178% (CI95% 1.32 OR – 5.86 OR; p = 0.007) and costs for receiving Lvm once of €8,939 (CI95% €‐590€ – €18,469; p = 0.066).

Conclusion

More than every second PwD received Lvm once, up to 12 months or continuously over 24 months, negatively impacting patient‐reported HRQoL, hospitalizations, and costs. While continuous Lvm intake decreased patients' HRQoL, receiving Lvm in the short term was relevant regarding further increases in hospitalizations and costs. Innovative approaches are needed to encourage prescribers to avoid and replace Lvm in dementia care.
Perceptions about Dementia Clinical Trials
Authors: Leggins Brandon , Jackson Ashley , Hart Danielle M , Windon Charles , Levenson Robert W , Merrilees Jennifer , Chiong Winston
Published: December 2023

Background

The research community has historically failed to enroll diverse populations in dementia clinical trials. A unique aspect of dementia care research is the requirement of a study partner, who can attest to the care recipient’s clinical and functional capacity. The aim of this study is to assess racial and ethnic differences and the importance of various trial considerations, among dementia caregivers, in their decision to participate in clinical research as study partners.

Method

We embedded a vignette about a hypothetical dementia clinical trial in a nationally representative survey of dementia caregivers, oversampling Black non‐Hispanic and Hispanic caregivers. They were asked about their willingness to participate in the trial with their care recipient, and rated the importance of nine considerations in hypothetical decisions to participate. Caregiver demographic characteristics, care recipient characteristics, and relational characteristics were analyzed as predictors of trial participation in a demographic model. In a second model, caregiver demographic characteristics and the rated importance of the nine considerations were separately analyzed as predictors; both models used survey‐weighted logistic regression.

Result

The sample consisted of 610 caregivers, including 156 Black non‐Hispanic and 122 Hispanic participants. In the demographic model, hypothetical trial participation was negatively associated with caregiver age [OR (odds ratio) = 0.46, P = <0.001], and with care recipient male gender [OR = 0.34, P = 0.007]. In the second model, responsibility to help others by participating in research was significantly associated with participation [OR = 1.56, P = 0.049], while the possibility of the care recipient experiencing serious side effects was negatively associated with participation [OR = 0.51, P = 0.003]. In both models there was no significant difference in hypothetical participation between non‐Hispanic Black and non‐Hispanic White caregivers, or between Hispanic and non‐Hispanic White caregivers.

Conclusion

Hispanic and non‐Hispanic Black dementia caregivers were not less likely than non‐Hispanic White dementia caregivers to participate in a hypothetical dementia clinical trial. Our study suggests that failures to recruit diverse populations in dementia clinical research are not attributable to less willingness among members of underrepresented groups, but may instead reflect structural barriers and historic exclusion from trial participation.
PROGNOSTIC VALUE OF AT(N) CLASSIFICATION IN CSF USING CLUSTERING ANALYSIS
Authors: Gil‐Moreno María José , Hernández‐Lorenzo Laura , Ortega‐Madueño Isabel , Cruz Cárdenas‐Fernández María , Díez‐Cirarda María , Delgado‐Álvarez Alfonso , Palacios‐Sarmiento Marta , Matias‐Guiu Jorge , Corrochano‐Sánchez Silvia , Ayala José Luis , Matias‐Guiu Jordi
Published: December 2023

Background

The biological definition of Alzheimer’s disease (AD) and the use of biomarkers according to the AT(N) system may improve the clinical characterization of patients and the sequence of events during the clinical course. However, some studies have raised challenges in the clinical application of AT(N) system. Unbiased, data‐driven techniques such as unsupervised machine learning may help optimize it. We aimed to optimize the classification using unsupervised machine learning algorithms (clustering analysis).

Method

We included 421 patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort and 165 from our centre. We included subjective memory complaints (SMC), early mild cognitive impairment due to AD (EMCI), late MCI due to AD (LMCI) and MCI without evidence of neurodegeneration (MCI‐NN) patients according to clinical manifestations, neuropsychological test and CSF biomarkers from our center and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. We clustered the biomarkers separately and all together using the KMeans algorithm for each cohort and compared them in terms of diagnosis, AT(N) system, biomarker values distribution, and risk of progression to dementia.

Result

The optimal number of clusters for all the biomarkers together was three. These clusters differed significantly in both cohorts according to diagnosis, AT(N) categories, biomarker values distribution, and progression to dementia. We found amyloid biomarkers to be more dichotomic, while Tau biomarkers were more continuous. Intergroup comparisons revealed the following groups: 1) non‐defined or unrelated to AD subjects, with no risk of progression to dementia; 2) early stages and/or more delayed risk of conversion to dementia subjects, and 3) more severe cognitive impairment subjects within the early stages of AD and with faster progression to dementia. Findings were largely similar between the two cohorts.

Conclusion

This new 3‐group classification, developed with a data‐driven approach, represents a novel perspective to assess the risk of conversion to dementia in a much more simplified way and is complementary to the AT(N) system classification
Alzheimer’s polygenic risk score is associated with Dementia and memory phenotypes in Down syndrome
Authors: Gorijala Priyanka , Aslam Muhammad Muaaz , Dang Lam‐Ha , Fernandez Victoria , Sung Yun Ju , Fan Kang‐Hsien , Feingold Eleanor , Kamboh M. Ilyas , Lee Joseph H. , Cruchaga Carlos
Published: December 2023

Background

Down syndrome (DS) is a complex neurological disorder manifested by triplication of chromosome 21, which includes the amyloid precursor protein (APP) gene. Triplication of APP which is known for the buildup of Amyloid Beta plaques, a hallmark of Alzheimer’s disease (AD) pathology. Although researchers have studied genetic factors of AD risk in DS, the overall genetic contribution of AD in DS is still not clear. While the polygenic risk score (PRS) explains the overall genetic architecture and overlap between complex traits, no study has used PRS to understand the relative burden of AD risk variants in DS.

Methods

We constructed PRS using Bellenguez et al (2022) summary statistics for five different cohorts: DS (n = 282), sporadic early‐onset (sEOAD, n = 395), sporadic late‐onset (sLOAD, n = 2259), familiar early‐onset (fEOAD, n = 196), familial late‐onset (fLOAD, n = 1413). Unrelated European ancestry samples were selected for analysis (4,545 cases, 2,890 controls). To understand AD risk beyond APOE, PRS including and excluding APOE region was calculated using PRSiceV2.3. Chromosome 21 was excluded from the analysis. We tested the association of PRS with clinical status in each cohort and compared it between cohorts. We further tested association of neuropsychological batteries for cognition/memory, and cerebrospinal fluid (CSF) biomarkers with the AD PRS for DS individuals.

Results

The PRS of AD was associated with sEOAD, fLOAD and sLOAD, but not with fEOAD. DS status was significantly associated with the AD PRS including APOE (OR = 0.62, P = 1.86×10−3). Down Syndrome Mental Status Examination (DSMSE) memory score was associated with AD PRS regardless of APOE inclusion (P = 8.61×10−4 with APOE, and P = 4.94×10−2 without APOE). In addition, DSMSE total score (P = 4.53×10−3), Dementia Questionnaire for People with Learning Disabilities (DLD) cognitive score (P = 1.46×10−2), CSF Aβ40 (P = 1.28×10−2), and Aβ42 (P = 4.21×10−2) were associated with the AD PRS including APOE.

Conclusions

Our study suggests that even if DS individuals were depleted with AD risk variants, the overall genetic architecture for AD is still associated with cognitive and memory phenotypes, as well as AD biomarkers. This suggests that AD risk modulates APP metabolism/Aβ formation and tau protein binding, thus playing a role in the onset and progression of dementia in DS.
Systolic Blood Pressure Levels and Probable Dementia : Secondary Analysis of a Randomized Clinical Trial
Authors: Jaeger Byron C , Gaussoin Sarah A. , Reboussin David M. , Rapp Stephen R. , Sachs Bonnie C. , Williamson Jeff D.
Published: December 2023

Background

Despite a significant 19% reduction in risk for mild cognitive impairment, the primary Systolic Blood Pressure Intervention Trial (SPRINT) analysis lacked sufficient evidence to assert statistical significance for the 17% reduction in probable dementia alone in intensive blood pressure (BP) control, defined as a target systolic BP < 120 mmHg, compared to the standard target of < 140 mmHg (p = 0.10). However, early termination of SPRINT may have caused these analyses to be under‐powered. We applied the statistical framework of joint models for longitudinal data and time‐to‐event outcomes to analyze the effect of systolic BP levels on probable dementia using the SPRINT data.

Methods

SPRINT was a multicenter randomized clinical trial that enrolled patients ≥50 years of age with hypertension and increased cardiovascular risk but without diabetes or history of stroke. In this secondary analysis, the primary outcome was occurrence of adjudicated probable dementia after randomization. Secondary outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. To analyze these outcomes, we applied joint longitudinal and survival models. In the longitudinal component of the joint model, systolic BP levels were modeled as a quadratic function of time since randomization, accounting for correlation in repeated measurements and for assignment to intensive BP control versus standard care. In the survival component, multi‐variable adjustment for race, education, and age at baseline was applied.

Results

Over a median follow up of 5.2 years, a total of 325 probable dementia and 640 mild cognitive impairment events occurred. After multi‐variable adjustment (as above), the hazard ratio per 10 mmHg decrease in systolic BP was 0.89 (95% confidence interval [CI] 0.79, 0.99) for probable dementia, 0.89 (95% CI 0.82, 0.96) for mild cognitive impairment, and 0.90 (95% CI 0.84, 0.97) for their composite outcome (Table). Dynamic predictions after 2 years of follow‐up provide a descriptive summary of systolic BP levels and predicted risk of probable dementia or mild cognitive impairment (Figure).

Conclusion

Reducing systolic BP decreases the risk of both probable dementia and mild cognitive impairment.