bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancing the insights of the Patient‐and care‐related benefits of amyloid PET imaging ‐ ENABLE ‐ study through a process evaluation: a study protocol
Authors: Grazia Alice , Goerss Doreen , Spottke Annika , Boecker Henning , Daamen Marcel , Graf Erika , Sahlmann Jörg , Buchert Ralph , Mohnike Wolfgang , Mohnike Konrad , Jessen Frank , Krause Bernd J , Boccardi Marina , Teipel Stefan , Kurth Jens
Published: January 2025

Background

Amyloid PET imaging is an established diagnostic tool for Alzheimer's disease, but its successful integration into clinical practice requires a comprehensive understanding of its impact on patients and the healthcare system. In 2022, the coverage with evidence development (CED) ENABLE study has been approved by the German Federal Joint Committee (trial registration: DRKS00030839). The study is scheduled to start in early 2024. Primary outcome of ENABLE is the change in patients' functional abilities at 18 months after diagnosis with amyloid PET versus without amyloid‐PET. Here we describe the design of an ENABLE sub‐study aimed at performing a process evaluation.

Method

We will conduct an outcome and process evaluation using a pre‐post descriptive design nested in ENABLE (Figure), based on the Medical Research Council's Process Evaluation (PE) framework. The PE will focus on acceptability and reach of the target groups of patients and care providers, as well as fidelity of delivery (% of adherence to protocol, study duration), contextual changes and mechanisms (e.g., ability to mirror routine care). We will collect patients’ data independently, but in parallel with ENABLE, using interviews, surveys and checklists to assess acceptance of the intervention, fidelity of adherence to the follow‐up procedures, perceived benefits and challenges. Healthcare providers and administrators will be interviewed to identify implementation hurdles and facilitators, contextual factors influencing uptake and underlying mechanisms. For data analysis we will employ a mixed‐methods approach.

Result

Expected outcomes will include acceptability and adherence, barriers and facilitators to implementation, contextual factors influencing implementation, perceived utility of the intervention by patients and providers, and mechanisms by which the intervention can be delivered as part of normal care.

Conclusion

This process evaluation can inform researchers on how to design future CED studies to be implemented into clinical care. The lessons learned during the development and approval process of the ENABLE project in Germany, as well as its process evaluation, can benefit other European CED studies and policy‐makers stakeholders in making informed decisions. Likewise, these findings can be generalized beyond the context of amyloid PET to other diagnostic biomarkers, ultimately improving the diagnosis and management of Alzheimer's disease.
Lower amygdala and hippocampal volume correlates with TDP‐43 load in limbic‐predominant age‐related TDP‐43 encephalopathy (LATE)
Authors: Wesseling Alex J. , Calandri Ismael Luis , Ossenkoppele Rik , Bouwman Maud M.A. , Deshayes Natasja A. C. , van de Berg Wilma D.J. , Rozemuller Annemieke J.M. , Pijnenburg Yolande A.L. , Hoozemans Jeroen J.M. , Jonkman Laura E.
Published: January 2025

Background

Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is often described as occurring in older individuals, either with or without co‐occurring neurodegenerative disease. Because the presence of LATE can only be determined post mortem, little is known about the clinical and neuroimaging features of LATE. The current study aims to assess the correlation between LATE and MRI‐measured amygdala and hippocampal volume in Alzheimer’s disease (AD) and Lewy Body Diseases (LBD), including Parkinson’s disease (PD), PD dementia, and dementia with Lewy Bodies

Methods

Post‐mortem in‐situ 3DT1 3T‐MRI data were collected for 51 cases (27 AD and 24 LBD) of which 17 had post‐mortem confirmed LATE neuropathological change (9 AD and 8 LBD), as well as 34 non‐LATE (18 AD and 16 PD) donors (matched on age, sex, and Braak stage). Right hemisphere amygdala and hippocampal volumes were calculated using Freesurfer. Pathological load of TDP‐43, p‐tau and α‐synuclein from the same regions were obtained using IHC and quantified using QuPath. Group differences were assessed with univariate analyses and correlations using linear mixed models, both using age, sex, post‐mortem delay and intracranial volume as covariates.

Results

Two AD cases with a disease onset below 65 showed LATE pathology. In the combined cohort, brain donors with LATE neuropathological change showed significantly lower amygdala (p=.003) and hippocampal (p=.002) volumes, even when corrected for p‐tau and Lewy body load (Figure 1a). In AD, this difference remained (amygdala p=.001, hippocampus p=.007, corrected for p‐tau), but not in the LBD group. In donors with LATE, TDP‐43 load correlated negatively with MRI measured amygdala and hippocampal volume when corrected for p‐tau and Lewy body load (r= .70; p=.005) (Figure 1b). The same association was found in AD (r=.70; p=.015 corrected for tau load) but not in LBD donors.

Conclusion

These results suggest that TDP‐43 inclusions plays a role in hippocampal and amygdala atrophy on MRI, even when correcting for effects of primary pathology. Moreover, a salient detail is that LATE also seems to play a role in the disease presentation of young‐onset dementia patients.
Influence of tau pathology and anxiety and depressive symptoms on metamemory in cognitively normal older adults
Authors: Crawford Jennifer L. , Adornato Alex , Matulonis Johanna , Hooker Jacob M. , Berry Anne S.
Published: January 2025

Background

The ability to accurately discern memory function (i.e., metamemory) decreases with age and is further diminished in Alzheimer’s disease (AD). As such, changes in metamemory may be a sensitive behavioral indicator of pre‐symptomatic AD.

Method

Cognitively normal older adult participants (N=48) completed a neuropsychological battery consisting of episodic memory tasks (California Verbal Learning Task, Face‐Name Associative Memory Exam) and self‐reported measures of metamemory (Multifactorial Memory Questionnaire) and anxiety and depressive symptoms (Geriatric Depression Scale, Penn State Worry Questionnaire, Mood and Anxiety Symptom Questionnaire). Z‐scores from each measure were combined into three separate composite scores: memory ability, metamemory, and anxiety and depressive symptoms. All participants also had a tau PET scan ([18F]MK‐6240) completed within 12.7 (SD = 11.6) months of neuropsychological testing in which standardized uptake value ratios (SUVR) referenced to the inferior cerebellar gray matter were calculated using Freesurfer‐defined ROIs for Braak I, Braak II, metatemporal, and amygdala regions of interest (ROIs). Linear regression models were used to test for the contribution of anxiety and depression symptoms, tau pathology, and memory ability on metamemory; education, age, and sex were entered as covariates in all models.

Result

Behavioral analyses suggest that anxiety and depression symptoms (t = ‐2.1, p=0.046), but not memory ability (t = 0.4, p=0.698), were related to metamemory. Interestingly, tau pathology helped to explain additional variance in the relationship between metamemory and anxiety and depressive symptoms. Specifically, amygdala tau interacted with anxiety and depression symptoms to predict metamemory (t = ‐2.61, p=0.013), when controlling for age, sex, education, and memory ability, such that participants with both high levels of anxiety and depressive symptoms and high levels of amygdala tau pathology had lower self‐reported metamemory (Figure 1). This relationship was not observed in Braak I, Braak II, or metatemporal ROIs (ps > 0.07).

Conclusion

Together, these results suggest that depressive and anxiety symptoms are an important metric to consider when examining the relationships between tau pathology and metamemory. Further, the results underscore that mechanisms supporting metamemory are likely distinct from those underlying memory ability and each merit unique consideration towards understanding their relationship to AD pathology.
Visual classification of tau‐PET detects four subtypes with different long‐term outcomes
Authors: Boccalini Cecilia , Mathoux Gregory , Hristovska Ines , Ribaldi Federica , Peretti Débora Elisa , Arnone Annachiara , Scheffler Max , Frisoni Giovanni B. , Hansson Oskar , Vogel Jacob W. , Garibotto Valentina
Published: January 2025

Background

Substantial variability in tau accumulation patterns in Alzheimer’s disease (AD) population has now become accepted. Subtype and Stage Inference (SuStaIn) has distinguished four distinct spatiotemporal trajectories of tau pathology: limbic (S1), medial temporal lobe‐sparing (S2), posterior (S3), and lateral temporal (S4). A visual method to validate and identify them is a requirement for their clinical translation. Our study aims to provide evidence for multiple tau accumulation patterns in a clinical setting by developing and testing a novel topographic visual method for tau‐PET based on SuStaIn subtypes.

Method

We included 245 participants from the Geneva Memory Clinic, who underwent 18F‐Flortaucipir‐PET. All scans were classified into different subtypes by visual ratings and the automated SuStain algorithm. Cohen's kappa (k) tested the agreement between raters and between visual and automated subtypes. Chi‐squared and Kruskal‐Wallis tests were used to test differences in clinical features, tau, and amyloid (Aβ) loads between subtypes. Differences in cognitive trajectories were tested using linear mixed‐effects models, controlling for age, sex, and tau stages.

Result

A substantial agreement between raters was found in visually interpreting tau pattern subtypes (k>0.65, p<0.001) and a fair agreement between visual and automated subtypes (k=0.39, p<0.001), with the automated approach detecting a higher rate of negative scans. According to the visual classification, individuals with S2 subtype were younger than S1 and S3 (p<0.001), had worse MMSE and verbal fluency scores (p<0.05) than S4 and S1, showed higher global tau than other subtypes (p<0.05), and a steeper cognitive decline.

Conclusion

Our results show that visual classification can reliably identify four tau patterns, differing in global tau loads, clinical characteristics, and long‐term outcomes, suggesting its clinical usefulness for the detection of higher‐risk AD variants. A clinically implementable classification in subtypes with faster decline is paramount for personalized diagnosis and therapy.
Brain Resilience to Targeted Attack of Resting BOLD Networks as a Measure of Cognitive Reserve
Authors: Argiris Georgette , Stern Yaakov , Habeck Christian G
Published: January 2025

Background

Recent advancements in connectome analyses allow for more fine‐grained measurements of brain network integrity. One measure of integrity is resilience, or the capacity of the network to retain functionality when confronted with endogenous or exogenous perturbations that result in damage or error. We assessed the impact of individual differences in the resilience of resting BOLD connectivity on the relationship between cognitive and brain changes in a lifespan cohort of cognitively healthy adults over a 5‐year period.

Method

One hundred twenty‐six cognitively healthy participants from the Reference Ability Neural Network (RANN) longitudinal lifespan cohort (age 20‐80 years) underwent resting‐state fMRI to measure functional connectivity and an out‐of‐scanner neuropsychological battery at baseline and five‐year follow‐up. Undirected weighted adjacency matrices were generated from Schaefer et al. (2018) 400 parcellation atlas. As a measure of whole‐brain network resilience, we adopted a targeted attack approach, whereby nodes are sequentially removed from the connectome in order of nodal strength. At each iteration of attack, nodal strength is recalculated based on the effect of prior lesioning and the largest connected component (LCC) is measured. We inferred that more resilient individuals will sustain larger LCCs over longer iterations of lesioning before decay in LCC becomes evident, with resilience operationalized as the iteration of steepest slope in LCC.

Result

We tested whether our operationalization of brain resilience (BR) moderated the effect of brain integrity (i.e., cortical thickness; CT) on out‐of‐scanner neuropsychological test performance across four domains of cognition in the context of longitudinal change (∆) over time. After accounting for baseline differences in change variables and adjusting for the demographic factors of Age, Sex, NART IQ, and Education, we observed a significant negative interaction between ∆CT and ∆BR on ΔCognition for the Fluid Reasoning domain. That is, individuals with increased brain resilience over time were less sensitive to the effect of changes in cortical thickness on changes in cognition.

Conclusion

Our finding supports evidence for targeted attack as a measure of cognitive reserve, where higher brain network resilience may have permitted individuals with reduced brain integrity to better cope with structural loss and enhance preservation of cognitive function.
Systematic Review of Scalable Biomarkers of Alzheimer’s Disease
Authors: Suresh Shivani , Raymont Vanessa , Bauermeister Sarah
Published: January 2025

Background

Alzheimer's disease (AD) impacts over 50 million individuals and imposes a substantial burden on patients, caregivers, and society at large. Recent research suggests that AD is a continuum comprising preclinical, prodromal, and dementia stages, with underlying pathology manifesting well before symptoms appear. Early and accurate diagnosis is therefore crucial for optimal clinical outcomes; yet current diagnostic methods, such as neuroimaging and cerebrospinal fluid lumbar puncture, are expensive and invasive. This highlights the need for more scalable and cost‐effective alternatives, particularly blood biomarkers. In addition to their diagnostic potential, these biomarkers can also screen at‐risk individuals and offer valuable prognostic insights. Therefore, a systematic review of existing literature on scalable AD blood biomarkers is essential to address the current literature gap and highlight advancements in the field.

Method

To conduct this systematic review, a comprehensive search of the literature will be performed across multiple databases, including PubMed, EMBASE, Global Health, Journals@OVID, and PsycINFO. In light of the recent NIA‐AA recommendations, focus will be laid on articles assessing the clinical utility of plasma phosphorylated tau‐217 (p‐tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). The search criteria will be limited to human studies and English‐language journal articles published within the last 5 years. The review will include a qualitative synthesis of selected studies, and if feasible, a random‐effects meta‐analysis may be conducted. The meta‐analysis will pool studies based on the specific biomarkers under assessment to provide a quantitative overview of findings.

Result

The systematic review aims to highlight advancements in scalable AD biomarkers, with a specific focus on plasma p‐tau217, GFAP, and NfL. An initial search of the literature brought up 3086 papers. After removing duplicates and conducting a preliminary screening, 159 articles have been selected for review. Through the qualitative synthesis of selected studies and potential meta‐analysis, the review intends to provide a comprehensive overview of the clinical utility of these biomarkers.

Conclusion

This review will contribute to laying the foundation for improved clinical care practices in AD by summarizing key findings, identifying gaps in the literature, and outlining future applications of blood biomarkers in the diagnosis and management of AD.
Mitochondrial DNA copy number from human blood is associated with specific cognitive function
Authors: Tian Qu , Zweibaum David A. , Oppong Richard , Qian Yong , Pilling Luke C , Casanova Francesco , Atkins Janice L , Melzer David , Ding Jun , Ferrucci Luigi
Published: January 2025

Background

The mitochondrial cascade hypothesis suggests that mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer’s disease dementia. Recent data have shown that mitochondrial DNA copy number (mtDNAcn) in human blood is associated with dementia risk and cognitive function, but which specific cognitive measures or domains are associated with mitochondrial dysfunction and whether this relationship is affected by health deterioration such as physical frailty or mitochondrial somatic mutations is not clear.

Methods

We measured mtDNAcn and heteroplasmies using fastMitoCalc and MitoCaller, respectively, from UK Biobank Whole Genome Sequencing (WGS) data at study entry (2006‐2010). Pre‐frail/frail status was determined by the presence of slow gait, weight loss, low grip strength, exhaustion, or low physical activity. Cognitive function was assessed in a subset of participants (mean age=64.1,51.7% women, 97.0% White) on average 8.9 years after study entry, including processing speed via Digit Symbol Substitution Test (DSST)(n=13,940), attention via Trail Making Test (TMT) part A(n=13,482), executive function via delta TMT(n=13,428) and tower rearranging task(n=13,819), memory via paired associative learning task(n=14,094), and fluid reasoning via matrix pattern completion task(n=13,935). We examined the associations between mtDNAcn and cognitive measures using multivariate linear regression, adjusted for demographic factors, smoking status, follow‐up time, measures related to mtDNAcn assessment, and Apolipoprotein E ε4 status. We then stratified the analysis by frailty status and levels of heteroplasmy load.

Results

Overall, more mtDNAcn was significantly associated with higher DSST (p=0.036) but not with other cognitive measures. After stratification by frailty status, mtDNAcn was associated with DSST, delta TMT, and paired associative learning in the pre‐frail/frail participants only (p=0.047,0.007, and 0.044, respectively). After stratification by a median split of heteroplasmy load, mtDNAcn was associated with DSST and paired associative learning in those with higher heteroplasmy load (p=0.039 and 0.031, respectively). Results remained similar after excluding participants with dementia diagnosis (n=15).

Conclusions

Higher mitochondrial DNA copy number from human blood is associated with higher cognition in specific measures. The associations with processing speed, executive function, and memory are prominent in individuals with health deterioration of physical frailty or high level of mtDNA heteroplasmy. Future studies are warranted to understand the biological underpinnings.
Investigating covert awareness in individuals with Alzheimer’s Disease using functional near‐infrared spectroscopy (fNIRS)
Authors: Gupta Garima , Kolisnyk Matthew , Kazazian Karnig , Shahid Rafeh , Urian Diana , Novi Sergio , Pantazopoulos Koula , Abdalmalak Androu , Huntley Jonathan D , Debicki Derek , Pasternak Stephen H , Owen Adrian
Published: January 2025

Background

Alzheimer’s disease (AD) is a form of dementia that impairs memory, language, and daily functioning. With disease progression, AD patients reportedly experience disturbances in their awareness of self, others, and their environment. These disturbances are associated with unfavourable clinical outcomes, which prompts critical questions about how AD patients experience the world around them. The present study utilizes a validated neuroimaging paradigm to ‘map’ conscious experiences through changes in brain activity. The premise is that similarity (i.e., synchrony) in conscious experiences of different people can be detected by investigating activity in fronto‐parietal areas linked with higher‐order processing essential for plot‐following. This paradigm was previously used to assess conscious states of behaviorally non‐responsive brain‐injured patients, showing that the internal mental experience of some patients was similar to that of healthy controls.

Methods

In this study, patients with mild‐moderate AD (n = 9) and age‐matched healthy controls (n = 29) underwent a 40‐minute functional near‐infrared spectroscopy (fNIRS) scan. During the scan, participants watched two short movies, each with an intact‐ and scrambled‐plot version. Scrambled versions were included to demonstrate that synchrony was associated with higher‐order processing rather than the mere presentation of audio‐visual stimuli. Inter‐subject correlations (i.e., Pearson correlation coefficients between the hemodynamic activity of one or more AD patients and the remaining participants, including healthy controls) were used as the metric for synchrony.

Results

Compared to the scrambled plot conditions, healthy controls showed robust synchronization in the frontal and parietal regions in the intact‐plot conditions. AD patients, in contrast, did not demonstrate a consistent pattern of synchronization in these regions during the intact‐plot conditions. Single‐subject analyses (i.e., comparing individual patients to the control group) further revealed that only one AD patient exhibited some degree of synchronization with the healthy controls during the audio‐visual stimuli.

Conclusion

These preliminary findings indicate that AD patients may be experiencing the world differently from healthy individuals. The variability noted in synchronization across AD patients may be reflective of the heterogeneity in disease‐related impairments. Understanding deficits and patient needs from the lens of impaired conscious processing could support disease prognosis and promote improvements in person‐centered care.
Effect of Scanner on beta amyloid quantification in a head‐to‐head comparison of 18F‐NAV4694 Centiloid measurements between Biograph Vision, Gemini and Biograph mCT
Authors: Dore Vincent , Gillman Ashley G , Bourgeat Pierrick , Villemagne Victor L , Fripp Jurgen , Huang Kun , Williams Robert , Shishegar Rosita , O'Keefe Graeme , Cox Timothy , Li Shenpeng , Krishnadas Natasha , Feizpour Azadeh , Bozinovski Svetlana , Rowe Christopher C.
Published: January 2025

Background

New generation PET scanners achieve superior resolution and sensitivity, but the implications on beta amyloid (Aβ) quantitation are not well understood. The Centiloid (CL) scale (Klunk et al., 2015) was introduced to promote consistent Aβ burden quantification across different positron emission tomography (PET) tracers and quantification pipelines, but was not intended to control for hardware or reconstruction changes. Instead, post‐reconstruction smoothing harmonisation (Joshi, Koeppe, Fessler, 2009) is assumed to harmonise inter‐scanner Centiloid measurements. In this work, we compare paired Centiloid measurements between the Siemens Biograph Vision and one of Siemens Biograph mCT or Philips Gemini.

Method

28 AIBL participants underwent MPRAGE‐MRI and 18F‐NAV4694 imaging on two scanners (of Vision, mCT or Gemini) within a year, reconstructed per the ADNI protocols for each scanner. Centiloid was quantified using the standard SPM framework and corrected for expected accumulation between scans. We investigated difference in Centiloid and effectiveness of PET resolution harmonisation, i.e., smoothed to 6mm‐equivalent point spread function using estimates from Hoffman scans. Statistical significance was evaluated using empirical, one‐sided, non‐parametric bootstrap estimates.

Results

Figure 1 shows representative differences between the Vision and Gemini, and Figures 2,3 depict per‐scanner scatter and Bland‐Altman plots of Centiloid with and without resolution harmonisation, respectively. Even with harmonisation, Centiloid from Vision was found to be significantly higher than from Gemini (p=0.000) and from mCT (p=0.031); the difference followed a linear association with slope>1 (p=0.000 and p=0.010, respectively). The difference at 0CL was negligible, but at 100CL (Gemini) was +10.5% and at 100CL (mCT) was +11.7%. Resolution harmonisation only reduced ∼20% of scanner differences at most.

Conclusion

Scanner changes led to different Centiloid quantification, with difference proportional to the participant’s Centiloid itself. The standard resolution harmonisation procedure did not correct for scanner difference. For high‐amyloid individuals, the measured difference between Vision and Gemini or mCT (> +10%) was greater than the expected annual accumulation rate and so significant for longitudinal studies. Some scanners may exaggerate measured changes in Centiloid, or longitudinal scanner changes may mask or amplify changes. The fact that the effect between scanners was found linear is promising that scanner calibration methods are possible, further investigation is warranted.
Seeding and propagation of Tau from the retina to the brain in TAU58 mice
Authors: Walkiewicz Grzegorz , Ronisz Alicja , Ospitalieri Simona , Tomé Sandra O. , Vandenberghe Rik , Groef Lies De , Thal Dietmar Rudolf
Published: January 2025

Background

The retina, an integral part of the central nervous system, can exhibit protein accumulation (Aβ and pTau) associated with neurodegenerative diseases such as Alzheimer’s disease (AD). Biochemical analysis revealed the existence of a distinct primary retinal tauopathy (PReT), differing from AD and primary age‐related tauopathy (PART) brain lysates, suggesting it as a potential precursor for AD tauopathy with possible diagnostic value. However, it remains unclear whether retinal pTau pathology can spread from the eye into the brain.

Method

Brain lysates from human autopsy cases (PART and AD) from UZ Leuven biobank, Belgium, were homogenized and tau protein were extracted. Subretinal injections of brain homogenates, as well as phosphate‐buffered saline as negative control, were performed in two‐month‐old TAU58 mice (n=10/group) overexpressing human mutant 4‐repeat tau (P301S). Thirty‐three non‐injected TAU58 mice at various ages (6, 9, 12, 15 months) were used to examine age‐related retinal pTau pathology and neuronal loss. Paraffin‐embedded tissue sections were used for anti‐tau (AT8), anti‐RBPMS, and anti‐NeuN immunostainings, and Gallyas‐staining was used to visualize fibrillar tau pathology. Quantification of neuronal density and pTau pathology in brain samples and retinas were performed with QuPath software.

Result

The retinal changes associated with pTau in TAU58 mice were characterized. We observed pTau threads and cytoplasmic pTau accumulation, predominantly in the central retina, increasing with age. Retinal pTau was linked to neuronal loss in both central and peripheral retinal regions. Subretinal injection of the brain homogenates accelerated retinal pTau pathology without increased ganglion cell loss. Anterograde seeding of pTau from the eye to the brain occurred in mice receiving subretinal injections from AD brain lysates, showing significant pTau pathology in the zonal layer of the superior colliculus.

Conclusion

These results suggest that subretinal injection of human brain homogenates can induce tau seeding in the retina. The anterograde spreading of pTau pathology from the retina to the brain requires abundant pTau seeds, notably present in the AD brain and absent in cognitively normal PART cases.

Funding: SAO/FRA 2020/017
Optimizing PET Intensity Normalization for the Analysis of Cerebral Metabolism: A Study in Simulated and Real Data from an Alzheimer's Disease Model
Authors: Chamberlain‐Alvarado Helena , Cortes‐Canteli Marta , Casquero‐Veiga Marta
Published: January 2025

Background

Alzheimer's Disease (AD) has a long preclinical stage, in which brain metabolic alterations precede the symptoms onset. Therefore, an early and proper diagnosis of AD is essential for prevention and therapeutic evaluation. Current diagnosis and staging procedures rely on neuroimaging techniques, such as positron emission tomography (PET), which require intensity normalization to ensure the correct interpretation of the data. However, the variety of normalization methods and lack of standardization produce a major drawback regarding the proper interpretation of AD data by these techniques.

Method

We formally analyzed the performance of six well‐established intensity normalization methods (proportional scaling and data‐driven approaches) on brain PET images of fluorodeoxyglucose (FDG) obtained from healthy mice (N=10). The accuracy of each method was determined based on the recovery of different computer‐simulated patterns in the FDG‐PET scans achieved with voxel‐wise analyses. Furthermore, we applied this newly acquired knowledge to evaluate differences in cerebral FDG uptake in 16 and 62 weeks‐old AD mice (N16w=7; N62w=10) of the TgCRND8 model, and their wild‐type littermates (N16w=10; N62w=5).

Result

Our results showed a remarkable ambivalence between and within each normalization method under different simulation scenarios. They supported the use of an iterative histogram‐based normalization (iHN, Martí Fuster et al., 2013) when the data compared is not clearly biased (Figure 1B). Nonetheless, the reference cluster technique based on preserved regions (Yakushev et al., 2009) stood out for patterns with large and accentuated bias in the data (Figure 1A). Thus, the iHN method helped us to evaluate AD‐related differences in real FDG‐PET images, identifying genotypic effects that change with age (Figure 1C).

Conclusion

This study evidences the crucial importance of understanding the distribution of the radiotracer uptake in PET studies before selecting an intensity normalization strategy. Furthermore, our results provide simple and accurate guidelines to help to choose a proper normalization method in preclinical PET imaging, demonstrating its applicability in real data from AD mice.

References:

Martí Fuster et al., 2013. Neuroinformatics 11(1), 77‐89.

Yakushev et al., 2009. Neuroimage 44(1), 43–50.

Funding: EU Joint Programme – Neurodegenerative Disease Research (JPND), BrightFocus Foundation, and JDC2022‐048922‐I funded by MCIN/AEI/10.13039/501100011033 and European Union NextGenerationEU/PRTR.
Multivariate analysis of white matter crossing fibers reveals correlations with aMCI and dementia diagnoses
Authors: Bender Andrew R. , Weissman Caleb , Scheel Norman , Jung Youjin , Damoiseaux Jessica S. , Peltier Scott J , Hampstead Benjamin M.
Published: January 2025

Background

Diffusion magnetic resonance imaging (dMRI) permits characterizing differences in white matter microstructure associated with amnestic mild cognitive impairment (aMCI) and Alzheimer's dementia (AD). However, most dMRI measures aggregate signals across multiple axonal fiber populations with varying spatial orientations, which limits the sensitivity and specificity of clinical diagnosis. To overcome this shortcoming, we estimated fiber density (FD) measures, independently from crossing fiber populations, and extracellular cerebral spinal fluid (CSF). We hypothesized that aMCI and AD diagnoses are associated with differential patterns of FD changes in larger and smaller diameter fiber populations.

Method

We evaluated cross‐sectional dMRI data from 179 clinically characterized participants enrolled in the University of Michigan Memory and Aging Project. Image processing leveraged the MRtrix3 multi‐shell multi‐tissue fixel‐based analysis framework to estimate FD, separately for three fiber orientations, and CSF. Data analysis used multi‐block partial least squares correlation (PLS‐C) to estimate factors from multidirectional FD and CSF images correlated with differences between cognitively unimpaired (CU; n=98) and those diagnosed with aMCI (n=52) or AD (n=29).

Result

The PLS‐C model yielded three significant latent variables (LVs; Figure 1), reflecting patterns of both significant positive and negative associations between diagnosis and FD in crossing fibers. LV1 explained 80% of the differences from CU to aMCI to AD, demonstrating a stepwise reduction of FD and increased CSF with greater disease severity. However, LV2 and LV3 showed FD differences in smaller crossing fibers, distinguishing clinical diagnoses. Intriguingly, participants in the aMCI and AD groups showed different regions with increased or decreased FD in smaller crossing fibers, relative to CU participants. Pairwise PLS‐C models showed aMCI and AD diagnoses were associated with similar patterns of FD changes in smaller crossing fibers in overlapping regions.

Conclusion

The present study found distinctive patterns of white matter alterations that systematically differ across diagnostic severity in MCI and Alzheimer’s dementia. These results highlight the value of decomposing signals from crossing fibers as a sensitive neuroimaging correlate to clinical diagnosis. These findings challenge the common perspective that MCI and Alzheimer’s dementia are associated with monotonic declines in white matter integrity.
Visual‐Somatosensory Integration: A novel behavioral marker of preclinical Alzheimer’s disease?
Authors: Mahoney Jeannette R , Ayers Emmeline , Verghese Joe
Published: January 2025

Background

Growing evidence suggests that Alzheimer’s pathology manifests in sensory association areas well before appearing in neural regions involved in higher‐order cognitive functions, such as memory. The ability to successfully integrate sensory information across multiple sensory modalities is a vital aspect of everyday functioning and mobility. Our research suggests that multisensory integration, specifically visual‐somatosensory integration (VSI), could be used as a novel marker for preclinical AD given previously reported associations with important motor (balance, gait, and falls) and cognitive (attention) outcomes in aging.

Method

243 older adults (77 ± 6.5yrs; 52% female) with and without cognitive impairments that provided blood (plasma) specimens for amyloid‐beta (Aβ) testing were included in this cross‐sectional observational study. Participants completed a multisensory simple reaction time test in response to visual, somatosensory, and combined visual‐somatosensory stimulation. Magnitude of VSI was computed and served as the independent variable, while Aβ probability scores served as the dependent variable.

Result

Linear regression revealed a significant association between magnitude of VSI and Aβ probability scores, even after controlling for several key covariates (β = ‐.17; p <.01). Results indicate an inverse association of Aβ probability with magnitude of VSI, where increased Aβ probability scores were associated with worse multisensory integration performance.

Conclusion

These findings provide support for VSI as a potential novel non‐cognitive, non‐invasive biomarker of preclinical Alzheimer’s disease.
Community Psychiatry Clinic’s Impact on Dementia Care: Insight from Rythm Community Mental Healthcare Program
Authors: Vaseel M , Uvais Nalakath A.
Published: January 2025

Background

Dementia, a major concern in India (1‐10% prevalence), is challenging, particularly in rural areas with a significant treatment gap. Community psychiatry offers a promising solution, aiming to provide essential dementia care in underserved rural India, reflecting innovative approaches to extend mental health services equitably.

Methods

This study, employing a descriptive approach, examines the impact of Rythm community psychiatry clinics, an initiative by IQRAA International Hospital and Research Centre, on dementia care. The analysis focuses on key community activities, volunteer roles, provided services, and the engagement of Community‐Based Organizations (CBOs).

Results

Since August 2022, among the 8 Rythm community clinics with a total of 298 psychiatry patients, 4 clinics specifically address dementia cases. In these 4 clinics, 29 dementia cases were identified in the community, ranging in age from 68 to 95 years, with an average age of 77.5 years. Of the 29 cases, 25 were females, and 4 were males, resulting in a male‐to‐female ratio of 1:6. A post‐retirement group in Kodencherry, a CBO, alone identified 17 out of the total 29 cases, constituting 58% of the total. Nearly 90% of patients are under homecare follow‐up due to mobility restrictions, while the rest utilize clinic‐based consultations. Two rural community clinics also serve tribal patients with dementia. Dementia causes vary, including Alzheimer’s, vascular dementia, and Parkinson’s disease. Targeted case‐finding approaches effectively identify dementia cases early in the community through trained community volunteers, leading to referrals to community clinics and home‐based consultations. Caregiver education, behavioral management, symptomatic relief, psychological services, and specialist referrals contribute to comprehensive community‐level dementia care. Medications such as Donepezil, Memantine, Quetiapine, and Melatonin are employed based on symptom profiles, with Quetiapine being a commonly used antipsychotic. The results indicate a reduction in caregiver burden, fewer hospital admissions, increased access to primary and behavioral care, early case detection, referrals, and improved community awareness, subsequently reducing stigma surrounding dementia.

Conclusion

Community psychiatry clinics significantly impact dementia care by offering targeted case identification, caregiver education, and comprehensive services, ultimately contributing to improved community‐level dementia care and awareness.
Inhibition of Lyn kinase: A novel approach to treatment of Alzheimer’s disease
Authors: Benitah Avi L , Richardson Timothy I. , Weerawarna Pathum M , Robo Michael T , Mason Emily R
Published: January 2025

Background

The TREAT‐AD centers aim to improve Alzheimer’s Disease (AD) research by offering free, high‐quality tools and technologies.

Lyn is a tyrosine kinase that belongs to the Src family kinases. The expression of Lyn and its activity have been implicated in AD. This class of proteins is involved in TREM2 mediated microglial activation and phagocytosis, a process which is beneficial for clearing neurotoxins such as Aβ oligomers in the brain. Lyn inhibition may activate microglia. Given the relationship between accumulation of Aβ and its exacerbation of neurodegenerative diseases such as AD, selective inhibition of Lyn has been proposed as a novel therapeutic approach to treating early‐onset AD. However, potent, selective, and brain penetrant Lyn inhibitors are unavailable to test this hypothesis.

Method

We screened a variety of known kinase inhibitors to determine their activity towards inhibition of Lyn using the biochemical HotSpot kinase assay. With this data in hand, we identified imatinib as a starting point for the design of novel Lyn inhibitors. Structure‐based design and computational docking models were used to propose more active and selective Lyn inhibitors, which were synthesized. The activities were determined, and multiple parameter optimization (MPO) informed iterative Structure Activity Relationship (SAR) studies. The best compounds were evaluated in assays of microglia activation, and their drug metabolism and pharmacokinetic (DMPK) properties were determined.

Result

A series of novel type II inhibitors are now available for testing. The results demonstrate a unique tail group provides the novel scaffold with potent activity and selectivity towards inhibition of Lyn, exceeding that of imatinib.

Conclusion

Computational models, SAR, and MPO provided potent and selective Lyn inhibitors with good DMPK properties. Further studies are under way to determine the impact of these compounds on TREM2 mediated activation of microglia both in vitro and in vivo.

Author List:

Avi Benitah PhD,

Pathum M Weerawarna PhD,

Michael Robo, PhD,

Shaoyou Chu, PhD

Emily R Mason, PhD

Timothy I Richardson, PhD
Impact of Study Partner Type on Participant Retention Across Global Regions in the Tauriel and Lauriet Trials for Alzheimer’s Disease
Authors: Ritchie Marina , Datta Seema , Monteiro Cecilia , Toth Balazs , Teng Edmond
Published: January 2025

Background

Participant retention is a key determinant for a successful clinical trial. In Alzheimer’s disease (AD) trials, participants are typically required to enroll with a study partner, which adds barriers to retention. Previous analyses of North American trial data found that most study partners were spouses and that such dyads had higher study completion rates than other study partner types. We sought to determine whether these findings could be confirmed in additional trials conducted across broader geographic regions.

Method

Our post‐hoc analyses used data from two phase II trials of semorinemab, Tauriel (prodromal‐to‐mild AD; NCT03289143) and Lauriet (mild‐to‐moderate AD; NCT03828747), we examined the proportion of participants completing the trials by study partner type (Domestic Partner vs. Other) and geographical region (North America and Europe). We fit logistic regression models to assess whether participant retention differed by study partner type in the two trials (separately and combined) and adjusted the models for region, study partner type, participant age, sex, education, APOE4 status, and study partner sex. We considered potential effect modification by region by including an interaction term between study partner type and region. We conducted sensitivity analyses excluding participants who discontinued based on adverse events or death.

Result

We observed effect modification by region in the association between study partner type and retention (Tauriel: p = 0.011, Lauriet: p = 0.015; combined: p = 0.003). In Europe, Other study partner types had significantly lower odds of trial completion compared to domestic partners in Tauriel (OR: 0.21; CI: 0.06, 0.74) and in the combined analysis (OR: 0.28; CI: 0.11, 0.65). While not statistically significant, we observed similar trends in Lauriet (OR: 0.36; CI: 0.10, 1.22). No clear differences in retention were observed across study partner types in North America for either trial.

Conclusion

Data from the two semorinemab trials suggest that there may be regional differences in the impact of study partner type on retention. Further studies are needed to assess the generalizability of these findings, with an emphasis on cohorts with more representative samples of non‐spousal dyads.
IUSM‐Purdue TREAT‐AD Center Capabilities and Strategy to Enable and Advance Novel Therapeutic Targets for the Treatment of Alzheimer’s Disease
Authors: Mowery Stephanie A. , Huang Kun , Mesecar Andrew D. , Dage Jeffrey L. , Clayton Brent , Lamb Bruce T. , Palkowitz Alan D. , Richardson Timothy I.
Published: January 2025

Background

The TaRget Enablement to Accelerate Therapy Development of Alzheimer’s Disease (TREAT‐AD) Centers are dedicated to identifying and validating targets from the NIH Accelerating Medicines Partnership for Alzheimer’s Disease (AMP‐AD). The centers develop Target Enabling Packages (TEPs) to explore new therapeutic target hypotheses, moving beyond the traditional focus on amyloid or tau pathologies. In accordance with open science principles, data, methods, and tools are freely shared with the research community via an open‐access platform, the AD Knowledge Portal. The Indiana University School of Medicine and Purdue University TREAT‐AD (IUSM Purdue TREAT‐AD) Center comprises four technical cores: Bioinformatics and Computational Biology (BCB), Structural Biology and Biophysics Core (SBB), Assay Development and High Throughput Screening (ADHTS), and Medicinal Chemistry and Chemical Biology (MCCB). These cores collaborate to develop research tools that are used to validate biological targets and assess their druggability with an initial focus on understanding the role of neuroinflammation in AD.

Method

The BCB Core supports target selection and validation with data and analysis. The SBB Core provides proteins for assay development, biophysical assays, and structural studies to aid in mode of action and Structure Activity Relationship (SAR) studies. The ADHTS Core develops in vitro and in vivo assays for SAR studies and translational PD biomarker strategies to assist in determining early phase clinical dosing regimens. The MCCB Core selects therapeutic modalities (small molecules, antibodies, siRNA) and discovers pharmacological tools, employing strategies for SAR studies to balance pharmacological and drug‐like properties.

Result

Target Enabling Packages (TEPs) are now available via the AD Knowledge Portal for microglia targets that were prioritized for early drug discovery studies. TEPs include bioinformatics analysis, biological reagents and protocols, protein production methods, and recommended chemical probes with detailed information (Figure 1). Novel small molecule hits and leads were identified for SHIP1, PLCG2, SHP1 and LYN/HCK.

Conclusion

A pipeline of prioritized microglia targets were selected and enabled for early drug discovery. The IUSM Purdue TREAT‐AD Center is now working with AMP‐AD researchers to explore biological hypothesis in addition to the role of neuroinflammation in AD.
The role of Community Health Workers in supporting caregivers of Hispanic/Latino older adults with dementia and the need for workforce expansion
Authors: Turner Wesli H , Patrick Shannon , Aguilar Saúl Juárez , Pinzon Maria C Mora
Published: January 2025

Community Health Workers (CHWs), also known as Promotores de Salud expand health equity to underserved and hard‐to‐reach communities by providing increased access to healthcare and support services for caregivers and persons living with dementia (PLWD). CHWs have been particularly useful in supporting Hispanic/Latino communities, who are 1.5 times more likely to develop Alzheimer’s Disease and related dementias than non‐Hispanic whites and are less likely to access support services due to language and cultural barriers. CHWs offer support in culturally appropriate ways, linking families to much needed services and assistance acting as a crucial support system for many who lack the knowledge of where to access services or face cultural or linguistic barriers to accessing those services. When CHWs are integrated into care teams, they can reduce the burden on other health professionals by focusing on addressing the social determinants of health, allowing health professionals to focus on their area of expertise with patients. CHWs can increase awareness of the disease, promote activities that reduce the risk factors for ADRD, provide navigation services, and facilitate caregiver support groups.

This presentation will highlight the value of CHWs in providing culturally and linguistically appropriate dementia caregiver support within Hispanic/Latino communities. Presenters will discuss outcomes from a CHW‐led caregiver support program that showed a 22% increase in knowledge of ADRD (p <0.001), 56% increase in caregiver preparedness skills (p <0.001) and showed a 33% reduction in depression symptoms among participants (p <0.001). To date, 82 caregivers have been served through this program, supporting the development of the CHW workforce in assisting caregivers and PLWD.

Presenters will also detail a novel HRSA‐funded CHW training program that creates a workforce pipeline from the community to the healthcare system providing paid training through a federal grant. From March 2023 to January 2024, 105 CHWs have been trained across 17 counties in Florida, of which 58% identify as Hispanic/Latino. By demonstrating the possibilities of a workforce pipeline, this presentation will provide the “How” and “What” of bridging the growing labor gap in supportive services for Hispanic/Latino persons living with dementia and their caregivers using CHWs.