bluuebunny/crossref_metadata_2025 huggingface dataset:
Auditory Intervention Program for Older Adults with Cognitive Impairment: Systematic Review and Metaanalysis
Authors: Piyajarawong Teeraya , Limkitisupasin Patcharaorn , Manum Pornnapat , Utoomprurkporn Nattawan
Published: January 2025

Background

The elderly population is particularly susceptible to the development of age‐related hearing loss and cognitive impairment. The gradual decline in auditory perception often goes unnoticed, leading to a detrimental impact on their quality of life, mental well‐being, and overall communication skills. Extensive research indicates that prolonged social isolation can exacerbate cognitive decline. Fortunately, hearing intervention has the potential to prevent this devastating consequence.

Method

Three independent reviewers meticulously reviewed the selected articles. The Covidence was utilized to identify and eliminate any duplicate publications. In cases of disagreement, a fourth reviewer was consulted for adjudication. For inclusion criteria, the studies had to be in the English language and conducted on a population aged 50 years or older who were diagnosed with cognitive impairment. Animal studies and those lacking control groups (either healthy controls or pre‐ and post‐intervention tests) were excluded. We utilized the National Institute of Health (NIH) criteria for evaluating the quality of studies.

Result

Out of the initial 7,069 search results, we selected 39 articles for inclusion in this study. Among these, the majority comprised randomized trials (10 out of 39) and pre‐ and post‐intervention tests (10 out of 39). The hearing interventions were categorized into four distinct groups: hearing aids, cochlear implants, medication, and sound therapy. It was observed that medication showed the least efficacy while hearing aids and cochlear implants demonstrated the most significant improvements. Following the prescription of hearing aids and cochlear implants, patients experienced enhanced quality of life, despite significant improvement not only in cognition but also in psychological and social well‐being. Additionally, sound therapy exhibited promising results in terms of stress relief and improvement in instrumental and lyric recognition among cognitively impaired patients.

Conclusion

Our findings indicate that hearing aids, cochlear implants, and sound therapy significantly enhance psychological and social health in individuals with cognitive impairment or dementia. Furthermore, there is a statistically significant improvement in quality of life with appropriate hearing interventions. However, we observed no substantial improvement in cognitive status as assessed by the Montreal Cognitive Assessment (MoCA) and the Mini‐Mental State Examination (MMSE), although there is a suggestive trend towards cognitive enhancement.
The atrophy of specific amygdala subnuclei is associated with temporal tauopathy in preclinical AD individuals
Authors: Salman Yasmine , Gérard Thomas , Huyghe Lara , Colmant Lise , Quenon Lisa , Malotaux Vincent , Boyer Emilien , Ivanoiu Adrian , Lhommel Renaud , Dricot Laurence , Hanseeuw Bernard J
Published: January 2025

Background

In AD, tauopathy and atrophy start in the mesiotemporal lobe, including the amygdala‐hippocampal complex. Until recently, subnuclei and subfields within these structures were indistinguishable in‐vivo. FreeSurfer 7.0 now enables their segmentation. Our goal was to study hippocampal and amygdala subregions’ atrophy in preclinical AD to assess whether specific subregion atrophy could indicate early tauopathy at the preclinical stage.

Methods

We conducted an exploratory study in the ADNI3 cohort including 144 amyloid‐positive cognitively‐normal adults (Aß+CN) with 3DT1‐MRI and [18F]AV‐1451 Tau‐PET data. We identified hippocampal and amygdala subregions explaining at least 1% of the variance of the Tau‐PET signal from the temporal meta‐ROI defined by Jack (2017). We validated these results with our in‐house data, including 112 individuals with 3DT1‐MRI and [18F]MK6240 Tau‐PET scans. Groups were categorized by visual Braak‐stage or bioclinical classification based on cognition (CN/MCI) and amyloid status (Aß‐/Aß+).

Results

In ADNI3, amygdala and hippocampal volumes were not associated with temporal tauopathy in Aß+CN (R²<0.001). However, four amygdala subnuclei (cortical, central, medial, and accessory‐basal nuclei) out of nine and the hippocampal tail (out of twelve subfields) each explained over 1% of the variance in temporal tauopathy in Aß+CN (one‐tail p<0.10). These tau‐associated subnuclei were pooled into an amygdala aggregate whose volume was significantly associated with temporal tauopathy in Aß+CN, even after adjusting for amygdala volume. In Aß+MCI (n=132), global structure volumes were significantly associated with temporal tauopathy, with subnuclei atrophy adding no explanatory power (Figure 1). Within our in‐house data, individuals with early Tau‐PET signal (Braak I‐II) had similar global amygdala and hippocampal volumes than Braak 0 individuals. However, the tau‐associated amygdala aggregate generated in ADNI3 was significantly smaller in Braak I‐II individuals. Similarly, only the aggregate was significantly smaller in Aß+CN compared to Aß‐CN (Figure 2). These results remained significant after adjusting for global structures (Figure 3).

Conclusion

We identified four amygdalae subnuclei whose atrophy is earlier than global amygdala. Atrophy in these subnuclei is associated with temporal tauopathy in preclinical AD, distinguishing visual Braak‐stage I‐II from Braak‐stage 0 individuals. Measuring amygdala subnuclei volumes in older adults is a promising approach to identify individuals at‐risk of progression to clinical AD.
The importance of AT(N)‐V imaging biomarkers differs in diverse populations
Authors: Meeker Karin L.
Published: January 2025

Background

Investigations into the amyloid, tau, and neurodegeneration (ATN) framework, which is used to stage Alzheimer disease (AD) and advance clinical trials, typically consist of clinic‐based non‐Hispanic White (NHW) populations. The present study sought to cross‐sectionally characterize AT(N) and vascular (V) imaging markers (i.e., amyloid and tau positron emission tomography [PET], AD cortical thickness signature, and white matter hyperintensities), and determine the relative importance of each marker in predicting cognitive status (Clinical Dementia Rating Scale Sum of Boxes) in a large ethnically and racially diverse sample.

Method

Data were obtained from the community‐based Health and Aging Brain Study – Health Disparities (HABS‐HD) and included Mexican Americans (MAs, n=669), African Americans (AAs, n=747), and NHWs (n=768). Group differences in AT(N)‐V biomarkers were assessed using Kruskal Wallis ANOVAs. Age and gender were included as covariates. Dominance analysis determined the relative ‘importance’ of each biomarker in predicting cognitive status in the entire cohort and separately for each group. All analyses were performed for the entire cohort, and for individuals on the AD trajectory (i.e., amyloid PET+).

Result

Across the entire cohort, amyloid was significantly greater in AAs compared to NHWs (p’s < 0.01). Tau and neurodegeneration were greater in MAs and AAs compared to NHWs (p’s < 0.01). White matter hyperintensities were greater in AAs and NHWs compared to MAs (p’s < 0.01). There were no significant group differences in AT(N)‐V measures in individuals who were amyloid PET+ (p’s > 0.05). In the entire cohort, A was the most important biomarker (as evidenced by greater R2 values; see Figure 1) in predicting cognitive status. In MAs and AAs, A was also the most important while in NHWs, T was the most important. When constraining to amyloid PET+ individuals, T was most important across all individuals and in NHWs while N was most important in MAs and AAs.

Conclusion

These results are important for evaluation of the new AT(N) criteria and suggest that the magnitude and overall contributions of AT(N)‐V imaging biomarkers in predicting cognitive outcomes may vary among ethno‐racial groups. Possible differential effects of AD biomarkers should be considered in research, clinical trials, and response to treatment.
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.
The association between tau pathology and later stages of memory processing is mediated by medial temporal lobe atrophy in typical Alzheimer's Disease
Authors: Wuestefeld Anika , Cui Salena , Das Sandhitsu R. , Xie Long , McGrew Emily , Yushkevich Paul A. , Wisse Laura , Wolk David A
Published: January 2025

Background

Tau pathology is closely related to cognitive decline in Alzheimer’s disease (AD). Neurodegeneration is the putative mechanism by which tau leads to cognitive deficits. However, there is limited work on the associations between tau, neurodegeneration, and specific cognitive domains. We investigate potential mediating effects of medial temporal lobe (MTL) and neocortical neurodegeneration for different cognitive domains in amyloid‐ß‐positive (Aß+) adults.

Method

We included 325 positron emission tomography (PET) Aß+ individuals across the AD spectrum from the Alzheimer’s Disease Neuroimaging Initiative (age: 72±8 [55–90]; 51.1% female, education: 16±2 years). Hippocampal volume and cortical thickness were measured from T1‐weighted structural magnetic resonance imaging in typical AD regions (Fig. 1). Using flortaucipir‐PET, tau was quantified for two composite regions (MTL, neocortical). Included cognitive measures are shown in Fig. 1. Mediation analyses between tau‐PET, thickness/volume, and cognition were performed. Cognitive measures were adjusted to isolate the function of interest (Fig. 1).

Result

Higher tau‐PET uptake and lower thickness were associated with lower performance on all cognitive measures. In simple mediations, tau‐immediate recall associations were mediated by MTL, parietal, and temporal regions (Fig. 2A). Tau‐delayed recall associations were mediated by MTL regions. Tau‐late recall and tau‐recognition associations were mediated by MTL and parietal regions. Tau‐fluency and tau‐executive functioning associations were mediated by MTL and parietal regions, as well as temporal regions for fluency. Complex mediations investigated significant mediators simultaneously (Fig. 2B+3). Depending if MTL/neocortical tau remained significant when covarying for the other tau measure in a regression, the complex mediation models focused on MTL and/or neocortical regions (Fig. 2B description). Hippocampus mediated the tau‐late recall and tau‐recognition associations. Brodmann area 35 mediated the tau‐delayed recall association. Tau‐fluency was, at a trend level, mediated by inferior temporal thickness. Tau‐executive functioning did not demonstrate a mediation effect, potentially due to limited frontal atrophy. All mediators were partial mediators explaining up to 23% of variance.

Conclusion

The results suggest that MTL tau pathology, partially mediated by macrostructural changes, lead to impairments in specific memory domains in early AD. Impairments in fluency and executive functioning, however, seem more likely to follow from tau‐induced effects in neocortical regions.
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 (Aß) 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.
Comparison of tau‐PET tracers for in vivo Braak staging: the HEAD Study
Authors: Macedo Arthur C. , Therriault Joseph , Rahmouni Nesrine , Servaes Stijn , Wang Yi‐Ting , Tissot Cécile , Lussier Firoza Z , Arias Jaime Fernandez , Socualaya Kely Monica Quispialaya , Hosseini Seyyed Ali , Ferreira Pamela C.L. , Bellaver Bruna , Ferrari‐Souza João Pedro , Aguzzoli Cristiano Schaffer , Povala Guilherme , Pascual Belen , Gordon Brian A. , Lowe Val J. , Oh Hwamee , Soleimani‐Meigooni David N. , Baker Suzanne L. , Pascoal Tharick Ali , Rosa‐Neto Pedro
Published: January 2025

Background

Tau‐PET tracers allow for in vivo Braak staging of individuals in the Alzheimer’s disease (AD) continuum. The impact of tracers’ characteristics for Braak staging using tau‐PET remains unclear. Therefore, we performed a head‐to‐head comparison of Braak staging using first‐ and second‐generation tau‐PET tracers.

Method

We assessed 51 cognitively unimpaired (CU) and 49 cognitively impaired participants (mean [SD] age 69.4 [7.5] years) with at least two tau‐PET ligands ([18F]MK6240, [18F]AV1451, and/or [18F]RO948) at McGill University, as part of the HEAD study. We calculated standardized uptake value ratios (SUVR) in Braak‐like regions of interest (ROI) for each ligand and investigated their association using Spearman’s correlation. Thresholds defined the presence of tauopathy in each Braak ROI, which was used to assign a Braak stage to each participant. Finally, we assessed the agreement between the Braak staging provided by each tracer, both for the traditional (using separate Braak stages – 0, I, II, III, IV, V, and VI) and simplified (using joint Braak stages – 0, I‐II, III‐IV, and V‐VI) frameworks.

Result

In all Braak ROIs, we found positive correlations between the SUVR values of the three tracers (Fig. 1). The strongest correlation was between [18F]MK6240 and [18F]RO948 in Braak II (r=0.94), and the weakest between [18F]AV1451 and [18F]RO948 in VI (r=0.51). Inter‐tracer agreement regarding the latest stage of abnormality was substantial or nearly perfect between pairs of tracers but moderate between the three tracers (Fig. 2A). The simplified framework presented greater agreement compared to traditional Braak staging, except between [18F]MK6240 and [18F]RO948. At the ROI level, the lowest agreements were observed for Braak II and I‐II, when [18F]MK6240 and [18F]RO948 were compared to [18F]AV1451 (Fig. 2B‐C). [18F]AV1451 had the highest probability of overestimating the Braak stage assigned by [18F]MK6240 and by [18F]RO948, especially at earlier stages (Fig. 3).

Conclusion

The ligands presented moderate to nearly perfect agreement for in vivo staging of AD severity. Off‐target binding of [18F]AV1451 to the choroid plexus might explain disagreements at early stages. Overall, slight improvements in agreements were achieved with the simplified framework, as observed in histopathological staging.
Neuropsychiatric symptoms and brain aging in mild cognitive impairment and early dementia: A multicenter study
Authors: Sone Daichi , Beheshti Iman , Tagai Kenji , Kameyama Hiroshi , Takasaki Emi , Kashibayashi Tetsuo , Takahashi Ryuichi , Ishii Kazunari , Kanemoto Hideki , Ikeda Manabu , Shigeta Masahiro , Shinagawa Shunichiro , Kazui Hiroaki
Published: January 2025

Background

Despite the clinical importance and significant social burden of neuropsychiatric symptoms (NPS) in dementia, the underlying neurobiological mechanism remains poorly understood. Recently, neuroimaging‐derived brain‐age estimation by machine‐learning analysis has shown promise as an individual‐level biomarker. We investigated the relationship between NPS and brain‐age in amnestic mild cognitive impairment (MCI) and early dementia.

Method

Clinical data, including neuropsychiatric inventory (NPI), and structural brain MRI of 499 individuals with clinical diagnoses of amnestic MCI (N=185), early Alzheimer’s disease (AD) (N=258) or dementia with Lewy bodies (DLB) (N=56) were analyzed. We established a brain‐age prediction model using 694 brain structural MRI scans of healthy subjects and support vector regression model and applied it to the patients’ data. Finally, the brain predicted age difference (brain‐PAD: predicted age minus chronological age) were calculated.

Result

All clinical diagnostic groups showed significantly increased brain‐PAD, and the median (IQR) brain‐PAD was 4.3 (5.4) years in MCI, 6.3 (6.2) years in AD, and 5.0 (6.5) years in DLB. The NPI scores were subdivided into the following four categories: (i) Agitation and Irritability, (ii) Depression and Apathy, (iii) Delusions and Hallucinations, and (iv) Euphoria and Disinhibition. We found a significantly positive correlation between brain‐PAD and the depression/apathy factor (Spearman’s rs = 0.156, FDR‐corrected p=0.002), while no significance was shown in the other NPS factors.

Conclusion

Abnormal brain aging may be involved in depression and apathy symptoms presented in MCI to early dementia stages, and brain‐age analysis may be useful as a novel biomarker for assessment or monitoring of NPS.
Sleep and Physical Activity are Associated with Cognition and Resting‐State Functional Imaging Measures of Network Segregation in Non‐demented Older Adults
Authors: Callow Daniel
Published: January 2025

Background

Greater physical activity and better sleep are associated with reduced risk of cognitive decline and dementia among older adults, but little is known about their associations with measures of brain function and neuropathology.

Method

This study investigated potential independent and interactive cross‐sectional relationships between actigraphy‐estimated total volume of physical activity (TVPA) and sleep patterns [i.e., total sleep time (TST), sleep efficiency (SE)] with cognitive performance (n = 157). In a subset of participants, the physical activity and sleep measures were also evaluated in relationship to resting‐state functional magnetic resonance imaging (rs‐fMRI) measures of large‐scale network connectivity, and positron emission tomography (PET) measures of amyloid‐ß (n = 135). Participants were part of the BIOCARD study including 136 cognitively normal individuals and 21 participants with mild cognitive impairment (mean age = 71.7 years). Using linear regression analyses, we assessed the association between TVPA, TST, and SE with cognition, connectivity within the default‐mode, salience, and fronto‐parietal control networks, and with network modularity, a measure of network segregation.

Result

Greater TVPA and SE each were positively associated with better global cognitive composite scores and executive function. Importantly, a TVPA by SE interaction suggested that adults with the poorest SE experienced the greatest benefit from physical activity in relation to cognition. In the imaging subsample, higher TVPA and SE were independently associated with greater network modularity, although the positive relationship of SE with modularity was only present in amyloid‐negative individuals. Additionally, higher TVPA was associated with greater connectivity within the default‐mode network, while greater SE was related to greater connectivity within the salience network. In contrast, longer TST was associated with lower network modularity, particularly among amyloid‐positive individuals, suggesting a relationship between longer sleep duration and greater network disorganization. Physical activity and sleep measures were not associated with amyloid positivity.

Conclusion

These data suggest that greater physical activity levels and more efficient sleep may promote better cognition and more segregated and potentially resilient functional networks, as well as greater functional connectivity within specific large‐scale networks. Additionally, the relationship between sleep and functional networks connectivity may depend on amyloid status while associations with physical activity may be independent of amyloid status.
Investigating Spatial Characteristics of Brain Atrophy in Alzheimer's and LATE neuropathology
Authors: Saifullah Khalid , Ridwan Abdur Raquib , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos
Published: January 2025

Background

Alzheimer’s disease neuropathologic change (AD‐NC) and limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) are common in older adults and have been associated with brain atrophy, cognitive decline, and dementia. Since AD‐NC and LATE‐NC are often comorbid and due to the fact that LATE‐NC can only be detected at autopsy, in this work, we combined deformation‐based morphometry (DBM) on ex‐vivo brain MRI and detailed neuropathological evaluation in a large number of community‐based older adults to investigate the difference in brain atrophy patterns associated with AD‐NC and LATE‐NC.

Method

Cerebral hemispheres from 912 older adults participating in four longitudinal, clinical‐pathologic cohort studies of aging were included in this work: MAP, ROS, MARS, and AA Core of the Rush Alzheimer’s Disease Research Center (Rush ADRC) (Figure 1). All hemispheres were imaged ex‐vivo on 3T clinical MRI scanners approximately 1‐month postmortem while immersed in 4% formaldehyde solution. T2‐weighted images of all hemispheres were non‐linearly registered and logarithm of the Jacobian determinant (LogJ) of the deformation field was calculated in each voxel. Following ex‐vivo MRI, the pathologies that were assessed were AD‐NC, LATE‐NC, Lewy bodies, gross infarcts, microscopic infarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. AD‐NC‐pos was defined as moderate or severe AD‐NC according to the NIA‐AA criteria, and LATE‐NC‐pos was defined as LATE‐NC stages 2 or 3. Voxel‐wise linear regression was used to test the association of the deformations observed in the smoothed log Jacobian maps with the four different groups, controlling for all other neuropathologies, demographics, postmortem intervals, and scanner. We used 5000 permutations, and statistical significance was set at p<0.05 after family wise error (FWE) correction.

Result

Both the AD‐NC‐pos LATE‐NC‐neg group (Figure 2a) as well as the AD‐NC‐neg LATE‐NC‐pos group (Figure 2b) were associated with lower tissue volume mainly in medial temporal lobe structures. The AD‐NC‐pos LATE‐NC‐pos group (Figure 2c) showed substantially lower volume in the temporal, frontal, and parietal lobes. Interestingly, the AD‐NC‐neg LATE‐NC‐pos group showed lower volume in the anterior portion of the hippocampus than the AD‐NC‐pos LATE‐NC‐neg group (Figure 2d).

Conclusion

The findings suggest that in the presence of LATE‐NC, the volume of the hippocampus cannot serve as a marker of AD‐NC.
Similarity of regional brain blood flow and glucose utilization imaging biomarkers in older adults
Authors: Lepping Rebecca J , Taylor Jasmine M , Honea Robyn A , Hess Benjamin J , Vidoni Eric D , Brooks William M , Burns Jeffrey M , Swerdlow Russell H
Published: January 2025

Background

Cerebral blood flow (CBF) and glucose utilization have both proven sensitive biomarkers of brain function in Alzheimer’s disease. However, while blood flow supplies glucose to cells to meet local demand, and therefore, are inter‐related, the two aspects are physiologically distinct. Our goal was to conduct a region‐to‐region correlation of magnetic resonance imaging (MRI) and 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) biomarkers of cerebral blood flow and glucose utilization to determine whether these physiologically distinct biomarkers yield functionally distinct information.

Method

108 older adults who were cognitively unimpaired (n = 71), or had mild cognitive impairment (n = 17) or dementia due to Alzheimer’s disease (n = 18), and who were enrolled in the KUMC Alzheimer’s Center Cohort completed both MRI T1‐weighted structural and pseudocontinuous arterial spin labelling (PCASL) and FDG‐PET scanning. Participant‐unique brain regions were created by segmentation of the T1‐weighted images with FreeSurfer, combined into large regions of interest for anterior/posterior cingulate, frontal, temporal, and parietal cortices. Preprocessing in SPM12 and AFNI were conducted for the PCASL and FDG‐PET data separately, and regional CBF and glucose utilization (specific uptake value ratio [SUVR]) were extracted. Correlation analysis was conducted in SPSS 29.

Result

CBF and FDG‐PET SUVR were significantly positively correlated in the ACC‐PCC (r = .22, p = .02), Temporal (r = .26, p<.01), and Parietal (r = .37, p<.001) cortices, but not in the Frontal cortex (r = .13, p = .19). The correlations were modest, with the largest at .37 in Parietal cortex.

Conclusion

Our results indicate an expected, yet somewhat modest correlation in the majority compared regions. Additionally, the correlation was not identical across the brain, and non‐significant in frontal regions. This analysis revealed that CBF and FDG‐PET are complementary measures that provide non‐overlapping information. We conclude that these two biomarkers yield unique information and may have unique value in elucidating the relationship between blood flow and neuronal function, potentially more so for frontal rather than parietal regions.
KLOTHO‐VS heterozygosity ameliorates the effects of APOE ε4 on longitudinal hippocampal atrophy
Authors: Zhang Linda , Alfayate Eva , Calero Miguel , Medina Miguel , Grothe Michel J. , Sanchez‐Juan Pascual , Strange Bryan A.
Published: January 2025

Background

KLOTHO‐VS heterozygosity (KL‐VShet+) has been posited to be a protective factor against age‐related disease and cognitive decline, having been associated with increased cortical volumes and brain connectivity, as well as improved cognition in healthy elderly individuals. Conversely, the APOE‐e4 allele is a primary risk factor for the development of Alzheimer’s disease (AD), with e4 carriers more likely to have greater ß‐amyloid burden, earlier age of AD onset, and accelerated rates of cognitive decline. Relatively few studies have investigated the interaction between these two genetic factors, with those that have presenting conflicting findings.

Methods

720 cognitively normal elderly participants (mean age: 74.7 years, range: 69‐87) with 3T T1‐weighted MRI, APOE and KL‐VS genotyping were selected for cross‐sectional analyses from the Vallecas Project cohort, a single‐centre 12‐year longitudinal study with annual follow‐ups. Of these participants, 443 had at least two visits and were included in longitudinal analyses (average follow‐up 4.7 years). Linear regression models were conducted to study the interaction between KL‐VS heterozygosity (KL‐VShet‐ vs. KL‐VShet+: n = 539 and 181, respectively) and APOE‐e4 (carrier vs. non‐carrier: n = 135 and 585, respectively) on FreeSurfer‐derived hippocampal volumes, neuropsychological test scores, and plasma AD biomarkers (available for a subset, n=186), controlling for age, sex, education (in models with neuropsychological outcomes), and total intracranial volume (when considering hippocampal volume). Linear mixed‐effects models were used for longitudinal analyses of the same variables.

Results

No significant interactions between genotypes were found for any cross‐sectional comparisons. A significant KL‐VShet+ by APOE‐e4 interaction was observed in longitudinal right hippocampal volumes, where KL‐VShet+ e4‐carriers had similar rates of hippocampal atrophy compared to e4‐noncarriers, and slower rates compared to KL‐VShet‐ e4‐carriers (ß=52.94, SE=25.03, p=0.03). No significant interactions were found for neuropsychological scores or biomarker levels.

Conclusion

Our study provides additional evidence to suggest that KL‐VS heterozygosity attenuates the detrimental effects of APOE‐e4 on brain structure in healthy elderly adults, although the effects are not apparent in cognitive performance. Plasma AD biomarker levels did not vary significantly as a function of genotype, although this may be due to the smaller sample size. Further analyses will be conducted as more samples continue to be processed.
Clusters of modifiable risk factors provide resilience to the cognitive effects of β‐amyloid pathology in aging
Authors: Bhade Mohini , Pezzoli Stefania , Giorgio Joseph , Ward Tyler J. , Landau Susan M. , Jagust William J.
Published: January 2025

Background

Although it has been estimated that modifiable risk factors account for around 40% of population variability in dementia risk, understanding how risk factors are related to one another and to brain pathology and cognition has been challenging. We used a clustering approach to examine patterns of risk factor interrelationships and to investigate how these patterns affect relationships between pathology and cognition.

Method

We collected risk factor data concerning health, lifestyle, sleep, and personality from 149 cognitively normal older adults (73±6.2 years), as well as PET‐measured amyloid (11C‐Pittsburgh compound‐B, PiB) and, in a subsample (n = 126), PET‐measured tau (18F‐Flortaucipir, FTP). All participants completed longitudinal neuropsychological testing (follow‐up 8.1±4.2 years). K‐means clustering was used to assign participants to different risk profiles that reflected how risk factors were interrelated. Linear mixed‐effects models were used to assess associations between decline in 1) episodic memory (EM) and 2) non‐memory (NM) cognition composite scores, with cluster assignment and PiB‐status (±) or entorhinal FTP uptake as predictors. Analyses were age and sex adjusted.

Result

K‐means clustering generated 3 distinct risk‐related profiles, with more favorable profiles seen for participants in cluster 1 (physical/cognitive activity, education) and cluster 2 (sleep, depression, personality) than cluster 3 (Figure 1). In a model predicting NM decline with PiB‐status as a predictor, we observed a significant three‐way interaction between PiB‐status, cluster, and time (p<0.01) with an attenuated effect of Aß on NM decline in cluster 1 (ß = 3.7, p<0.01) and cluster 2 (ß = 3.7, p<0.01) compared to cluster 3. A model predicting EM revealed no significant interaction between cluster, PiB‐status and time (Figure 2). While a significant entorhinal tau x time effect was observed in a model predicting EM decline, cluster assignment did not modify this relationship. Results were similar when APOE4 status was included in the models.

Conclusion

Favorable risk profiles (cluster 1 and 2) attenuated the effect of Aß, but not tau, on cognitive decline. These findings suggest that different risk profiles moderate pathology‐cognition relationships, and demonstrate that different factors may operate together in reducing risk. This highlights the role of groups of modifiable resilience factors in mitigating the effects of Aß deposition.
Accelerated Temporal Cortex Tau Accumulation Mediates the Effects of Low Physical Activity on Faster Cognitive Decline in Preclinical Alzheimer's Disease
Authors: Yau Wai‐Ying Wendy , Kirn Dylan , Rabin Jennifer S , Properzi Michael J , Schultz Aaron P , Rentz Dorene M. , Johnson Keith A , Sperling Reisa A , Chhatwal Jasmeer P.
Published: January 2025

Background

Physically inactivity is associated with increased risk of dementia including Alzheimer’s disease (AD). Prior work from the Harvard Aging Brain Study (HABS) suggests that lower baseline physical activity in cognitively unimpaired individuals with elevated amyloid burden is associated with faster prospective cognitive decline. However, whether this detrimental effect on cognition in preclinical AD is mediated by accelerated tau pathology remains unclear.

Method

We examined 293 baseline cognitively unimpaired older adults from HABS (Table 1). Baseline physical activity (mean steps per day) was measured using a waistband‐mounted pedometer (HJ‐720ITC; Omron Healthcare) worn over 7 consecutive days during waking hours. Using linear mixed effects models, we examined the interactive effects of baseline physical activity and amyloid PET burden (Pittsburgh Compound‐B) on longitudinal cognitive decline (Preclinical Alzheimer Cognitive Composite‐5 [PACC5]), adjusting for age, sex and education (APOE not significant). In a subset of 169 participants, we examined the interactive effects on longitudinal tau pathology (Flortaucipir PET) in 36 whole‐brain FreeSurfer cortical and limbic ROIs (FDR‐correction). We further investigated if the physical activity effects on PACC5 decline in preclinical AD are mediated by changes in tau.

Result

In a larger sample of HABS participants with up to 13 years of cognitive follow‐up, we replicated the significant interaction between lower physical activity and elevated amyloid burden on faster prospective cognitive decline (ß=0.09, t=3.42, p<0.001; Figure 1A). We further demonstrated a novel interactive effect on tau pathology, where lower physical activity was associated with accelerated amyloid‐related tau accumulation in inferior temporal (ITC) and middle temporal (MTC) cortices (ITC: ß=‐0.10, t=‐3.36, FDR‐p=0.02; MTC: ß=‐0.09, t=‐3.27, FDR‐p=0.02; Figure 1B). Importantly, moderated mediation analyses revealed that accelerated tau accumulation fully mediated the effects of lower physical activity on faster cognitive decline in the setting of elevated amyloid (p<0.001, 100% mediated; Figure 2).

Conclusion

Our findings provide strong support for promoting physical activity as a lifestyle intervention, in conjunction with anti‐amyloid therapy, to slow the onset and/or progression of early neocortical tau pathology and cognitive decline in preclinical AD.
Alpha Synuclein co‐pathology is associated with faster Ab‐related tau accumulation in Alzheimer's disease
Authors: Roemer Sebastian Niclas , Dehsarvi Amir , Steward Anna , Dewenter Anna , Pescoller Julia , Wagner Fabian , Levin Johannes , Brendel Matthias , Höglinger Günter , Franzmeier Nicolai
Published: January 2025

Background

Lewy body pathology consisting of aggregated alpha‐Synuclein (a‐Syn) is the hallmark pathology in Parkinson’s disease, yet a‐Syn aggregates are also commonly observed post‐mortem as a co‐pathology in Alzheimer’s disease (AD) patients. Preclinical research has shown that a‐Syn can amplify Ab‐associated tau seeding and aggregation, hence a‐Syn co‐pathology may contribute to the Ab‐induced progression of tau pathology in AD. To address this, we combined a novel CSF‐based RT‐QuIC seed‐amplification assay to determine a‐Syn positivity, with PET‐neuroimaging in a large patient cohort ranging from cognitively normal to dementia, to determine whether a‐Syn co‐pathology accelerates Ab‐driven tau accumulation.

Method

In 261 Ab‐positive vs. 272 Ab‐negative subjects ranging from cognitively normal to dementia we employed amyloid‐PET, Flortaucipir tau‐PET and a CSF‐based a‐Syn RT‐QuIC assay for in vivo detection of abnormal a‐Syn aggregation. A subset of 136 Ab‐positive vs. 102 Ab‐negative subjects had longitudinal tau‐PET across ∼2.5years. Using linear regression, we tested whether a‐Syn positivity was linked to stronger Ab‐related tau aggregation (i.e. interaction a‐Syn x amyloid‐PET on tau‐PET).

Result

Prevalence of a‐Syn positivity rose across increasing clinical severity and was particularly pronounced in Ab+ (i.e. CN/MCI/Dementia=20/23/47%) vs. Ab‐ subjects (i.e. CN/MCI/Dementia=15/10/29%), suggesting that a‐Syn co‐pathology is more common in clinically advanced AD (chi‐squared‐test, p<0.001). When testing the interaction between a‐Syn and global amyloid‐PET, we found that a‐Syn positivity was associated with stronger Ab‐related tau deposition (Figure 1A, p<0.001), and faster Ab‐related tau accumulation rates (Figure 1B, p=0.010) in typical tau vulnerable brain regions (i.e. temporal meta ROI), adjusting for age and sex. Regional analyses confirmed that higher regional amyloid‐PET was associated with stronger temporal‐lobe tau deposition (Figure 2A) and faster tau accumulation in downstream regions (Figure 2B) in a‐Syn positive individuals. In addition, there was an independent effect of a‐Syn positivity on faster temporal lobe tau accumulation rates controlling for age, sex and global amyloid, suggesting that a‐Syn may also independently contribute to tau aggregation (Figure 3).

Conclusion

a‐Syn co‐pathology as detected by CSF seed‐amplification assays is more common at clinically advanced AD and related to faster Ab‐related tau aggregation. This suggests that a‐Syn co‐pathology may actively contribute to AD‐related tau accumulation and therefore contribute to dementia development.
A single nucleotide polymorphism from a differentially‐expressed gene shared across four neurodegenerative diseases increases tau accumulation independently of amyloid
Authors: Ramos Vanessa G. , Carello‐Collar Giovanna , Schlickmann Thomas Hugentobler , Siebert Marina , Cristino Alexandre Santos , Bastiani Marco De , Zimmer Eduardo R.
Published: January 2025

Background

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Huntington's disease (HD), Multiple Sclerosis (MS), and Parkinson's disease (PD) are characterized by the accumulation of misfolded proteins and progressive loss of neurons. However, whether a neurodegeneration transcriptomic signature exists remains uncertain. Thus, we aimed to explore differentially expressed genes (DEGs) in common to AD, HD, MS, and PD. We also seek to evaluate the effect of single nucleotide polymorphisms (SNPs) derived from the NDs‐shared DEGs on AD pathophysiology.

Methods

We obtained RNA‐sequencing and microarray datasets of vulnerable brain regions of AD, HD, MS, and PD individuals from the Gene Expression Omnibus. Differential gene expression analysis (adjusted p‐value < 0.05) was conducted to identify DEGs in common among these four NDs. Then, we examined the impact of shared DEG‐related SNPs on amyloid and tau burden in AD through a linear regression model adjusted for the covariates of age, sex, and ApoEe4 status. We obtained DEG‐related SNPs and amyloid‐ and tau‐PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Results

We identified 467 DEGs in common among AD, HD, MS, and PD vulnerable brain regions (Figure 1, p‐value < 0.05). From these DEGs, 15,574 SNPs were available in ADNI. Linear regression analysis revealed that IQGAP2 rs79679327 carriers had higher tau accumulation independently of amyloid burden (Figure 2, p‐value = 0.001; carriers: n = 21, mean age ± standard deviation (SD) = 72.76 ± 4.54; non‐carriers: n = 176, mean age ± SD = 71.64 ± 6.85).

Conclusion

Here, we show transcriptional similarities across four NDs. In AD, individuals carrying the IQGAP2 rs79679327 variant exhibited greater tau accumulation, regardless of amyloid. Our findings may provide insights into neurodegenerative traits, through a common signature of neurodegeneration.
Volumetric Characterization of Medial Temporal Lobe in Down Syndrome Along the Alzheimer's Disease Continuum
Authors: Zsadanyi Sara E , Buehner Bejamin J. , Morcillo‐Nieto Alejandra O. , Aranha Mateus Rozalem , Arriola‐Infante José Enrique , Vaqué‐Alcázar Lídia , Arranz Javier , Rodríguez‐Baz Íñigo , Maure‐Blesa Lucía , Videla Laura , Barroeta Isabel , Hoyo Laura Del , Benejam Bessy , Fernandez Susana , Hernandez Aida Sanjuan , Bargalló Núria , González‐Ortiz Sofía , Giménez Sandra , de Flores Robin , Alcolea Daniel , Belbin Olivia , Lleo Alberto , Carmona‐Iragui Maria , Fortea Juan , Bejanin Alexandre
Published: January 2025

Background

Individuals with Down Syndrome (DS) almost invariably develop Alzheimer's Disease (AD), but detecting early clinical changes is challenging due to comorbid intellectual disability, highlighting the importance of non‐invasive biomarkers. Neuroimaging of the medial temporal lobe (MTL), a key site of tau pathology, shows promise as an early AD biomarker. Here, we aimed to characterise volumetric patterns of the MTL in DS across the AD clinical continuum, and define associations with AD cerebrospinal fluid (CSF) biomarkers.

Method

253 adults with DS and 190 euploid controls from the Down Alzheimer Barcelona Neuroimaging Initiative underwent a 3T‐MRI protocol, and a comprehensive clinical assessment. T1‐weighted images were used to parse the medial temporal lobe using the Automated Segmentation of Hippocampal Subfields (ASHS) pipeline. Segmentation quality was visually inspected and W‐scores were computed for MTL subregions (anterior and posterior hippocampus, entorhinal cortex (ERC), parahippocampal cortex (PHC), and Brodmann areas Br35 and Br36) to adjust volumes for total intracranial volume, age and MRI scanner. Non‐parametric statistical tests were employed to assess volumes by AD clinical stage, age, and CSF biomarkers of AD.

Result

Hippocampal and Br36 volumes gradually decreased with AD clinical stage, and all subregions were decreased at the dementia stage (dDS) compared to asymptomatic (aDS) and prodromal (pDS) stages (Fig. 1). Surprisingly, significantly larger ERC, PHC and Br35 volumes were found at the asymptomatic DS stage compared to controls. All subregions had decreased volumes with age, with inflexion points around 40y for the hippocampus, ERC and Br36, 45y for Br35 and 50y for PHC (Fig. 2). Most subregions exhibited significant correlations with CSF Aß42/40 ratio, p‐tau‐181 and neurofilament light chain, and the strongest associations were found with anterior and posterior hippocampus (Fig. 3).

Conclusion

AD clinical stage and age are associated with progressive decreasing MTL volumes. Among all subregions, the hippocampus correlated best with CSF measures and appears particularly sensitive to detect early disease processes. These results indicate effectiveness of MTL volumes as a biomarker of early AD pathological changes in DS. Further studies are required to determine the pathological substrate of MTL atrophy and understand the increased volumes in some subregions.
A Study on the Expression Profile of Genes Coding for Secretory Proteins Using in vitro Model of Alzheimer's Disease
Authors: Singh Ravinder , Sunkaria Aditya
Published: January 2025

Background

Age‐related neurological illness like Alzheimer's disease (AD) is steadily becoming more prevalent among the aged population in India and around the world. Cognitive deficits are caused by a progressive loss of normal brain functions. Increased production of amyloid (Aß) and the development of neurofibrillary tangles (NFTs) are the two most significant pathogenic events that take place during AD progression. Until today, many attempts have been made towards discovering novel targets which are more precise and could identify the progression of the disease at very early stage.

Method

In the present study the Human Protein Atlas (HPA) database was used to filter out total human secretome. Using single cell type proteome of the HPA database, neuronal proteins were compared with total human secretome to discover overlapping proteins and their respective genes. Further, Alzheimer's disease associated genes were extracted using DisGeNet database and ranked according to their gene‐disease association (gda) score. Further, different proteoforms of Aß were used to treat neuronal cells in vitro to mimic early stages of AD like pathology. The expression of secretory protein genes from in vitro model system has been analysed.

Result

Out of 1678 genes, 24 neuronal genes were identified that were coding for secretory proteins. These genes were further categorized according to their proteins function. Specific primers for the top gda score genes were designed and expression analyses were conducted. Analyses revealed modulation in the expression of APOE, MAPT, NPY, NGF, and RELN genes.

Conclusion

The aim of this study was to discover early‐stage biomarkers for Alzheimer's disease. In the present study we have tried to identify modulation in the genes coding for secretory proteins which might be reflected at protein levels also. Currently our lab is working on to fully understand the modulation of AD secretome which would enable us to identify AD specific early stage biomarkers.