bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between Default Mode Network Connectivity Compared Between Two Tau Tracers (Flortaucipir vs. MK6240) – HEAD Study
Authors: Karim Helmet T. , Povala Guilherme , Bauer‐Negrini Guilherme , Lussier Firoza Z , Pascual Belen , Gordon Brian A. , Lowe Val J. , Oh Hwamee , soleimani‐meigooni David N. , Rosa‐Neto Pedro , Jagust William J. , Klunk William E , Baker Suzanne L. , Pascoal Tharick Ali
Published: January 2025

Background

Default mode network (DMN) resting state connectivity has been correlated with heightened amyloid and tau – hallmarks of Alzheimer’s Disease (AD). Tau is postulated to impact a meta‐temporal area including DMN‐associated regions like amygdala, entorhinal cortex, fusiform gyrus, parahippocampus, inferior temporal, and middle temporal gyrus. We recruited individuals with varying cognitive status to undergo resting state connectivity and imaging with two tau tracers (Flortaucipir and MK6240). We investigated the association between DMN connectivity and both global and regional (meta‐temporal) tau.

Methods

We studied 149 adults who were young cognitively healthy (n = 10, 21‐25 years, 5F), older cognitively healthy (n = 85, 50‐83 years, 51F), had MCI (n = 43, 53‐84 years, 23F), or had AD (n = 11, 62‐84, 6F). All individuals underwent resting state imaging and PET imaging with both Flortaucipir and MK6240 tau tracers. Resting data was preprocessed and DMN connectivity was estimated using bilateral posterior cingulate gyrus as region of interest. Tau tracer uptake was preprocessed (Pascoal. et al), and voxel‐wise standardized uptake value ratio (SUVR) was computed using inferior cerebellar gray matter as reference. We computed universal and meta‐temporal uptake for both tracers. We conducted four voxel‐wise associations between DMN connectivity and uptake in each tracer. We corrected for multiple comparisons using SnPM13 to estimate non‐parametric p‐values (10,000 permutations), we used a cluster forming threshold of p = 0.001 and corrected for multiple comparisons by controlling the family‐wise error rate (FWE) at p = 0.05.

Results

Greater universal Flortaucipir uptake was associated with lower within‐network DMN connectivity (bilateral posterior cingulate, precuneus, angular/supramarginal gyrus, and inferior parietal) but greater between‐network DMN connectivity (superior parietal, postcentral gyrus; Figure 1A). Greater universal MK6240 uptake was associated only with greater DMN‐cerebellum connectivity (Figure 1B). Greater meta‐temporal Flortaucipir was associated with lower within‐network DMN connectivity similar to universal uptake with addition of medial prefrontal cortex and middle temporal gyrus (Figure 2A). Greater meta‐temporal MK6240 was only associated with greater DMN‐superior parietal connectivity (Figure 2B).

Conclusions

These preliminary findings show that uptake using different tau tracers may lead to varying conclusions on association with connectivity. This may have implications for understanding the role of tau in altering resting state connectivity findings.
Potential Relative Effect of Intensive Systolic Blood Pressure Control on Preventing White Matter Damage Across Age Groups
Authors: Pruzin Jeremy J. , Kern Kyle C , Reboussin David M. , Cushman William C. , Gupta Aditi , Wright Clinton B. , Williamson Jeff D. , Tariot Pierre N. , Nasrallah Ilya M. , Pajewski Nicholas M.
Published: January 2025

Background

In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic blood pressure (SBP) lowering slowed progression of white matter injury (WMI) on MRI. We hypothesized that intensive lowering would be equally as effective and may confer greater benefits for brain health at younger ages compared to older ages. We tested whether the relative effects of intensive lowering on WMI differed by age using 2 MRI measures: white matter hyperintensity volume (WMHv) and peak‐width skeletonized mean diffusivity (PSMD) in SPRINT.

Method

Participants were age =50 with cardiovascular risk and randomized to intensive (SBP goal <120 mm Hg) or standard treatment (SBP goal <140 mm Hg). We calculated WMHv and PSMD in a subgroup of participants who had a baseline and follow‐up MRI. WMHv were inverse‐hyperbolic sine‐transformed, and the ratio of follow‐up to baseline used to quantify progression. PSMD progression was quantified as a difference. Using mixed‐effects linear models, we estimated the effects of age on relative progression in MRI markers between groups. Age effects were investigated as categorical (<65, 65‐75, or =75 years) or continuous.

Result

For participants in the intensive group (n=251 with follow‐up), mean SBP was 122 mmHg versus 135 mmHg in the standard group (n=201) over a median 3.9‐year MRI interval. The largest treatment effect on WMHv progression was found in the <65 age group (i.e. greatest relative reduction with intensive treatment): ‐0.19, 95%CI [‐0.27, ‐0.11]), followed by the 65‐75 age group (‐0.11, [‐0.21, ‐0.01]), and least in the >75 age group (‐0.06, [‐0.20, ‐0.08]) (Figure 1). Intensive treatment resulted in a 73%, 52%, and 20% reduction in WMHv progression respectively, although this was not statistically significant (p=0.21). Analyses of PSMD progression produced similar results (Figure 2). When using age as a continuous measure, the beneficial effect of intensive treatment waned with increasing age (Figure 3) without reaching statistical significance (p=0.19).

Conclusion

Intensive SBP lowering was equally as effective and may have a greater relative effect on reducing WMI when implemented at younger ages compared to older ages. Large prospective interventional studies that include younger individuals are needed to determine the effects of SBP on white matter integrity across the lifespan.
Creating Universal Tau PET Scale (Uniτ) Parametric Images – The HEAD Study
Authors: Povala Guilherme , Bauer‐Negrini Guilherme , Bellaver Bruna , Lussier Firoza Z , Amaral Livia , Ferreira Pamela C.L. , Finn Quentin , Zatt Bruno , Tudorascu Dana , Jagust William J. , Klunk William E , Lowe Val J. , Soleimani‐Meigooni David N. , Oh Hwamee , Pascual Belen , Gordon Brian A. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick Ali
Published: January 2025

Background

The HEAD study focuses on collecting an extensive dataset from various tau‐PET tracers, aiming to establish robust anchor values, which are essential for harmonizing tau‐PET measurements. Here, we aim to showcase the capability of converting 3D tau‐PET images into a common scale using the Universal Tau‐PET Scale, Uniτ (tau), and to use these 3D images to subsequently obtain ROIs as needed.

Methods

We assessed 185 individuals across the aging and AD spectrum from the HEAD study, with [18F]Flortaucipir and [18F]MK‐6240 tau‐PET tracers. Tau‐PET SUVR images were standardized to a common 8mm FWHM, using the inferior cerebellar gray matter as the reference region. We generated Uniτ Tau‐PET 3D images using a single formula based on Meta‐temporal parameters in two steps: first, within‐tracer anchoring based on young (<25 years) and cognitively impaired individuals; second, between‐tracer anchoring using a piecewise transformation from [18F]Flortaucipir to [18F]MK‐6240, with smoothing at the piecewise inflection point. Subsequently, we extracted mean Uniτ values from these 3D images for key ROIs, including meta‐temporal, mesial, temporo‐parietal, frontal, and Braak stages III‐VI. Finally, we correlated Uniτ values across ROIs between the two tracers to evaluate the accuracy of estimates from the voxel‐wise transformation.

Results

The original SUVR images present large differences between the two tau‐PET tracers (Figure 1). However, upon applying the Uniτ piecewise transformation with smoothing to all brain voxels, we were able to reasonably harmonize these images to the Uniτ scale, substantially reducing visual variability. Notably, the mean Uniτ values for the ROIs extracted from these harmonized 3D tau‐PET brain images demonstrated a high level of association between the two tracers (Figure 2). Furthermore, estimates generated from ROIs or extracted from our 3D parametric Uniτ model yielded identical estimates (Figure 3).

Conclusion

The strong associations between tracers after directly harmonizing 3D images to Uniτ scale using the piecewise transformation with smoothing, underscore the effectiveness of the proposed method. This approach provides a reliable and standardized way to compare tau‐PET data across different tracers. Our results indicate the feasibility of harmonizing 3D tau‐PET images without relying on pre‐established ROIs, overcoming the limitation of restricting the analysis to only few brain regions.
The effect of traumatic brain injury and post‐traumatic stress disorders on AD pathologies, small vessel changes and ultimately cognitive function
Authors: Sibilia Francesca , Cen Steven , Choupan Jeiran , Hazany Saman , Ayala Rene , Cheng Jocelyn , Nejatpoor Tiana , Sheikh‐Bahaei Nasim
Published: January 2025

Background

Although many studies have shown that traumatic brain injury (TBI) and post‐traumatic stress disorder (PTSD) regardless of their severity, are associated with a significantly increased risk of all‐cause dementia, the specific pathophysiological mechanisms that underlie these associations remain poorly understood, resulting in discordance findings among different studies and contradictory claims in the current literature. In this study we investigated the effect of TBI and PTSD on the level of amyloid, tau, as well as markers of small vessel health including white matter hyperintensity and perivascular spaces and consequently assessed their effect on the cognitive function in order to understand the pathways through which TBI and PTSD may result in dementia.

Method

The participants in this study were MCI cases drawn from the ADNI‐DOD (n=58). Cognitive performance was assessed using the Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR). Inclusion criteria for TBI involved the history of moderate to severe nonpenetrating head trauma as well as combat history or presence in the battlefield. Inclusion in the PTSD group required a minimum Clinician Administered PTSD Scale (CAPS) score of 40 points. PET images with tracers AV1451 and AV45 were obtained. Perivascular spaces (PVS) volume fraction in the total white matter and basal ganglia was obtained using automated segmentation pipeline developed at our institute, as well as the grade of white matter hyperintensities.

Result

The volume of PVS in the white matter was found to be significantly higher in veterans with PTSD (p=0.01) or with TBI (p=0.02) after age adjustment. Elevated amyloid was also found in veterans with PTSD 1.3 (1.23‐1.39) vs. 1.23 (1.1‐1.53), p=0.05 and trend of increased amyloid with TBI 1.3 (1.18‐1.44) vs. 1.28 (1.23‐1.31), p=0.09. Our day also indicates a strong correlation between amyloid and CDR (adjusted ranking score correlation of 0.45 (p<0.01) among veteran sample.

Conclusion

Preliminary evidence showed the association from PTSD to amyloid as well as TBI to amyloid. Since amyloid strongly associated with cognitive function, it may suggest a biological pathway from PTSD and/or TBI through amyloid deposition to cognitive decline in veteran. Larger sample will be needed to confirm the causal pathway.
Occipital amyloid‐β burden and clinical correlates in Lewy body disease
Authors: Vossler Hillary , Abdelnour Carla , Young Christina B. , Winer Joseph R. , Smith Alena , Smith Viktorija , Shahid Marian , Wilson Edward N. , Davidzon Guido A. , Mormino Elizabeth , Poston Kathleen L.
Published: January 2025

Background

Accurate assessment of amyloid‐ß burden in Lewy body disease (LBD) is crucial due to the frequent co‐occurrence of amyloidosis. Current amyloid‐ß PET imaging protocols often overlook the occipital lobe, a relevant area in Lewy body disease (LBD). We aimed to determine whether regional amyloid‐ß in LBD is associated with global cognition, daily functioning, and neuropsychological performance.

Method

We included 193 Stanford research participants: 78 Cognitively Normal (CN), 42 Alzheimer’s disease (AD), 38 LBD‐Cognitively Normal (LBD‐CN), and 35 LBD‐Cognitively Impaired (LBD‐CI) who underwent 18F‐Florbetaben PET imaging (Table). We calculated SUVRs for the frontal, cingulate, parietal, temporal, and occipital regions using the cerebellum as the reference region. We then used linear regression models adjusted for age, sex, and education to examine the association between regional amyloid‐ß burden and global cognition (measured with MoCA), daily functioning (measured with CDR‐SB), and performance in memory, executive function, visuospatial function, and attention/working memory/processing speed (measured with composite scores).

Result

In the LBD‐CI group, amyloid‐ß burden in all regions, except the cingulate, was associated with worse MoCA (ß = ‐14.31 (SE = 3.59), p < 0.0001) (Figure) and CDR‐SB scores (ß = 5.05 (SE = 1.71), p < 0.004). Similarly, amyloid‐ß burden in the frontal (ß = ‐1.27 (SE = 0.60), p < 0.05), cingulate (ß = ‐1.24 (SE = 0.59), p < 0.05), parietal (ß = ‐1.42 (SE = 0.62), p < 0.05), and temporal (ß = ‐1.68 (SE = 0.70), p < 0.05) regions was associated with worse memory performance, whereas amyloid‐ß burden in the occipital region (ß = ‐1.76 (SE = 0.88), p < 0.05) was associated with worse executive function. However, only the association between occipital amyloid‐ß burden and MoCA scores survived multiple comparison correction. In the LBD‐CN group, regional amyloid‐ß burden showed no associations with clinical outcomes.

Conclusion

Our study suggests the potential significance of the occipital region in assessing amyloid‐ß burden among individuals with cognitive impairment due to LBD, as it is associated with worse global cognition. Further validation studies should include the occipital region when calculating SUVRs should be considered in people with LBD.
In vivo 18F‐MK6240 tau PET imaging in relation to peripheral inflammation and episodic memory in late middle‐aged adults
Authors: Malarte Mona‐Lisa , Chiotis Konstantinos , Ioannou Konstantinos , Rodriguez‐Vieitez Elena
Published: January 2025

Background

Detecting early stages of Alzheimer's disease (AD) remains a crucial yet complex challenge. While recent interest has surged in detecting biomarkers linked with the disease preclinical phase, a comprehensive understanding of the concomitant peripheral biological pathways before the potential disease onset is necessary. We aim to explore the associations between the 18F‐MK6240 tau PET tracer with plasma inflammatory markers, other AT(X)N biomarkers and episodic memory.

Method

The cross‐sectional sample consisted of n=132 cognitively unimpaired late middle‐aged Hispanic individuals (64.5 ± 3.4 years old, 34.1% APOE4 carriers, 69.7% female, 10.7 ± 4.0 years of education) from Northern Manhattan (AD Knowledge Center database). All individuals underwent multi‐modal imaging with T1‐weighted MRI, T2‐weighted FLAIR MRI, Aß PET (18F‐florbetaben), tau PET (18F‐MK6240), plasma measures of inflammation (OLINK panel of 92 markers), plasma neuronal injury (NfL), and neuropsychological assessments. Data on demographics: age, sex, education, APOE, body mass index (BMI), and diabetes mellitus, were also included. Using the median split to dichotomize global Aß and NfL measures, the study sample was stratified into four groups: “Aß‐low, NfL‐low” (Group 0); “Aß‐high, NfL‐low” (Group 1); “Aß‐high, NfL‐high” (Group 2); and “Aß‐low, NfL‐high” (Group 3).

Result

Our results revealed that 18F‐MK6240 tau PET is sensitive in detecting early neocortical tau pathology, even without evident neuronal injury (Fig. 1). Plasma inflammation was not directly linked with Aß or tau pathologies but strongly associated with NfL (Fig. 2). Markers of neuronal injury (NfL), cerebrovascular injury (WMH) and specific inflammatory markers were associated with lower episodic memory (Fig. 1). High NfL correlated with factors such as high inflammation, BMI, diabetes and older age.

Conclusion

The study emphasizes the complex nature of early AD markers suggesting that, aside from Aß and tau, peripheral markers of NfL and inflammation are also central. Our findings call for a broader perspective in identifying early AD markers, underscoring the interplay between neuronal damage, inflammation, comorbidities and early cognitive changes.
Cognitive impairment due to ischemic stroke in female rats is associated with secondary neurodegeneration, and attenuated with microRNA‐20a‐3p as assessed by diffusion tensor MR imaging and histological analysis
Authors: Sampath Dayalan , Singer Jacob , Gopalakrishnan Balaji , Akbari Zara , Villarreal Monserrat , Hurst David A , Noarbe Brenda P , Obenaus Andre , Sohrabji Farida
Published: January 2025

Background

Our studies show that the small non‐coding RNA, mir20a‐3p, is neuroprotective for stroke in the acute phase and also attenuates long term cognitive decline in middle‐aged female rats. Cognitive decline due to vascular diseases, such as stroke, is associated with secondary neurodegeneration in cortex and limbic structures. In this study, we assessed the volume of white matter, ventricles and regional diffusion‐weighted MR imaging measures to delineate pathological tissue characteristics from the postmortem brain of stroke rats.

Method

Middle‐aged females were subjected to ischemic stroke using the vasoconstrictor endothelin 1, injected adjacent to the left middle cerebral artery (MCA). Mir‐20a‐3p mimic (n=10) or scrambled oligo (n=8) was administered i.v. 4h, 24h and 70d post stroke. Animals were assessed periodically for cognitive performance up to 100d after stroke using both the cued fear conditioning test and the novel object recognition test (NORT). After perfusion fixation, T2 and diffusion tensor imaging (DTI) magnetic resonance imaging were performed on postmortem tissue. Subsequently, brains were processed for histology, including the Weil myelin stain.

Result

Stroke resulted in impairment in both the cued fear conditioning test and the NORT, which was attenuated by mir‐20a‐3p treatment (Sampath et al., 2023). Weil myelin‐stained sections showed that both the corpus callosum and internal capsule had a reduction in volume in the ischemic hemisphere as compared to non‐ischemic hemisphere in vehicle treated (scrambled oligo) MCAo animals. In contrast, sham and MCAo+Mir‐20a‐3p animals displayed no hemispheric differences in the volume in either tract. A similar volume asymmetry was also observed in the ventricles in the MCA0+ Scrambled group. Entorhinal cortex volume (diffusion tensor MR images) was also asymmetric in the MCAo+scrambled oligo group.

Conclusion

Cognitive changes measured with remote fear memory retrieval and NORT were associated with reduced density of major forebrain white matter tracts due to stroke and enlarged ventricular volume indicative of cell loss. This was observed in the entorhinal cortex, a region involved with contextual memory processing. These stroke‐induced deficits were attenuated in Mir‐20‐3p treated animals, indicating that microRNA treatment attenuated secondary neurodegeneration.
qEEG as Biomarker for Alzheimer’s Disease:Investigating Relative PSD Difference and CoherenceAnalysis
Authors: Simfukwe Chanda , Youn Young Chul , An Seong Soo
Published: January 2025

Background

Electroencephalography (EEG) is a non‐intrusive technique that provides comprehensive insights into the electrical activities of the brain’s cerebral cortex. The brain signals obtained from EEGs can be used as a neuropsychological biomarker to detect different stages of Alzheimer’s disease (AD) through quantitative EEG (qEEG) analysis. This paper investigates the difference in the abnormalities of resting state EEG (rEEG) signals between eyes‐open (EOR) and eyes‐closed (ECR) in AD by analyzing 19‐ scalp electrode EEG signals and making a comparison with healthy controls (HC).

Method

The rEEG data from 534 subjects (ages 40‐90) consisting of 269 HC and 265 AD subjects in South Korea were used in this study. The qEEG for EOR and ECR states were performed separately for HC and AD subjects to measure the relative power spectrum density (PSD) and coherence with functional connectivity to evaluate abnormalities. The rEEG data were preprocessed and analyzed using EEGlab and Brainstorm toolboxes in MATLAB R2021a software, and statistical analyses were carried out using ANOVA.

Result

Based on the Welch method, the relative PSD of the EEG EOR and ECR states difference in the AD group showed a significant increase in the delta frequency band of 19 EEG channels, particularly in the frontal, parietal, and temporal, than the HC groups. The delta power band on the source level was increased for the AD group and decreased for the HC group. In contrast, the source activities of alpha, beta, and gamma frequency bands were significantly reduced in the AD group, with a high decrease in the beta frequency band in all brain areas. Furthermore, the coherence of rEEG among different EEG electrodes was analyzed in the beta frequency band. It showed that pair‐wise coherence between different brain areas in the AD group is remarkably increased in the ECR state and decreased after subtracting out the EOR state.

Conclusion

The findings suggest that examining PSD and functional connectivity through coherence analysis could serve as a promising and comprehensive approach to differentiate individuals with AD from normal, which may benefit our understanding of the disease.
Digital assessment of turning behaviours in Alzheimer’s disease and Lewy body disease and their association with cognitive function
Authors: Ardle Ríona Mc , Din Silvia Del , Rehman Rana Zia , Galna Brook , Thomas Alan J , Rochester Lynn , Alcock Lisa
Published: January 2025

Background

Digital mobility outcomes (DMOs) can be captured using body‐worn inertial measurement units (IMUs) in lab‐based and real‐world environments. DMOs may support differential diagnosis of dementia; for example, Alzheimer’s disease (AD) and Lewy body disease (LBD) show unique signatures of gait impairment. Growing evidence suggests that turning impairments are related to cognitive decline. Turning outcomes can be captured via IMUs and may complement use of existing DMOs. This study aims to assess differences in turning outcomes between AD, LBD and older adult controls, and explore their clinical and cognitive correlations.

Method

Participants completed six intermittent 10‐metre walks while wearing a IMU (APDM, Opal 128Hz) attached to their lower back. Following each walk, they made a 180degree turn. Two spatiotemporal (turn duration, angular velocity) and two acceleration‐based (combined direction [anterior‐posterior/medio‐lateral/vertical] Root Mean Square (RMS) and Jerk RMS) turning outcomes were extracted using validated algorithms. Analysis of covariance assessed between‐group differences in turning outcomes, controlling for age and sex. Tukey HSD tests for multiple comparisons determined where differences occurred. Correlations (Spearman’s rho) between significant turning outcomes and age, motor disease severity (MDS Unified Parkinson’s Disease Rating Scale III), global cognition (standardised Mini Mental State Examination; sMMSE), information processing (Trail Making Task A), and executive function (FAS Verbal Fluency Test) were assessed.

Results

98 eligible participants from the GaitDem study were included: 28 controls (Age (mean±SD):74±9 years, sMMSE:29±1), 35 AD (Age:77±6, sMMSE:23±4), and 35 LBD (Age:76±6, sMMSE:24±3). Both dementia disease subtypes demonstrated lower jerk RMS compared to controls (p<.05), while people with LBD also showed lower angular velocity, RMS and Jerk RMS (p<.05; Fig.1). For AD, turning impairments were associated with greater motor disease severity (Fig.2). For LBD, slower angular velocity was associated with greater motor disease severity, slower information processing and worse executive function (Fig.3).

Conclusions

Results suggest that dementia disease subtypes have significant turning impairments compared to normal ageing, but not compared to each other. However, turning impairments were related to discrete motor‐cognitive profiles in dementia disease subtypes. Further work should explore other turning characteristics (i.e. related to turn phase, signal direction, turn strategy) as differential markers of dementia.
Amyloid‐associated hyperconnectivity drives tau spreading across connected brain regions in Alzheimer’s disease
Authors: Roemer Sebastian Niclas , Wagner Fabian , Evangelista Lisa , Rauchmann Boris‐Stephan , Dehsarvi Amir , Steward Anna , Dewenter Anna , Biel Davina , Zhu Zeyu , Pescoller Julia , Gross Mattes , Perneczky Robert , Malpetti Maura , Ewers Michael , Schöll Michael , Dichgans Martin , Höglinger Günter , Brendel Matthias , Jäkel Sarah , Franzmeier Nicolai
Published: January 2025

Background

In Alzheimer’s disease, Aß triggers tau spreading which drives neurodegeneration and cognitive decline. However, the mechanistic link between Aß and tau remains unclear, which hinders therapeutic efforts to attenuate Aß‐related tau accumulation. Preclinical research could show that tau spreads across connected neurons in an activity‐dependent manner, and Aß was shown to trigger neuronal hyperactivity and hyperconnectivity. Therefore, we hypothesized that Aß induces neuronal hyperactivity and hyperconnectivity, thereby promoting tau spreading from initial epicenters across connected brain regions.

Methods

From ADNI, we included 140 Aß‐positive subjects across the AD spectrum plus 69 Aß‐negative controls, all with baseline amyloid‐PET, 3T resting‐state fMRI and longitudinal Flortaucipir tau‐PET data. For validation, we included cross‐sectional tau‐PET, amyloid‐PET and resting‐state fMRI data of 345 preclinical AD patients from A4. PET and fMRI data were parceled into 200 cortical ROIs, ROI‐wise longitudinal tau‐PET change rates were computed using linear mixed models. Resting‐state fMRI connectivity was computed across the 200 ROIs. Subject‐specific tau epicenters were defined as 5% of ROIs with highest baseline tau‐PET. Further, we included post‐mortem brain tissue from 5 AD patients vs. 4 controls stained for Aß and c‐Fos, i.e. a marker of ante‐mortem neuronal activity.

Results

In the AD spectrum cohort, we confirmed that Aß induces hyperconnectivity of temporal lobe tau epicenters (Fig.1) to posterior brain regions that are highly vulnerable to tau accumulation in AD (Fig.2A‐C). This was fully replicated in the validation cohort of preclinical AD patients with low cortical tau‐PET, suggesting that the emergence of Aß‐related hyperconnectivity precedes neocortical tau spreading (Fig.2D). Supporting that Aß‐associated fMRI‐based hyperconnectivity may mirror neuronal hyperactivity, we found that neurons in AD post‐mortem tissue expressed higher levels of c‐Fos compared to controls, i.e. a Calcium‐sensitive marker of ante‐mortem neuronal activity (Fig.3). Lastly, using longitudinal tau‐PET, we confirmed that Aß‐related connectivity increases of the tau epicenters to posterior brain regions mediated the effect of Aß on tau accumulation and triggered faster tau spreading (Fig.4).

Conclusions

Our translational results suggest that Aß promotes tau spreading via increasing neuronal activity and connectivity. Therefore, Aß‐associated neuronal hyperexcitability may be a promising target for attenuating tau spreading in AD.
Enhancing Cognitive Health in Aging through New Language Acquisition: Insights from Behavioral and Neuroimaging Studies
Authors: Saidi Ladan Ghazi
Published: January 2025

Background

I will look at the impact of new language acquisition on cognitive performance and reserve in older adults, an area not extensively explored in contrast to the well‐documented cognitive benefits in lifelong bilinguals. Previous research has shown that lifelong bilingualism may enhance cognitive reserve, evidenced by better performance on specific tasks of executive function, reflecting superior cognitive control and interference management in aging (Van den Noort, et al., 2019). Drawing on the cognitive demands of language learning, which include executive functions such as inhibition, selection, and conflict management (Ghazi Saidi et al., 2013; 2017a; 2017b), we and others hypothesize that new language learning in older adults can boost these cognitive processes, which often decline with age (Albinet, et al., 2012; Lee & Chung, 2012).

Method

In the past five years, we and others have conducted a series of behavioral and neuroimaging studies to address the gap in understanding the effects of language learning later in life, particularly as a potential non‐pharmaceutical intervention to enhance cognitive health in aging. In this presentation, I will review these studies and will present our new findings.

Results

We are others bring evidence that Language learning in older adults can enhance cognitive control, as evidenced by improved performance on domain specific tasks such as the Stroop task, as well as global cognition and is associated with functional neuroplasticity in brain areas responsible for cognitive control (Kliesch, et al.,2018; Meltzer, et al., 2023; Nilsson, et al., 2021; Bubbico, et al., 2019; Wong, et al., 2019. These results suggest that new language acquisition in monolingual older adults may improve cognitive reserve and contributes to overall cognitive health, potentially slowing the progression of cognitive decline.

Conclusion

Thus, learning a new language may represent an accessible and cost‐effective cognitive intervention in aging, though the effectiveness is influenced by the intensity and duration of the learning experience.
Longitudinal changes in neuroimaging markers of small vessel disease: Implications for clinical trials
Authors: Lao Patrick J. , Edwards Natalie C. , Flores‐Aguilar Lisi , Rizvi Batool , Smith Anna C. , Tudorascu Dana , Rosas H. Diana , Yassa Michael A. , Handen Benjamin L , Christian Bradley T. , Gutierrez Jose , Wilcock Donna M. , Head Elizabeth , Brickman Adam M.
Published: January 2025

Background

Adults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, around the same time as amyloid and tau, but the regional rates of accumulation within individuals are unknown.

Method

Adults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n = 78; age = 50±6; 40% women) have two timepoints of T2 FLAIR MRI (1.2±0.6 years apart) quantified as white matter hyperintensity volume (WMH), which represents ischemic small vessel disease. Participants underwent consensus diagnosis at both timepoints (59% Cognitively‐Stable at both timepoints, 9% Cognitively‐Stable to MCI‐DS, 8% MCI‐DS at both timepoints, 14% MCI‐DS to AD, 10% AD at both timepoints). The annual rate of change in frontal, temporal, parietal, and occipital WMH volume was assessed, adjusting for baseline WMH volume.

Result

The annual rate of change in frontal WMH was not significantly different by diagnosis. The annual rate of change in temporal (0.7 [0.4, 1.1], p<0.001) and in occipital WMH (1.6 [0.7, 2.5], p = 0.0008) was faster in the group that remained AD at both timepoints compared to the group that remained Cognitively‐Stable at both timepoints. The annual rate of change in parietal WMH was greater in the group that progressed from MCI‐DS to AD (0.6 [0.1, 1.0], p = 0.02) and in the group that remained AD at both timepoints (1.1 [0.6, 1.7], p = 0.0002) compared to the group that remained Cognitively‐Stable at both timepoints.

Conclusion

In adults with DS, parietal WMH accumulates fastest in those that progress to or have a diagnosis of AD, while temporal and occipital WMH accumulate fastest in those with a diagnosis of AD. Posteriorly distributed WMH may have specificity for AD progression in adults with DS with implications for anti‐amyloid therapeutics that have cerebrovascular side effects.
Microglial activation impacts amyloid‐β effects on reactive astrogliosis
Authors: Ferrari‐Souza João Pedro , Povala Guilherme , Bellaver Bruna , Ferreira Pamela C.L. , Lussier Firoza Z , Leffa Douglas Teixeira , Aguzzoli Cristiano Schaffer , Soares Carolina , Carello‐Collar Giovanna , Borelli Wyllians Vendramini , Therriault Joseph , Rahmouni Nesrine , Macedo Arthur C. , Servaes Stijn , Stevenson Jenna , Gauthier Serge , Souza Diogo O. , Schilling Lucas Porcello , Lourenco Mychael V , Tudorascu Dana , Rosa‐Neto Pedro , Pascoal Tharick A. , Zimmer Eduardo R.
Published: January 2025

Background

Glial reactivity is a key phenomenon in Alzheimer’s disease (AD) and is closely associated with amyloid‐ß (Aß) pathology. Although compelling experimental data suggest that microglial activation modulates reactive astrogliosis, it remains to be elucidated whether microglial activation influences the association of Aß pathology with reactive astrogliosis in the living AD human brain. Here, we tested the association of microglial activation and Aß pathology with reactive astrogliosis in individuals across the aging and AD clinical spectrum.

Method

We studied 101 participants (62 cognitively unimpaired [CU], 26 with mild cognitive impairment [MCI], and 13 with AD dementia) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Individuals had available positron emission tomography (PET) for Aß ([18F]AZD4694) and microglial activation ([11C]PBR28), as well as magnetic resonance imaging. We further assessed reactive astrogliosis with plasma glial fibrillary acidic protein (GFAP). Linear regression analyses were used to investigate the associations between Aß, microglial activation and GFAP.

Result

Demographic characteristics of the study population are reported in Table 1. Regression analyses revealed a significant positive association between Aß PET burden and plasma GFAP levels in microglial activation‐positive but not in microglial activation‐negative individuals (Fig. 1A). A significant interaction between continuous values of Aß PET burden and [11C]PBR28 PET uptake on plasma GFAP levels (Fig. 1B) supported that microglial activation affects the association of Aß pathology with reactive astrogliosis. Analysis of variance further confirmed that the model with the interaction term was the most adequate to describe the association of Aß PET and microglial activation PET with plasma GFAP (P = 0.007). In additional analyses investigating the topography of the observed findings, we found that higher Aß PET burden was associated with higher plasma GFAP levels only in the presence of microglial activation positivity across Aß‐vulnerable cortical brain regions (Fig. 1C).

Conclusion

Our results suggest that microglial activation impacts Aß‐dependent reactive astrogliosis in the living AD brain. This can help to better understand the complementary roles of glial cells in neurodegenerative diseases, as well as provide insights for the development of novel therapeutic strategies for AD targeting the interplay between Aß and glial reactivity.
Impact of regional MAPT, APOE, and Aβ on tau propagation in Alzheimer’s disease: Insights from a connectome‐based simulation model
Authors: Xiao Yu , Strandberg Olof , Bazinet Vincent , Shafiei Golia , Behjat Hamid , Spotorno Nicola , Smith Ruben , van Westen Danielle , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Stomrud Erik , Misic Bratislav , Dagher Alain , Hansson Oskar , Vogel Jacob W.
Published: January 2025

Background

Tau pathology, a hallmark of Alzheimer’s disease (AD), is thought to spread cell‐to‐cell via axonal connections, beginning focally before expanding throughout the brain. This study uses computational models to investigate the interplay between network spread and regional vulnerability in influencing tau spread, focusing specifically on MAPT and APOE genes, and Aβ plaques.

Method

66 regional (Desikan‐Killiany atlas) tau‐PET standardized uptake value ratio (SUVR) values were extracted from participants in the Swedish BioFINDER‐2 study: 429 cognitively normal (CN), 91 subjective cognitive decline (SCD), 168 mild cognitive impairment (MCI), and 182 AD. Values were adjusted for mean choroid plexus signal and converted to tau‐positive probabilities using two‐component Gaussian mixture models. The Susceptible‐Infectious‐Recovered (SIR) model (Fig. 1A) was employed to simulate tau spread through brain networks measured using structural connectivity from young individuals. We examined the roles of MAPT, APOE, and Aβ in tau propagation by parameterizing them regionally to influence tau synthesis, clearance, spreading, or misfolding. Regional MAPT and APOE were extracted from Allen Brain Atlas, and Aβ from Aβ‐PET. Performance of both baseline models (connectivity‐only) and models incorporating regional biological information were evaluated based on their ability to reconstruct observed regional tau levels. Performance was evaluated across the whole sample and groups based on diagnosis, APOE e4 carriage and Aβ positivity.

Result

The SIR model recapitulates observed tau patterns, suggesting connectivity‐based propagation in early‐stage regions (Fig. 1B, C). Allowing regional MAPT to moderate normal tau synthesis improved the model fit overall, and for all groups except CN or Aβ‐ participants (Fig. 2,3). Regional APOE or Aβ information did not enhance the model performance overall (Fig. 2B, C). However, allowing regional APOE to moderate tau clearance showed better performance in APOE e4 carriers vs. non‐carriers, and allowing regional Aβ to moderate tau spread improved performance compared to baseline model among Aβ+ individuals (Fig. 3).

Conclusion

Our results suggest that brain connectivity explains early temporal lobe tau spread patterns, while regional intrinsic (MAPT) and disease‐related (Aβ) susceptibility may influence spread of tau into other regions at later stages. Future work will test other hypotheses of tau spread by refining this model with additional biological information.
Delaying symptom onset in Dominantly Inherited Alzheimer’s Disease: Long‐term gantenerumab treatment results from the DIAN‐TU trial
Authors: Bateman Randall J. , Li Yan , McDade Eric , Llibre‐Guerra Jorge J. , Clifford David B. , Atri Alireza , Mills Susan , Santacruz Anna , Wang Guoqiao , Supnet Charlene B , Benzinger Tammie L.S. , Gordon Brian A. , Ibanez Laura , Klein Gregory , Baudler Monika , Doody Rachelle S. , Kerchner Geoffrey A.
Published: January 2025

Background

Amyloid‐plaque removal by monoclonal antibody therapies slows progression in symptomatic Alzheimer’s disease (AD), but effects on preventing the onset of symptoms and dementia in asymptomatic people with amyloid plaques are unknown. We report the final primary and secondary outcomes of the Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) trial to evaluate amyloid‐plaque removal in delaying disease progression, including symptom onset, in symptomatic and asymptomatic dominantly inherited Alzheimer’s disease (DIAD) individuals treated for up to a decade.

Method

This double‐blind, phase 2/3 trial (2012‐2019), followed by open‐label extension (OLE), investigated varying gantenerumab doses up to 1500 mg subcutaneous q2 weeks [NCT01760005]. The primary outcome was assessed for time to symptom onset and progression with the Cox proportional hazards model, comparing the treatment cohort to controls (double‐blind placebo participants who didn’t enter OLE, plus external controls). Estimated years to symptom onset (EYO) was included as a covariate and the average year of symptom onset relative to EYO was calculated. Other clinical and cognitive measures will be reported per the statistical analysis plan.

Result

In asymptomatic participants at baseline treated with gantenerumab (n = 53), the overall HR (95% CI) was 1.00 (0.47, 2.14) for time to first Clinical Dementia Rating (CDR) global progression, and 0.76 (0.45, 1.29) for recurrent CDR‐Sum of Boxes (CDR‐SB) progression. In the longest‐treated group (n = 22, average 8 years), the HR (95% CI) was 0.50 (0.17, 1.47) for CDR global and 0.50 (0.25, 0.99) for CDR‐SB. The average age of dementia symptom onset for the longest gantenerumab exposure was 3 to 6 years later when compared to placebo or external controls.

Conclusion

While no clinical effect was observed in the total group, results suggest potential delayed symptom onset and 50% dementia progression reduction in asymptomatic DIAD mutation carriers following long‐term, high‐dose gantenerumab treatment. Exploratory evaluation indicates that years of dementia free survival may be achieved with prevention. However, this analysis included a small cohort in an OLE with external controls, limiting conclusions. Ongoing follow‐up of this cohort will continue to inform future prevention trial designs and these results may represent the first clinical evidence of AD prevention with amyloid removal.
Comparison of plasma p‐tau217 and Aβ42/Aβ40 biomarkers by race to detect Alzheimer’s disease
Authors: Cousins Katheryn A Q , Korecka Magdalena , Yang Wan , Vulaj Amberley , Brown Christopher , Tropea Thomas F. , Chen‐Plotkin Alice , Lee Eddie B , Irwin David J , Wolk David A , Shaw Leslie M.
Published: January 2025

Background

To guide blood biomarker implementation to detect Alzheimer’s disease (AD), evaluations in clinically and racially diverse samples are needed. Here, we compare plasma biomarkers phosphorylated tau 217 (p‐tau217), β‐amyloid (Aβ) 1‐42/1‐40 (Aβ42/Aβ40) ratio, and p‐tau217/Aβ42 ratio in a University of Pennsylvania (UPenn) sample that includes self‐identified White and Black/African American individuals with and without cognitive impairment, and independently validate findings in the first 100 AD Neuroimaging Initiative (ADNI) autopsy participants.

Methods

UPenn inclusion criteria were plasma p‐tau217, Aβ42, and Aβ40 (n = 213) assayed using the automated Fujirebio platform, self‐reported race (156 White [including 1 Hispanic White, 2 multiracial] and 57 Black), and 18F‐florbetaben PET scan to determine Aβ positivity by visual read (87 Aβ+, 126 Aβ‐). Participants were cognitively Normal (n = 128) or Impaired (n = 85) according to National Alzheimer’s Coordinating Center (NACC) Uniform Dataset 3.0 criteria. Linear models tested if plasma biomarkers (dependent variable, log‐transformed) differed by race and/or Aβ PET status (±). To confirm observed racial differences, linear models tested the interaction of race by global Aβ PET standardized uptake value ratio (SUVR). Models covaried for age at plasma, sex, 2021 national area deprivation index (ADI), and APOE ε4. Receiver operating characteristic (ROC) with bootstrapping (2000 iterations) compared biomarker performance (area under the curve [AUC]) and calculated 2 thresholds at 0.95 sensitivity and 0.95 specificity. Plasma p‐tau217 cutpoints were validated in ADNI autopsy sample (n = 100); high/intermediate AD neuropathologic change considered AD+.

Results

P‐tau217/Aβ42 had the highest performance to discriminate Aβ+ from Aβ‐ (Table 1A,1B; all AUC≥0.90), and p‐tau217 showed excellent accuracy in ADNI sample (0.96; Table 1B). Linear models showed that Black individuals had significantly higher Aβ42 (β = 0.098, p = 0.0014); no difference was observed for p‐tau217 or p‐tau217/Aβ42 (both p≥0.43) (Figure 1). A Race X Aβ PET SUVR interaction confirmed this difference for plasma Aβ42 (β = ‐0.44, p = 0.00051; Figure 2).

Conclusion

Findings indicate plasma p‐tau217 levels do not differ by race, while plasma Aβ42/Aβ40 was higher in Black individuals even after accounting for differences in Aβ PET SUVR and ADI. Future work will test biomarkers in a larger sample, and examine the influence of comorbidities on differences in plasma levels and accuracy.
Approach for developing interpretative cut‐points during implementation of a plasma p‐tau217 assay in the clinical laboratory
Authors: Algeciras‐Schimnich Alicia
Published: January 2025

Background

Implementation of Alzheimer disease blood‐based biomarkers (AD BBBs) in the clinical laboratory requires careful evaluation of test performance and selection of interpretative cut‐points to prevent patient misclassification that may lead to further evaluation, misdiagnosis, and/or potentially unnecessary treatment.

Method

Participants with mild cognitive impairment or mild dementia (n = 427) and with an EDTA‐plasma sample available within 6 months of amyloid‐PET imaging were selected through the Mayo Clinic Study of Aging and the Mayo Clinic Alzheimer’s Disease Research Center in Rochester, Minnesota. Amyloid‐PET was performed with 11C‐Pittsburg Compound B; abnormal amyloid (A+) was defined as Centiloid ≥25 (SUVR≥1.52) (n = 274 A+, 153 A−). EDTA‐plasma samples were measured using the ALZpath Simoa pTau217 assay and the Fujirebio Lumipulse pTau217, Aβ42/Aβ40 and pTau217/Aβ42 ratio assays. The clinical performance of a 1‐cutpoint as well as a 2‐cutpoint model that incorporates an intermediate range were assessed. For the 2‐cutpoint model, various combinations of sensitivity and specificity were examined to identify thresholds that maximize overall test performance.

Result

While both pTau217 assays displayed high ROC AUC (>0.90), neither assay achieved ≥90% in both sensitivity and specificity using a 1‐cutpoint model. Using a 2‐cutpoint model for the Lumipulse pTau217 assay, the combination of 92% sensitivity and 96% specificity to define lower and upper cutpoints provided the optimal balance of false positives and false negatives, while keeping 20% or fewer results categorized as intermediate. For the ALZpath assay, 92% sensitivity and 96% specificity could only be achieved with 39% of the patients in this cohort falling into the intermediate range. Using this approach, the Lumipulse pTau217 assay would reduce more costly CSF or PET testing by 80%.

Conclusion

Cutpoints for the identification of amyloid pathology were defined in a cohort of individuals with MCI and mild dementia. Information obtained on the performance of these defined cut‐points was used to select the most appropriate assay and cut‐points to implement in clinical practice.