bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of pulsations in the brain and cerebrospinal fluid using ultra‐high field magnetic resonance imaging
Authors: de Almeida Bruno , Martins Tiago Amaro , Wu Minjie , Wilckens Kristine A , Minhas Davneet S , Ibinson James W , Aizenstein Howard J , Santini Tales , Ibrahim Tamer S
Published: January 2025

Background

Brain fluid flow plays a crucial role in maintaining brain health by eliminating potentially harmful waste products like amyloid‐beta and tau [1‐2]. This process is potentially facilitated by pulsations in the perivascular space, influenced by the neurovascular unit and autonomic nervous system, which may vary in brain diseases such as Alzheimer’s disease (AD) [3‐4]. Using a 7 Tesla MRI scanner and ultrafast echo‐planar imaging (EPI), we developed a non‐invasive neuroimaging methodology to characterize the in‐vivo frequency and amplitude responses of pulsations of cerebrospinal fluid (CSF) flow.

Method

Brain images from six volunteers were acquired using a 7T MRI Scanner and an in‐house developed 16‐channel Tic‐Tac‐Toe transmit array with a 32‐channel receive coil. The human‐connectome EPI multiband MR sequence was optimized to present a real‐time visualization of the CSF flow in the brain. For the first volunteer, two axial and one sagittal slices were obtained, while whole‐brain coverage was acquired for the remaining volunteers, where the acquisition was divided into 19 slabs, each consisting of 3 axial slices. A spectral analysis based on Fast Fourier Transform (FFT) was conducted for the whole brain and grey matter, white matter, and CSF regions.

Result

Figure 1 presents the processed axial and sagittal slices acquired from the first volunteer, demonstrating the presence of a periodic variation of the CSF signal. Figure 2 presents the identification of peaks in the spectrum acquisitions of whole‐brain segments for one volunteer, which exhibited similar frequencies, magnitudes and bandwidths among different volunteers. Quantitative results of this analysis are summarized in Table 1.

Conclusion

This project developed a real‐time visualization of CSF pulsations based on a non‐invasive ultrafast EPI obtained with a 7T MRI scanner. The identification of similar frequency peaks (around 0.3, 0.8, 1.1, 2.3 and 3.1 Hz) and magnitudes among healthy volunteers suggests its potential as a feasible biomarker. Future work will examine this technique’s potential to identify changes in brain fluid dynamics associated with AD progression and pathology.

Funding: NIH R01AG063525, R01MH111265, University of Pittsburgh CRC's RRID:SCR_022735.

References:

Nedergaard, 2013

Xie et al., 2013

Peng et al., 2016

Ramanathan et al., 2015
Using image‐text similarity scores from picture descriptions for differentiating the logopenic variant of progressive aphasia from amnestic Alzheimer’s dementia
Authors: Pugalenthi Lokesha , Dial Heather R , Li J. Jessy , Schmitz Suzanne , Henry Maya L. , Wauters Lisa , Keller Jeffrey N. , Largent Avery , Chang Patrick , Chang Joshua , Foil Heather , Lester‐Smith Rosemary A , Toprac Paul , Hilsabeck Robin C.
Published: January 2025

Background

Primary progressive aphasia (PPA) is a language‐led dementia associated with underlying Alzheimer’s disease (AD) or frontotemporal lobar degeneration pathology. As part of the Alzheimer’s spectrum, logopenic (lv) PPA may be particularly difficult to distinguish from amnestic AD, due to overlapping clinical features. Analysis of linguistic and acoustic variables derived from connected speech has shown promise as a diagnostic tool for differentiating dementia subtypes. Here we investigate the utility of a machine learning (ML)‐based classifier for differentiating lvPPA from amnestic AD using an image‐text similarity metric derived from a picture description task.

Method

Monolingual English speakers diagnosed with lvPPA (n=18) and amnestic AD (n=14) were asked to describe a picture (Cat Rescue). A similarity score between the image and patient’s transcription was derived with each model of the Vision‐Language encoder CLIP. This involved computing the cosine similarity between the image‐ and transcription‐based representation vectors. These image‐text similarity scores were fed into 10 ML classification algorithms to differentiate lvPPA from amnestic AD.

Result

For differentiating lvPPA from amnestic AD, our CLIP‐based feedforward neural network classifier achieved F1, AUC, and Accuracy scores of 81%, 80%, and 81% respectively. This outperformed our baselines of stratified random sampling and uniform random sampling by 30%.

Conclusion

The current study shows promising differentiation of lvPPA from amnestic AD through the single feature of image‐text similarity. This approach holds potential as an automated connected speech analysis tool for differential diagnosis of dementia subtypes. Future directions include evaluating performance in a larger dataset and comparing the classification performance between image‐text similarity and acoustic‐linguistic features.
Evaluating impact of racialization on imaging and plasma biomarkers
Authors: Gogola Alexandra , Zeng Xuemei , Saeed Anum , Lopresti Brian J , Snitz Beth E. , Tudorascu Dana , Minhas Davneet S , Ikonomovic Milos D , Kofler Julia , Matan Cristy , Mason Neale S , Pascoal Tharick A. , Aizenstein Howard J , Mathis Chester , Klunk William E , Zetterberg Henrik , Blennow Kaj , Lopez Oscar L. , Reis Steven E. , Villemagne Victor L , Karikari Thomas K , Cohen Ann D
Published: January 2025

Background

Imaging and plasma biomarkers are widely used in Alzheimer’s disease (AD) observational studies and clinical trials. Due to the lack of racial or ethnic diversity in earlier studies, a more complete understanding of biomarker differences across racialized groups is needed. Further, results from the few previous studies have disagreed on both the magnitude and direction of AD biomarker differences in racialized groups. We evaluated differences in plasma biomarker and Aβ PET outcomes between participants racialized as either Black or African American (AA) or non‐Hispanic white (NHW).

Method

We evaluated 321 participants enrolled in observational studies at the University of Pittsburgh with PET imaging and plasma biomarker assessments including: Global PiB SUVR, plasma Aβ42/Aβ40, p‐tau181, p‐tau217, p‐tau231, NfL, and GFAP (Simoa HD‐X). Outlier analysis resulted in a total of 88 AA and 166 NHW participants. To further refine the comparison, AA and NHW participants were matched based on age, sex, and ApoE status, resulting in a matched set with 88 AA and 88 NHW participants. A second matched subset was established based on the availability of p‐tau217 measures. Group differences were assessed using Mann‐Whitney U tests.

Result

In both the full and matched sets, Aβ42/Aβ40, NfL, and GFAP showed no differences between the AA and NHW groups (p>0.05). Conversely p‐tau181 and p‐tau231 were higher in AA participants (p<0.05) and global PiB SUVRs and p‐tau217 were higher in NHW participants (p<0.01). (Table 1)

Conclusion

In both the full and matched datasets, the AA and NHW groups showed significant differences in Global PiB SUVR and p‐tau217 outcomes in the opposite direction of p‐tau181 and p‐tau231 outcomes. As such, racialization should be given more consideration in AD clinical research, particularly when biomarker results are used for inclusion or exclusion criteria. Future work will explore the influence of racialization on other imaging and plasma biomarkers and their relationship with cognitive performance.
Contribution of cardiovascular comorbidities to Alzheimer’s Disease (AD) among older adults with low plasma AD biomarker level
Authors: Gu Yian , Bahl Aanya , Honig Lawrence S. , Kang Min Suk , Mayeux Richard
Published: January 2025

Background

There has been a great advancement in clinical application of blood‐based biomarkers of Alzheimer’s Disease (AD) over the past years. We aimed to examine whether cardiovascular comorbidities may contribute to clinical cognitive impairment in individuals with low level of these biomarkers.

Method

The current cross‐sectional study included 969 elderly [562 cognitively unimpaired, 407 cognitive impairment (104 amnestic MCI and 303 AD)] participants of the Washington Heights, Hamilton Heights, and Inwood Columbia Aging Project (WHICAP) study. We used Quanterix SIMOA HD‐X platforms to measure phosphorylated Tau‐181 (P‐tau181), total (T‐tau), Amyloid beta (Aβ) 40, Aβ42, Glial Fibrillary Acid Protein (GFAP), and Neurofilament Light Chain. Individuals were characterized as ‘biomarker positive’ or ‘biomarker negative’ based on combined GFAP and P‐tau181/Aβ42 cut scores. Clustering of cardiovascular comorbidities was defined as the total number of conditions including diabetes, hypertension, heart disease, and stroke. The association between the cardiovascular comorbidities and cognitive impairment was examined using logistic regression, adjusted for age, sex, ethnic group, and years of education.

Result

Among individuals with 0 ‐ 4 cardiovascular comorbidities, 20%, 43%, 42%, 52%, and 70% had cognitive impairment, respectively (p<0.001). Individuals with more cardiovascular conditions were more likely to be Hispanics, but not different in biomarker positivity status, sex, age, or education. Based on GFAP and P‐tau181/Aβ42, 188 (19.4%) were biomarker positive. As expected, being biomarker positive was associated with higher odds (OR=2.0, 95%CI=1.3‐3.2, P=0.002) of having cognitive impairment, after adjusting for age, sex, ethnic group, and years of education, and comorbidities score. Still, 37% of the 781 biomarker negative individuals had cognitive impairment. We further found that among these biomarker negative individuals, having more comorbidities (OR=1.40, 95%CI=1.02‐1.92, P=0.035) was associated with higher odds, while education was associated with lower odds (OR=0.80, 95%CI=0.75‐0.85, P<0.001), of having cognitive impairment. No association of comorbidity and cognitive impairment (OR=1.2, 95%CI=0.68‐2.15, P=0.52) was found in biomarker positive individuals.

Conclusion

Plasma AD‐related biomarkers were associated with clinical cognitive impairment. Older adults with low level of AD biomarkers may still be at risk of developing cognitive impairment if they have high burden of cardiovascular comorbidities.
Short‐term Sirolimus Treatment Restores Hippocampus and Caudate Volumes and Global Cerebral Blood Flow in Asymptomatic APOE4 Carriers Compared with Non‐carriers
Authors: Flemister Abeoseh , Xing Xin , Overschmidt Jessica , Cassani Joanne , Green Stefan J. , Beversdorf David Q. , Woods Carter , Grinstead John W. , Altes Talissa A. , Lin Ai‐Ling , Govindarajan Maalavika
Published: January 2025

Background

Apolipoprotein ε4 allele (APOE4) is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). Compared with non‐carriers, cognitively normal APOE4 individuals have shown brain atrophy and lower cerebral blood flow (CBF) decades before AD pathological and clinical symptoms appear. The goal of the study is to determine if using Sirolimus, an FDA‐approved mTOR inhibitor, could restore the brain volumes in structures related to cognitive functions and global CBF (gCBF) for asymptomatic APOE4 carriers compared with non‐carriers.

Method

The study was performed at the University of Missouri. Low dose Sirolimus (1 mg/day) was given for 4 weeks to three middle‐aged, cognitively normal APOE4 carriers (F:M = 2:1) and two female APOE3 individuals (45‐65 yrs; MOCA > 27). Oral swabs were used to determine APOE status. 3T MRI‐based structural MPRAGE and T1‐weighted images, and pseudo‐continuous arterial spin‐labeled (PCASL, 1.7x1.7x4mm resolution) were acquired at baseline (pre‐treatment) and Post‐Sirolimus (the end of treatment). FreeSurfer 7.4 was used to automatically generate segments for volumetric analysis and PCASL images were analyzed via MANGO software for perfusion weighted gCBF.

Result

APOE4 carriers had significantly increased Caudate and Hippocampal volumes (Figure 1A) and gCBF (Figure 1B) after 4 weeks of Sirolimus treatment. These differences were not found in the non‐carriers (APOE3 participants). The quantitative data is shown in Table 1. It also shows that APOE4 carriers had significantly lower Hippocampal volume and gCBF at baseline compared with that of APOE3 participants (indicated by “**”), and Sirolimus tends to restore the values to closer to those of the non‐carriers. No side effects were observed, and no changes in blood glucose and HbAc1 levels were found in all the participants.

Conclusion

We show that short‐term Sirolimus treatment can effectively restore brain volumes and gCBF for asymptomatic APOE4 carriers. Specifically in the caudate and hippocampus, which play many roles integral in normal cognitive functioning including memory, learning, and emotional regulation, has considerable atrophy in AD. The findings imply that Sirolimus may be useful and effective to mitigate or prevent AD developments for asymptomatic APOE4 carriers.
Connectomic differences in cognitively normal APOE4 versus non‐APOE4 carriers at risk for Alzheimer’s Disease
Authors: Stout Jacques Andrew , Mahzarnia Ali , Moon Hae Sol , Han Zay Yar , Johnson Kim G , Badea Alexandra
Published: January 2025

Background

Alzheimer's disease (AD) causes a steady degradation of connections inside the brain. The apolipoprotein E is a protein where one of its subtypes, APOE4, is a major genetic risk factor for developing late onset AD. Using a combination of tensor network PCA (TN‐PCA) and bundle analysis, we sought to determine which specific connections differentiate APOE4 individuals relative to non‐APOE4 carriers, and whether these changes increase with age.

Method

Our study included 77 individuals from 20 to 83 years old, 37 male and 40 female, 41 possessing only the APOE3 allele and 36 with at least one APOE4 allele. Imaging was done using diffusion weighted imaging, with a T1w anatomical scan also obtained for atlas based labeling and co‐registration. The tracts were modeled in subject space using mrtrix with anatomically constrained tractography and brought into the same template image space using our SAMBA registration pipeline. Connectomes of number of streamlines and the average FA were calculated with mrtrix. FA connectomes were used with TN‐PCA, determining which connections had higher weight for separating the genotype groups between APOE3 and APOE4. Streamlines of specific connections were split into bundles using dipy quickbundles. Statistical analysis compared linear and quadratic models for age, genotype and the interaction of the two.

Result

TN‐PCA results indicate that connections of precuneus to other structures had an important weight in APOE3 to APOE4 differentiation, particularly their inter‐hemispheric connection, their connection to the superior‐parietal region. Linear modeling showed the FA of precuneus connected streamlines had noticeable differences between APOE3 and APOE4 groups. These differences were exacerbated in specific bundles: precuneus‐right to precuneus‐left, and precuneus‐left to superiorparietal‐left connection.

Conclusion

Our results indicate that the precuneus connections differentiate between APOE4 and non‐APOE4 carriers. Future studies will address separately the white matter and grey matter streamline sections, and we will add further analysis along the streamlines for increased specificity.
Inflammation links in Alzheimer’s Disease: connecting fluid proteomics and TSPO PET
Authors: Pola Ilaria , Ashton Nicholas J. , de Bastiani Marco Antônio , Brum Wagner Scheeren , Rahmouni Nesrine , Servaes Stijn , Stevenson Jenna , Tissot Cécile , Therriault Joseph , Pascoal Tharick A. , Blennow Kaj , Zimmer Eduardo R. , Zetterberg Henrik , Rosa‐Neto Pedro , Benedet Andrea L.
Published: January 2025

Background

Emerging evidence underscores the importance of neuroinflammation in the progression of Alzheimer’s disease (AD) pathophysiology. Recent studies indicate the involvement of the inflammatory mechanisms both in amyloid‐ β (Aβ) and tau deposition in the brain. Nevertheless, due to the complexity of the immune responses and the intricate interplay between the peripheral and the central nervous systems, identifying biomarkers that reflect the brain´s inflammatory state in AD has been a challenge. For this reason, the characterization of immune‐related proteins in cerebrospinal fluid (CSF) and plasma would contribute to the understanding of the role of neuroinflammation in the progression of AD.

Method

Participants from the Translational Biomarker for Aging and Dementia Cohort (TRIAD) incorporating within the AD spectrum, and with available amyloid Aβ ([18F]AZD4694), tau ([18F]MK6240) and TSPO ([11C]PBR28) PET data (positivity = 2.5 SD > mean ROI‐SUVR of young participants), had plasma (n= 151) samples analyzed with the NULISA technology (Alamar Biosciences®). Inflammation‐related proteins (n=72) were selected and included in our analysis, which differential expression was evaluated with linear models (LIMMA) contrasting TSPO groups. After FDR correction for multiple comparisons, the differentially expressed proteins were selected for further analysis, where protein levels were correlated with the PET uptake of 45 anatomical brain regions.

Result

The differential expression analysis unveiled 5 proteins that are in higher concentrations in the plasma of TSPO positive in comparison with TSPO negative participants (Figure 1): GFAP, CHI3L1, CST3, FABP3, and CHIT1. The correlation analysis between the plasmatic proteins and PET uptake showed significant overlapping correlations with TSPO, Aβ and tau PET in brain regions such as inferior frontal gyrus, inferior occipital gyrus and amygdala (Figure 2).

Conclusion

These preliminary findings underscore the relevance of GFAP, CHI3L1, CST3, FABP3, and CHIT1 at proxying immune‐related processes in AD, by linking peripherally quantified proteins to brain pathology, as suggested by the colocalized correlations with amyloid, tau and TSPO PET uptake. Further replication of this analysis on the CSF proteomic data of these participants will support the potential significance of these proteins as valuable indicators of neuroinflammation in AD pathology.
Compression and expansion in the aging brain is associated with clinical and cognitive outcomes
Authors: Adams Jenna N. , Escalante Yuritza Y , Yassa Michael A. , Janssen Niels
Published: January 2025

Background

The brain undergoes structural changes during aging, such as gray matter loss, enlarged ventricles, and sulcal widening. However, previous studies have primarily investigated these changes in isolation, without describing the complex spatial relationships between overall brain shape and regions. Here, we tested how gradients of expansion and compression of the global shape of the brain as well as between homologous brain regions across hemispheres are affected by age, and whether these changes further contribute to clinical impairment and cognitive deficits in older adults.

Method

We analyzed 2,039 structural MRIs from the Open Access Series of Imaging Studies (OASIS) dataset (42‐97 years; 56%F). MRIs were preprocessed using Freesurfer version v6.0. Gradients of whole‐brain expansion and compression were quantified by placing equally spaced points on the outer cortical surface (n=400) along inferior‐superior and anterior‐posterior directions (Figure 1A). To assess regional changes, we measured the Euclidean distance between left and right hemisphere homologues (Figure 1B). Age effects were evaluated continuously and by comparing groups of increasing age to a young control group (42.7‐59.9 years). Clinical impairment was defined as a Clinical Dementia Rating (CDR) >0, and neuropsychological testing were used to probe cognitive deficits.

Result

Increasing age was associated with global expansion in inferior‐anterior regions and with compression in posterior‐superior regions (Figure 2A). Cross‐hemisphere distances between regional homologues showed a progressive pattern of expansion in subcortical and medial/lateral temporal lobes and compression in posterior parietal areas across increasing age groups (Figure 2B). Controlling for age, these patterns were exacerbated in clinically impaired older adults (CDR>0) and related to episodic memory and executive function scores in a regionally‐specific manner (Figure 3). Global and regional results replicated in an independent sample of older adults (Cambridge Centre for Ageing and Neuroscience dataset; N=564, 30‐88 years, 51%F).

Conclusion

During aging, the overall shape of the brain undergoes patterns of expansion within inferior‐anterior and subcortical regions, and compression within superior‐posterior regions, that further contribute to clinical impairment and cognitive deficits. This suggests that changes to the complex spatial anatomy and geometry of the aging brain may impact its ability to function efficiently and lead to cognitive dysfunction in older adults.
Longitudinal change of cerebral amyloid and tau and its association with plasma biomarkers in preclinical Alzheimer's disease
Authors: Fajardo Alfonso , Yakoub Yara , Rudolf Jonathan Gallego , Remz Jordana , Soucy Jean‐Paul , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Breitner John C.S. , Poirier Judes , Villeneuve Sylvia ,   PREVENT‐AD Research Group
Published: January 2025

Background

For medical purposes, amyloid‐beta (Aβ) and tau biomarkers are typically dichotomized into positive (+) and negative (‐) status to define individuals with Alzheimer’s disease (AD) pathology. Nevertheless, such AD proteinopathies start accumulating years before reaching clinically‐defined abnormality thresholds. We examined longitudinal change in PET Aβ and tau in cognitively unimpaired (CU) individuals; then we explored their baseline plasma levels and demographic characteristics. Finally, we assessed the association between plasma/demographics and annual rate of change (aRC) of AD pathology.

Method

We included 110 CU participants from the PREVENT‐AD cohort who underwent longitudinal Aβ and tau PET scans (mean time between scans = 4.33 years, 0.44 SD). We created four accumulator groups: 1) a non‐accumulators group, 2) an Aβ‐only group which included individuals classified as Aβ+ at baseline (SUVr threshold of 1.25, 18 CL) plus those with an Aβ aRC > 2.19 CL, 3) a tau‐only group which included individuals classified as tau+ at baseline (2 SDs above the mean of young participants, SUVr=1.23) plus those with a temporal meta‐ROI aRC > 0.022 (a GMM‐derived cut‐point), and 4) an Aβ & tau accumulator group. We then compared demographic characteristics and baseline plasma biomarker levels of Aβ42/40, GFAP, NfL, pTau181 and pTau217 across the four groups. Finally, we fitted linear regression models to predict Aβ/tau aRC as continuous variables from demographics or baseline plasma, including age and sex as covariates.

Results

Aβ accumulator groups included a higher proportion of APOE4 carriers (Table 1). Compared to non‐accumulators or tau‐only accumulators, Aβ‐only accumulators and Aβ & tau accumulators showed higher baseline plasma levels of NfL and GFAP. When aRC was treated as a continuous value, APOE4 status and age were positively associated with higher rate of Aβ accumulation. Finally, higher baseline GFAP levels were associated with faster accumulation of both Aβ and tau in the brain

Conclusions

APOE4 status, increased age and plasma GFAP levels were closely related to faster Aβ aRC. Higher plasma GFAP levels were further associated with faster tau aRC. Therefore, GFAP might be an indicator of AD pathophysiological processes.
Inflammation in the white matter relates to core Alzheimer's disease pathophysiological processes
Authors: Ottoy Julie , Kang Min Su , Yin Eric , Rahmouni Nesrine , Stevenson Jenna , Soucy Jean‐Paul , Benedet Andrea L. , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Gauthier Serge , Black Sandra E , Rosa‐Neto Pedro , Goubran Maged
Published: January 2025

Background

In‐vivo PET imaging studies have demonstrated neuroinflammation (microglia reactivity) in the neocortex of Alzheimer’s disease (AD) patients. However, the extent and implication of microglia reactivity in white matter regions remains unclear. Here, we explored microglia reactivity in white matter using PET imaging of the translocator protein (TSPO) in relation to core AD biomarkers (amyloid, tau, and astrogliosis), microstructural damage, and cognitive decline.

Method

Ninety‐one participants from the Translational Biomarkers in Aging and Dementia cohort (45% Aβ‐positive, 39% cognitively impaired) underwent diffusion‐weighted MRI, TSPO‐PET (11C‐PBR28), amyloid‐PET (18F‐NAV4694), tau‐PET (18F‐MK6240), and plasma Aβ42/40, ptau181, ptau217, and ptau231. We investigated the associations of TSPO‐PET SUVR in white matter lobes (eroded by 2mm3) with each of the AD biomarkers, diffusion metrics, and cognition, adjusted for demographics and global cortical TSPO‐PET. Longitudinally, we investigated the interaction between time (up to 2y) and baseline white matter TSPO‐PET SUVR on cognitive decline, adjusted for demographics and cortical amyloid.

Result

White matter TSPO‐PET was increased globally with older age and frontally with male sex (p<0.05). In impaired individuals, TSPO‐PET was elevated in temporo‐occipital white matter regions compared to controls (p=0.01‐0.02). The occipital increases were associated with reactive astrogliosis (p=0.011) and higher‐Braak tau‐PET (p=0.003‐0.034 for Braak3‐4) and plasma ptau181 (p=0.014) (Figure 1A‐B), but not with Aβ, ptau231 or ptau217. In addition, higher occipital TSPO‐PET was associated with lower fibre integrity (fractional anisotropy, p=0.025) but not free water. Finally, in relation to cognition, higher occipital and parietal TSPO‐PET was significantly associated with impaired memory and language, respectively, independent of Aβ (Figure 1C). Longitudinally, within the same patient, higher white matter TSPO‐PET at baseline was significantly associated with favorable clinical outcome over time (Figure 1D).

Conclusion

Increased microglia reactivity (TSPO‐PET) in posterior white matter may indicate later‐stage AD associated with astrogliosis, tau, and dysfunction of the memory and language domains. Another novel finding is that individuals with higher white matter TSPO‐PET at baseline displayed better clinical prognosis over time. As such, assessing white matter inflammation could be promising to evaluate target engagement in clinical trials of anti‐inflammatory drugs and to subtype patients for better patient‐centric treatment outcome.
MRI findings in a dementia center from Recife, Brazil: applicability of the Fazekas’ score
Authors: Neto Francisco Sabino de Oliveira , Calixto Lucas Henrique , Soares João Pedro Wanderley , Arteiro Pedro Jatobá , Gondim Alice Batista , Araújo Luziany Carvalho , Barbosa Breno José Alencar Pires
Published: January 2025

Background

Data about dementia in Brazil are scarce and subnotified. Until 2018, 1,3 million people were estimated to have been affected. neuroimaging has a crucial importance to provide detailed information about cerebral structures and characteristics patterns of different types of dementia even as the progression of these injuries. One of the most used imaging scales since 1987 is the Fazekas’ scale, which graduate the lesions according to their distribution in cerebral parenchyma. we aimed to analyze the encephalon’s MRI from patients that are in outpatient follow‐up and caracterize main radiology white matter findings.

Method

It’s a transversal, retrospective and descriptive study about long‐sufferings which were in outpatient between 2017 and 2022 in a North East reference service. Were selected those which the MRI has been done in this service and evaluated by a neuroradiologist using the HORUS™ image analysis software, determining radiologic patterns using Fazekas’ scale

Result

Among ninety‐nine medical records evaluated, there were 26 CT Scans, 15 PET‐CT and 76 MRIs. From this exams, only 35 patients had MRI scans at this service. Two patients were excluded from the study because of the incomplete sequences, with no possibility of evaluation. About the 33 remaining patients, 3 of them had incomplete image sequences, but with an evaluable flair. The mean age was 64.9 years old (+/‐ 12.9), which 57% were female. About the associated comorbities, there were 18 cases of Hypertension (ASH), 4 of diabetes mellitus (DM), 9 of alcoholism and 10 of smoking. The Fazekas Score in these patients were: 0 in 2 patients, 1 in 14 patients, 2 in 9 patients and 3 in 8 patients

Conclusion

Although it’s an old instrument, the Fazekas’ scale is still an actual and with considerable applicability way to graduate lesions in patients with dementia and risky factors using of a simplified way.
Acute Aβ12‐28P administration targeting apoE/Aβ interaction rescues synaptic function and cognitive decline in advanced‐stage Alzheimer’s disease
Authors: Chen Shuo , Lam Nikolas , Li Zhiheng , Wang Ding , Liu Pengfu , Berbano Victoria , Xie Yu , Nguyen Tyra , Xu Yvonne , Yang John , Ha Karen , Semana Leonardo , Dias Rachel , Masurkar Arjun V. , Wisniewski Thomas
Published: January 2025

Background

Apolipoprotein E4 (apoE4) has been identified as the major genetic risk factor for late onset Alzheimer’s disease (AD). Our lab has demonstrated that chronic administration of Aβ12‐28P, a synthetic peptide that blocks apoE4/Aβ binding, in middle‐aged transgenic AD mice significantly ameliorates pathology progression, resulting in reduced Aβ plaques deposition and cerebral amyloid angiopathy (CAA) along with improved memory and cognition. However, whether blocking apoE4/Aβ interaction by Aβ12‐28P also has an ameliorating effect on the neuronal and cognitive function of old AD mice where Aβ pathology has been extensively developed remains unknown.

Method

Geriatric SwDI/APOE4 mice (18‐24 months old) were intraperitoneally injected daily with Aβ12‐28P, while control mice received only saline. Behavioral tests including anxiety in open field, locomotor activity, T‐maze, object recognition, and radial arm maze were performed 2 hours post‐injection to assess the acute effect of Aβ12‐28P. After 3 weeks of behavioral testing with daily treatment, acute hippocampal slices were prepared and subjected to in vitro physiology experiments to evaluate long‐term potentiation (LTP) of Schaffer collateral input to CA1. On the recording day Aβ12‐28P or saline was injected 2 hours before slice preparation.

Result

Acute Aβ12‐28P treatment resulted in significant cognitive improvement. While the treated mice did not show differences in locomotor activity, significantly enhanced cognitive performances were observed, including improved performance in one‐day T‐maze test (n = 10/group, p = 0.0005), one‐day novel object recognition test (n = 6/group, p = 0.018), and multiple‐days radial arm maze test (n = 8‐9/group, p = 0.0008). Aβ12‐28P administration also significantly reduced anxiety in open field (n = 6/group, p = 0.0081). We further compared the hippocampal Schaffer collateral LTP in slices from Aβ12‐28P‐treated versus non‐treated mice. Slices from the treated animals showed significantly enhanced LTP (n = 9‐10/group, p < 0.0001), suggesting rescued synaptic plasticity.

Conclusion

These results suggest that acute Aβ12‐28P administration blocking apoE/Aβ binding rescues synaptic plasticity and cognitive decline in old AD mice where extensive Aβ pathology has been developed. Our finding opens the possibilities to apply the strategy of targeting apoE/Aβ interaction for alleviating advanced‐stage AD symptoms in addition to ameliorating Aβ deposition during AD progression.
Assessing the correlations between imaging and plasma biomarkers within the AT(N) framework
Authors: Gogola Alexandra , Cohen Ann D , Zeng Xuemei , Lopresti Brian J , Snitz Beth E. , Tudorascu Dana , Minhas Davneet S , Ikonomovic Milos D , Pascoal Tharick A. , Kofler Julia , Matan Cristy , Mason Neale S , Aizenstein Howard J , Mathis Chester , Klunk William E , Zetterberg Henrik , Blennow Kaj , Lopez Oscar L. , Villemagne Victor L , Karikari Thomas K
Published: January 2025

Background

Given the increasing usage of plasma biomarkers for Alzheimer’s disease (AD) studies, it is necessary to better understand relationships between plasma biomarker and PET and MR imaging outcomes, particularly within the AT(N) framework.

Method

We evaluated plasma samples from 233 subjects (age 74.05.9y) who underwent 3T MR and both [11C]PiB and [18F]flortaucipir (FTP) PET imaging. SUVR values were calculated for Global PiB, and Meta‐Temporal FTP. An AD signature cortical thickness (CT) composite was derived from MR images using FreeSurfer 5.3, Blood samples were processed and sampled to obtain measures of plasma Aβ42, Aβ40, p‐tau181, p‐tau217, p‐tau231 and neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Imaging outcomes were split into infra (‐) and supra (+) threshold groups using 1.35 SUVR for Global PiB, 1.18 SUVR for Meta‐Temporal FTP, and 2.7 mm for CT. Plasma Aβ was expressed as Aβ42/Aβ40 ratio while p‐tau181, p‐tau217, p‐tau231, NfL, and GFAP were natural‐log‐transformed to normally distribute the data. Simple regression models between continuous variables of each imaging‐derived measure and all plasma biomarkers were evaluated.

Result

Full group regression model R2 and regional p‐values are shown in Table 1, suprathreshold regressions are shown in Table 2. Full Global PiB was significantly associated with all plasma biomarkers while CT was associated with NfL, p‐tau181, and p‐tau231. Meta‐Temporal FTP was associated with GFAP and p‐tau217. Additionally, A+Global PiB was significantly associated with Aβ42/Aβ40, GFAP, and p‐tau217; (N+) CT with NfL; and T+ Meta‐Temporal FTP with p‐tau181 and GFAP.

Conclusion

The significant associations between suprathreshold imaging and plasma biomarkers suggests that, in A+, T+, or (N+) both capture abnormal AD pathophysiology. Further, the absence of an association in the infrathrehold cases supports that the suprathreshold associations are not artifactual. Future work will explore plasma thresholds and concordance between imaging and plasma AT(N).
Optimizing tau‐PET referrals in memory clinics through a blood biomarker workflow
Authors: Brum Wagner Scheeren , Cullen Nicholas , Therriault Joseph , Janelidze Shorena , Rahmouni Nesrine , Stevenson Jenna , Servaes Stijn , Benedet Andrea L. , Zimmer Eduardo R. , Stomrud Erik , Palmqvist Sebastian , Zetterberg Henrik , Frisoni Giovanni , Ashton Nicholas J. , Blennow Kaj , Mattsson‐Carlgren Niklas , Rosa‐Neto Pedro , Hansson Oskar
Published: January 2025

Background

Blood‐based biomarkers have demonstrated great promise for identifying biomarker‐confirmed Alzheimer's disease. We aimed to evaluate whether blood‐based biomarkers could optimize the referral of memory clinic patients to a tau‐PET exam, which is crucial for prognostic evaluation.

Method

The study measured various plasma biomarkers (Aβ42/Aβ40, pTau181, pTau217, pTau231, NfL, and GFAP) and compared them with tau‐PET scan results in patients with subjective cognitive decline, mild cognitive impairment, or dementia. Participants were sourced from the Swedish BioFINDER‐2 study (548 individuals) and the TRIAD study (179 individuals). Cutoffs for each biomarker were established at 90%, 95%, and 97.5% sensitivity for detecting tau‐PET‐positivity. We then calculated the percentage of patients below these cutoffs (to potentially avoid unnecessary tau‐PET scans) and the tau‐PET‐positivity rate among those above the cutoffs.

Result

Plasma pTau217 showed the most promising results. At a 95% sensitivity cutoff in both cohorts, using pTau217 could avoid nearly half of the tau‐PET scans while maintaining a tau‐PET‐positivity rate of approximately 70% in those referred. Furthermore, tau‐PET was strongly associated with subsequent cognitive decline. In the BioFINDER‐2 cohort, tau‐PET predicted cognitive decline only in individuals above the plasma pTau217 referral cutoff, suggesting a more targeted and informative use of tau‐PET scans.

Conclusion

Plasma pTau217 demonstrates potential as a guiding biomarker for selecting Alzheimer’s disease patients for tau‐PET scans, particularly when accurate prognostic information is clinically valuable. This approach could lead to more efficient and informative use of tau‐PET scans, avoiding unnecessary procedures in patients unlikely to benefit from them.
The New Zealand‐Dementia Prevention Research Clinics: Plasma biomarkers and the Alzheimer’s disease continuum
Authors: Cawston Erin E , Griner Leon , Wong Celestine YE , Myall Daniel J , Ashton Nicholas J. , Gonzalez‐Ortiz Fernando , Blennow Kaj , Zetterberg Henrik , Williams Joanna M , Cutfield Nicholas J , Anderson Tim J , Dalrymple‐Alford John C , Tippett Lynette J ,   The New Zealand‐Dementia Prevention Research Clinics, New Zealand
Published: January 2025

Background

Single molecule array (Simoa) technology enables the detection of Alzheimer’s disease (AD) neuropathology in blood. This study compared cross‐sectional biomarker profiles for participants from the New Zealand‐Dementia Prevention Research Clinics (NZ‐DPRCs) who spanned the continuum from healthy older adults to a clinical diagnosis of AD.

Method

NZ‐DPRC participants were clinically classified as cognitively unimpaired adults (CU, n=34), subjective cognitive decline (SCD, n=65), non‐amnestic mild cognitive impairment (single and multi‐domain, non‐aMCI, n= 23), amnestic MCI (single and multi‐domain, aMCI, n=104), and AD (n=27). A cross‐sectional analysis quantified nine plasma biomarkers using the HD‐X Simoa analyser (Quanterix, Billerica, MA). These were: amyloid‐beta peptides (Aß1‐40; Aß1‐42); total and phosphorylated tau species (total‐tau; brain‐derived tau (BD‐tau); p‐tau181; p‐tau217; p‐tau231); neurofilament light (NfL); and, glial fibrillary acidic protein (GFAP). All biomarkers except for Aß1‐40, Aß1‐42 and the Aß1‐42/Aß1‐40 ratio were natural log‐transformed to approximate normality and improve homogeneity of variance. Plasma biomarkers across the five groups (CU, SCD, aMCI, non‐aMCI and AD) were assessed by linear regression adjusted for age and sex and Tukey’s HSD post‐hoc test was used for pairwise comparisons between classification groupings.

Result

This study included 253 participants from the NZ‐DPRCs (mean [SD] age, 69.8 [8.1] years, 131 females [52%], and 122 males [48%]). Biomarkers p‐tau217, GFAP, p‐tau181, Aß1‐42, BD‐Tau, Aß1‐42/Aß1‐40 ratio, p‐tau231 and NfL, all showed group differences (F(4,246); P<0.05; η2
p = 0.165, 0.109, 0.076, 0.073, 0.059, 0.058, 0.055, 0.044 respectively; Aß1‐40, P=0.06, η2
p = 0.035; total‐tau, P=0.67,η2
p = 0.010). Post‐hoc test for group comparisons showed significant differences (P<0.05) for GFAP between AD vs CU, SCD, non‐aMCI as well as SCD vs MCI; p‐tau181 for AD vs CU, SCD, aMCI, non‐aMCI; p‐tau217 for AD vs CU, SCD, non‐aMCI as well as aMCI vs CU and SCD; p‐tau231 for AD vs non‐aMCI; Aß1‐42 for aMCI vs CU and SCD; Aß1‐42/Aß1‐40 ratio and BD‐tau for SCD vs aMCI. ROC analysis will be reported for the diagnostic accuracy of these blood analytes.

Conclusion

Simoa‐quantitated blood biomarkers in the NZ‐DPRC cohort showed utility for differentiating cross‐sectional groupings spanning the AD continuum.
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.
Plasma p‐tau217 outperforms [18F]FDG‐PET in identifying biological Alzheimer’s disease in atypical and early‐onset dementia
Authors: Socualaya Kely Monica Quispialaya , Therriault Joseph , Aliaga Antonio , Macedo Arthur C. , Rahmouni Nesrine , Arias Jaime Fernandez , Stevenson Jenna , Wang Yi‐Ting , Tissot Cécile , Benedet Andrea L. , Ashton Nicholas J. , Karikari Thomas K , Pascoal Tharick A. , Soucy Jean‐Paul , Gauthier Serge , Vitali Paolo , Zetterberg Henrik , Rosa‐Neto Pedro
Published: January 2025

Background

Biomarkers promise to significantly improve the differential diagnosis of Alzheimer’s disease (AD). Plasma biomarkers, such as phosphorylated tau (p‐tau), have shown potential in diagnosing AD with high accuracy. Unlike the widely‐used [18 F]FDG‐PET diagnostic biomarker in clinical practice, plasma p‐tau is specific to AD and can provide an affordable and scalable diagnostic tool.

Method

We conducted a retrospective analysis of individuals with atypical dementia, and/or early‐onset dementia cases, who were assessed at a specialized memory clinic. All participants underwent measurements of CSF Aβ42, p‐tau181, and total tau levels, as well as brain [18F]FDG‐PET scans and plasma p‐tau217 measurement. The [18F]FDG‐PET data was visually examined by two nuclear medicine experts to determine whether they were compatible with AD. CSF biomarker results were categorized as either AD biomarker positive or negative. Contingency analysis was performed to assess the relationships between PET scan interpretation and fluid biomarkers (plasma p‐tau217 and CSF p‐tau181 and Aβ42). CSF biomarker and amyloid‐PET were treated as the reference standard.

Result

81 subjects with atypical dementia had CSF AD biomarker evaluation, [18F]FDG‐PET rating, and plasma p‐tau217 assessment. Both [18F]FDG‐PET and plasma p‐tau217 had high levels of agreement with reference standard AD biomarkers ([18F]FDG‐PET: 71%; plasma p‐tau217: 81%). Although both biomarkers had similar specificity for AD ([18F]FDG‐PET:70%, plasma p‐tau217:70%), plasma p‐tau217 had higher sensitivity for abnormal AD (97%). Overall accuracy was also higher for plasma p‐tau217 (AUC=84%, 95%CI = 0.75‐ 0.93). The same pattern of results was observed when using amyloid‐PET as the reference standard.

Conclusion

Our study provides evidence that plasma p‐tau217 has excellent diagnostic performance for AD in individuals with early‐onset or atypical dementia evaluated in specialized settings. Nevertheless, the topographical information from [18F]FDG‐PET may give complementary information.
Assessing the efficacy of BETTH‐derived tau thresholds to predict cognitive decline in non‐demented individuals
Authors: Gogola Alexandra , Lopresti Brian J , Snitz Beth E. , Tudorascu Dana , Minhas Davneet S , Dore Vincent , Ikonomovic Milos D , Shaaban C. Elizabeth , Kofler Julia , Matan Cristy , Bourgeat Pierrick , Mason Neale S , Rowe Christopher C. , Aizenstein Howard J , Mathis Chester , Klunk William E , Lopez Oscar L. , Cohen Ann D , Villemagne Victor L
Published: January 2025

Background

Tau PET thresholds should detect early tau deposition and predict cognitive decline. We evaluated the relationships between the BETTH‐derived sensitivity and specificity tau thresholds (Gogola et al, doi:10.2967/jnumed.123.265941, 2023) and cognitive changes in non‐demented participants.

Method

FTP scans from 314 non‐demented participants (age 73.17.1 years) and MK scans from 91 non‐demented participants (age 73.65.6 years) were processed and sampled to obtain regional SUVR values. Three cognitive measures were assessed: Clinical Dementia Rating Scale Sum of Boxes (CDR_SoB), Delayed Recall (DR), Logical Memory (LM), and Mini Mental State Examination (MMSE). Cognitive measures collected at the time of scanning were considered timepoint 0 (T0) and the most recently collected measures were considered timepoint 1 (T1). To evaluate the thresholds, SUVRs were split into below (T‐) and above (T+) threshold groups before assessment using both sensitivity (SEN) and specificity thresholds (SPC) for the FTP‐scanned participants and SEN thresholds for MK‐scanned participants, due to the limited number. Regression models between SUVR and change in cognitive measure, adjusted for age, gender, years of education, APOE status, Centiloids, cortical thickness and T0 cognitive score, were evaluated.

Result

The FTP and MK regression model regional and full‐model p‐values are shown in Tables 1 and 2. For FTP, the SEN thresholds yielded greater levels of significance than the SPC thresholds. Additionally, for FTP, the Meta Temporal region was the most significantly associated with cognitive decline in all four metrics (p<0.0001). For MK, Meta Temporal, Inferior Temporal, and Lateral Occipital were significantly associated with CDR_SoB (p<0.001) and Amygdala was significantly associated with LM (p<0.05). No other associations were significant.

Conclusion

The superior performance of the Meta Temporal region, for FTP, in all four cognitive measures indicates that cognitive decline is associated with cortical tau deposition. As seen with the MK results, this is particularly true as characterized by CDR_SoB. Moreover, the SEN thresholds were the best overall predictor of cognitive measure change, suggesting that they are the optimal regions and thresholds to apply in clinical diagnosis and therapeutic trials. Further work will assess the Meta Temporal SEN thresholds in relation to cognitive decline within the AT(N) framework.