bluuebunny/crossref_metadata_2025 huggingface dataset:
Attention Network Dysfunctions in Lewy Body Dementia and Alzheimer's Disease
Authors: Su Li
Published: January 2025

Background

Attention deficits are notable in Lewy body dementia (LBD) and in Alzheimer’s disease (AD), however, its underlying neurobiology and neuropathology are unclear. Functional magnetic resonance imaging (fMRI) and electroencephalograph (EEG) provides information about attention deployment and regional neural oscillatory deficits in LBD and AD. In this study, we combined fMRI and EEG to detect neural correlates of attention dysfunctions in LBD and AD.

Method

We recruited 33 patients with LBD, 15 patients with AD and 19 elderly healthy controls. All participants underwent a 3T fMRI scanning and a subsequently EEG recording. During fMRI and EEG, participants performed the same modifiedAttention Network Task (ANT) to investigate the alert, orient, executive and conflict attention dysfunctions. Here, we have focused on the EEG part of the study while using the fMRI data to localise the EEG signal on the cortex.

Result

Behaviourally, although both LBD and AD maintained a relative normal executive/conflict attention, we found that LBD had alert attention deficits and AD showed apparent orient attention dysfunctions. Based on source‐level EEG analyses, LBD had frontal‐central deficits for alert attention while AD showed inferior frontal and precentral impairments for orient attention. In addition, the insular and inferior frontal areas was hyper‐activated in LBD and AD for executive/conflict attention. Apart from these areas, LBD showed complementary temporal‐central‐occipital network for the modified ANT task. Furthermore, the oscillational sources for the ANT effects indicated that alpha and theta bands were partly impaired in dementia patients.

Conclusion

In summary, using source localised EEG, we found that attention dysfunctions in LBD and AD have engaged different neural networks. This has important implications in understanding the symptomology in LBD such as recurrent visual hallucinations and cognitive fluctuation.
Red Light Therapy Attenuates Prolonged LED light Exposure‐Associated Neuropathology and Mediates Circadian Clock Genes ‐ Per1 and Bmal1 Expression in Rats' Basal Ganglia
Authors: Obajuluwa Adejoke Olukayode , Babafemi Laoye John , Ndianefo Ogochukwu Jessica , Obajuluwa Tiwalola Madoc , Lech James Chrystopher , Okiki Pius Abimbola
Published: January 2025

Background

Prolonged exposure to LED‐light has been associated with impaired sleep quality and pathogenesis of various diseases, including Alzheimer’s Disease (AD). Red light therapy has been indicated as a non‐invasive way of reducing anxiety, mood and sleep optimization in neurodegenerative disorders but its endogenous mechanisms are insufficiently comprehended. Hence, we assessed the effects of scheduled red‐light exposure on clock genes‐Bmal1 and Per 1 expression, feacal boli frequency, and anxiety‐like responses in prolonged LED‐light exposed rats.

Method

Anxiety‐like indices of male rats was assessed using standard neurobehavioural methods under various light settings exposures (n=5) in groups: I) 12‐hour light/12‐hour dark (NC), II) 12‐hour light and 12‐hour dark + scheduled red light (PC), III) 24‐hour LED light, and IV) 24‐hour LED light + scheduled red light; every two weeks for a total of 60 days. Total RNA was isolated from the rats' basal ganglia and reverse transcription was performed with the ProtoScript cDNA synthesis kit. Quantification and purity of cDNA were assessed using 1µl in a DeNovix spectrometer. Sequenced primers were utilized for the analysis of mRNA expression levels of Bmal1, Per1, and the housekeeping gene (GAPDH) through real‐time PCR. The PCR products were resolved by electrophoresis on 1.5% agarose gels and visualized by SafeView staining.

Result

Feacal bolus frequency (p<0.001), closed arm entries (p<0.05), and time spent in the dark area of the light‐dark box (p<0.001) were significantly reduced in the 24‐h LED light+scheduled red light and control groups rats compared to the 24‐h LED light. Real‐time gene expression analyses of Per1 showed a significant decline in the 24‐hour LED‐exposed rats, as indicated by decreased mRNA expression levels (p<0.05), when compared to other groups. Bmal1 gene expression remained unchanged in groups I and II while AGE revealed 100bp and 150 bp banding patterns for Bmal1 and Per1, respectively.

Conclusion

The findings from this study revealed that red light therapy attenuates LED light‐exposure‐induced anxiogenic responses and Per1 gene expression impairment. Consequently, these findings have the potential to inform the development of non‐invasive treatment strategies targeting the improvement of sleep quality in the management of neurodegenerative disorders. However, safety assessments should be ensured for its validation.
Longitudinal loneliness changes are associated with cognitive decline and brain structure alterations: evidence from the Whitehall II cohort study
Authors: Zhang Ye , Tatewaki Yasuko , Liu Yingxu , Tomita Naoki , Thyreau Benjamin , Taki Yasuyuki
Published: January 2025

Background

Loneliness has been linked to cognitive decline and an elevated risk of Alzheimer's disease (AD). Previous studies measured loneliness at a single point time, which may not accurately capture the longitudinal changes of different loneliness types (e.g., recover form loneliness; persistent loneliness) and their impact in the neuropathology of AD. This study investigates five‐year longitudinal changes of loneliness and their associations with cognitive function and brain structure alterations using data from the Whitehall II cohort study.

Method

This study included 5346 participants with mean age = 65 year (Female:26.68 %) at baseline (2007‐2009). Loneliness was measured using one item form the Center for Epidemiologic Studies Depression Scale, and longitudinal loneliness changes were defined from two time points (2002‐2004; 2007‐2009). Linear mixed‐effect models were used to examine the association between different loneliness types and eight‐year changes of different cognitive domains (global cognition, reasoning, verbal fluency, and verbal memory). Robust linear regression models were employed to assess loneliness types and gray matter volumes (GMVs) in selected brain regions five‐year later (2012‐2012) using the Whitehall IIMRI substudy (N=711).

Result

We defined four types of loneliness changes: “No loneliness”, “Transient loneliness”, “Incident loneliness” and “Persistent loneliness”. Compared to no loneliness, persistent loneliness was associated with decline in cognitive function (global cognition: b= ‐0.20, p<0.001; reasoning: b= ‐0.29, p<0.001; verbal memory: b= ‐0.11, p<0.007; verbal fluency: b= ‐0.15, p=0.001;) after controlled for age, sex, education, and objective social isolation. Compared to no loneliness, persistent loneliness was associated with decreased GMVs in right posterior cingulate cortex (b= ‐0.17, pFDR‐corrected=0.041); transient loneliness was associated with increased GMVs in rostral anterior cingulate cortex (b= ‐0.48, pFDR‐corrected=0.025).

Conclusion

Persistent loneliness was associated with both longitudinal cognitive decline and decreased brain regions involved in emotional regulation, suggesting persistent loneliness feelings, no incident loneliness, could be a risk factor in the neuropathology of AD. Moreover, recovery from loneliness feeling (transient loneliness) could be protective in future brain structure alterations. Our study suggests that identifying participants has long‐term loneliness and developing strategies to overcome loneliness feeling could be important for AD prevention.
Implementation and Validation of Face De‐Identification (de‐facing) in ADNI‐4
Authors: Schwarz Christopher G. , Tosun Duygu , Yushkevich Paul A. , Choe Mark , Rossi Stephanie , Das Sandhitsu R. , Ittyerah Ranjit , Fletcher Evan , Maillard Pauline , Singh Baljeet , Harvey Danielle J. , Malone Ian B. , Prosser Lloyd , Senjem Matthew L. , Matoush Leonard C. , Ward Chadwick P. , Prakaashana Carl M. , Decarli Charles , Weiner Michael S. W. , Jack Clifford R.
Published: January 2025

Background

Recent advances in automatic face recognition have increased the risk that de‐identified research imaging data could be re‐identified from face imagery in brain scans.

Method

An ADNI committee of independent imaging experts evaluated 11 published techniques for face‐deidentification (“de‐facing”) and selected four algorithms (FSL‐UK Biobank, HCP/XNAT, mri_reface, and BIC) for formal testing using 183 longitudinal scans of 61 racially and ethnically diverse ADNI participants, evaluated by their facial feature removal on 3D rendered surfaces (confirming sufficient privacy protection) and by comparing measurements from ADNI routine image analyses on unmodified vs. de‐faced images (confirming negligible side effects on analyses).

Result

Effects of the de‐facing methods on FreeSurfer at UCSF (Figure 1‐top), ASHS at University of Pennsylvania (Figure 1 bottom‐left), and longitudinal atrophy at Mayo Clinic (Figure 1 bottom‐right) were comparable with each other and sufficiently small vs. unmodified scans to recommend de‐facing in ADNI‐4. The FSL and mri_reface methods were more thorough in removing facial features, partly because these also removed ears (Figure 2‐top). mri_reface was recommended for ADNI‐4 primarily because fewer (zero) images had modified brain (Figure 2‐bottom), and ADNI leadership approved de‐facing with mri_reface. ADNI performed a second validation of its latest version on another diverse sample of 100 ADNI‐3 participants. These analyses included: boundary shift interval at University College London, where average differences in measurements were all <0.05%; cortical white matter hyperintensities at UC Davis, where they found “minimum impact” (R>0.97); and others.

Conclusion

ADNI‐4 de‐faces all indicated image types (Table 1) before subsequent pre‐processing, analyses, and public release. Sites upload images to the central repository (LONI), where they are queued to the MRI Core at Mayo Clinic for de‐facing. Image types requiring de‐facing are de‐faced using mri_reface. Trained analysts inspect de‐faced images to confirm complete removal of the face and complete non‐modification of the brain, and any flagged images are re‐processed manually until issues are resolved. De‐faced images are converted back to DICOM and re‐uploaded for further distribution. Image types not requiring de‐facing are indicated to proceed directly to subsequent steps. In summary, ADNI‐4 has adopted mri_reface because it successfully de‐faces without substantially affecting brain measurements.
The genetic architecture of the human anterior commissure and its potential role as biomarker of neurodegeneration
Authors: Ochoa‐Rosales Carolina , Adams Hieab H.H.
Published: January 2025

Background

Commissural tracts are the white matter fibre bundles intercommunicating left and right brain hemispheres. They integrate many cognitive functions such as memory, verbal processing, motor and perceptual skills. Also, commissures connect specific layers of cortical neurons that are also lost in Alzheimer’s disease (AD) and other neurodegenerative disorders. Although highly heritable, commissures´ specific genetic determinants remain obscure. We aim to investigate the genetic determinants of the human anterior commissure. Given its presumed role in neurodegeneration, we aim to further provide mechanistic insights into neurological conditions that may result from its dysfunction.

Method

Two‐stage genome‐wide association study, (GWAS) (N=18,828) of the size of the anterior commissure. The discovery sample included seven cohorts (N=7,935) and was meta‐analyzed with ten replication cohorts (N=10,893). The size of the anterior commissure was manually derived from magnetic resonance imaging (1.5T/3T) with at least T1/T2‐weighted sequences. The genetic data was assessed through genotyping using SNP microarrays. We used voxel‐based morphometry to determine which regions are connected by the anterior commissure. To prove a functional validation of the identified variants, we performed a series of in silico experiments, including the study of the spatial expression patterns in human brains, quantitative trait loci (QTL), enrichment analysis and pleiotropy with neurodegenerative diseases.

Result

we identified six independent variants at four loci (p‐values from 4.1x10‐8 to 9.4x10‐22). We mapped the loci to probable causal genes involved in axon guidance (EPHA3 and SEMA6A), cognitive disorders (CTNND2), and growth factor signaling (RIT2). Voxel‐based morphometry revealed distinct associations of the variants with connected grey matter regions in the brain. We found enrichment for H3K4me1 peaks (marking enhancer sites), introns, and conserved sequences, as well as cell‐type‐specific annotations from the central nervous system and cardiovascular system. Furthermore, we identified pleiotropy between genes known to increase risk of neurodegenerative conditions including frontotemporal lobar degeneration gene TMEM106B. Variants associated to this gene have been related to dementia development.

Conclusion

these results shed light on the genetic architecture of commissural tracts and establish the size of the anterior commissure as a relevant biomarker of neurodegeneration.
Links Between Microvascular and AD‐related pathology in the Medial Temporal Lobe
Authors: Perosa Valentina
Published: January 2025

Background

Cerebral small vessel disease (CSVD), which includes cerebral amyloid angiopathy (CAA) and arteriolosclerosis, often co‐occurs with Alzheimer’s disease (AD) pathology. The medial temporal lobe (MTL) is susceptible to hosting multiple AD pathologies, such as neurofibrillary tangles (NFTs), amyloid‐ß plaques, phospho‐Tar‐DNA‐Binding‐Protein‐43 (pTDP‐43), as well as CSVD. Whether a causal relationship between these pathologies exists remains largely unknown, but one potential linking mechanism is the dysfunction of perivascular clearance. Our objective was to examine the burden of CSVD in the MTL of a pathological AD cohort and to establish the associations between CSVD and AD‐related pathologies, as well as between CSVD and enlarged perivascular spaces (EPVS), a potential indicator of clearance dysfunction.

Method

The study included 156 autopsy cases (mean age at death 79.4±10.9 years, 90 females) from the Massachusetts Alzheimer’s Disease Research Center (MADRC). One hemisphere was preserved in formalin, and 5 µm‐thick sections were cut from predefined regions of the hippocampal body and entorhinal cortex. These sections were subsequently stained using luxol fast blue with hematoxylin&eosin (LHE), and antibodies against amyloid‐ß, hyperphosphorylated tau (At8), and pTDP‐43, following standard histological and immunohistochemical protocols. Utilizing deep‐learning models (Aiforia®), we computed the burden of CAA, amyloid‐ß plaques, NFTs, and pTDP‐43 inclusions (Figure 1). Additionally, the severity of arteriolosclerosis and the % area of EPVS were evaluated on the LHE sections.

Result

In linear mixed effects models CAA was positively associated with the density of NFTs (Est=7.21; p=0.024; R2=69%) and amyloid‐ß plaque burden (Est=3.01; p<0.001; R2=61%) in all regions of interest. Arteriolosclerosis had no direct effect on parenchymal AD‐related pathologies but showed a positive interaction with CAA in the association with PVS enlargement. There was no relationship between pTDP‐43 inclusions and arteriolosclerosis.

Conclusion

These results point towards an association between microvascular pathology and AD‐related pathology, possibly mediated by clearance dysfunction.
Spatial Characterization of White Matter Hyperintensity Pathophysiology Across Disorders
Authors: Parent Olivier , Devenyi Gabriel A. , Bussy Aurelie , Pigeau Grace , Costantino Manuela , Fouquet Jérémie , Rodriguez Daniela Quesada , Dadar Mahsa , Chakravarty Mallar M.
Published: January 2025

Background

White matter hyperintensities (WMHs) are age‐related radiological abnormalities indicative of small vessel disease. It is unclear if WMHs in different regions represent similar pathophysiology and etiology. Here, we developed a framework to estimate WMH pathophysiology in vivo, which allowed us to precisely characterize spatial patterns of WMH tissue alterations associated with four disorders.

Method

We used data from 32,014 UK Biobank (UKB) participants. WMHs and normal‐appearing white matter (NAWM) were automatically segmented. Diffusion‐ and susceptibility‐weighted images were used to derive fluid‐, fiber‐, myelin‐ and iron‐sensitive microstructural markers. We calculated voxel‐wise normative models of NAWM microstructure using Bayesian linear regression with age (4th order B‐spline) and sex predictors in a custom UKB template space derived using multi‐spectral registration of T1w and fractional anisotropy (FA) images (Fig. 1A‐B). Within‐subject WMH pathophysiology was estimated as the difference between WMH microstructure and predicted NAWM microstructure (Fig. 1C).

Result

First, from between‐subject averages of WMH microstructural abnormality (Fig. 2A), we used spectral clustering to derive spatial patterns of WMHs that share similar pathophysiological properties (Fig. 2B). The first cluster (periventricular) has low abnormality. The second (posterior) and third (anterior) cluster both show fluid accumulation, fiber alterations, and myelin and iron loss, while the anterior cluster shows higher abnormality. Second, we assessed the differences between four disorders and age‐ and sex‐matched controls in terms of all WMH features with Cohen’s D. Ischemic heart diseases (n=2320) and hypertensive diseases (n=9852) demonstrated small but significant effects across measures, which were slightly higher in anterior regions. Stroke (n=320) demonstrated larger effects, which were more prominent in anterior regions. On the other hand, dementia (n=46) demonstrated smaller effects compared to stroke, reaching significance mostly in posterior regions despite the smaller sample size. Interestingly, the fractional anisotropy and orientation dispersion markers showed drastically inverted patterns of effects between stroke and dementia.

Conclusion

Our results separating anterior and posterior WMHs are consistent with accumulating evidence showing that posterior WMHs may be linked to Alzheimer’s pathology, whereas anterior WMHs may be associated with vascular pathologies. MRI pathophysiological markers may further help in distinguishing these etiologies.
Alzheimer’s disease genetic risk factors' influence on tau onset age
Authors: Deming Yuetiva , Teague Jordan P , Heston Margo B. , Hammad Yazan , De Chavez Elena Ruiz , Morse Jacob , Chappell Richard J , Langhough Rebecca E. , Zuelsdorff Megan L. , Engelman Corinne D. , Betthauser Tobey J.
Published: January 2025

Background

New methods developed to estimate when AD biomarkers became abnormal in individuals have shown considerable heterogeneity in amyloid and tau pathology onset age. This work used polygenic scores (PGS) generated from CSF Aß42 and ptau181 GWAS, individual‐level genetic data, and estimated tau onset age (ETOA) to identify genetic influences on tau onset beyond APOE.

Method

Participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with genetic data, CSF biomarkers (Aß42 and ptau181), and longitudinal [18F]Flortaucipir (FTP) tau PET were analyzed (N = 462). Sampled iterative local approximation (SILA) was used to model longitudinal FTP meta‐temporal SUVR and generate ETOA for T+ and T‐ participants who could become T+, based on tau‐positivity (T+) defined using Gaussian mixture modeling (SUVR>1.41). Amyloid‐ and ptau‐PGS were generated from publicly available summary data, excluding the APOE region (±500kb). APOE neuropathology‐based scores (APOEscore) were used to test APOE. We analyzed individually a set of 14 SNPs that were previously associated with AD risk (P<1×10‐5) and both CSF biomarkers (P<0.05). Amyloid‐PGS, ptau‐PGS, APOEscore, and individual SNPs were tested as ETOA predictors using Cox regression modeling.

Result

73 (16%) participants were T+ by their last tau PET (Table 1). APOEscore was significantly associated with earlier ETOA (P = 1.10×10‐13; Figure 1) as was the amyloid‐PGS (P = 0.036), but ptau‐PGS was not (P = 0.166; Table 2). An intronic variant in complement receptor 1 (CR1), rs1408077 (A allele, MAFEUR = 0.19) which was previously associated with higher AD risk and AD‐associated changes of CSF biomarkers, was also significantly associated with earlier ETOA (P = 0.005; Figure 1). The association remained significant (P = 0.017) after adding the APOEscore (P = 3.93×10‐13) and both were still significantly associated with ETOA (Prs1408077 = 0.022 and PAPOEscore = 1.50×10‐6) after accounting for amyloid‐positivity (P = 3.91×10‐5; Table 2).

Conclusion

Our preliminary results support a key role for CR1 in the age when tau pathology becomes abnormal in AD. The tested variant, rs1408077, is in high linkage disequilibrium with a missense variant, rs2296160, and was previously associated with CR1 expression in the temporal cortex. This adds to previous studies that reported an interaction between CR1 and APOE‐e4 associated with episodic memory decline. Future work will include genome‐wide analyses of biomarker timing and multi‐trait analyses.
Exploring Sex‐Specific Accelerated Hippocampal Atrophy Across AD Stages beyond APOE‐e4 Assessment in Genetic Risk Evaluation
Authors: Evans Tavia E , Vilor‐Tejedor Natalia , Rodrigo Albert , Genius Patricia , Rodríguez‐Fernández Blanca , Anastasi Federica , Navarro Arcadi , Adams Hieab H.H. , Gispert Juan Domingo
Published: January 2025

Background

Current evidence suggests that hippocampal subfields have partially different genetic architecture and may improve the sensitivity of the detection of Alzheimer’s disease (AD). In this study, we investigated whether genetic predisposition to AD contributes to the accelerated rate of hippocampal volume atrophy across sex and AD stages and how this contribution is specifically driven by functional variants located in the APOE gene.

Methods

The study comprised 1,051 participants from ADNI cohort (75.2 yo; 42.3% women), with complete demographic, genetic, and magnetic resonance imaging scans at baseline and every 6 months for a total of 96 months (Controls (amyloid negative), CUN = 363; mild cognitive impairment, MCIN = 474, AD patients, ADN = 214). Hippocampal subfields were extracted using the longitudinal processing method within FreeSurfer (v6.0). Genetic predisposition to AD was assessed through polygenic scoring with and without considering the APOE región. Effects of polygenicity of plasma APOE, functional APOE brain eQTLs and CSF pQTL were also considered. Linear mixed‐effect models with random‐ time slope and intercept for individuals were used to investigate the association between genetic predisposition to AD and hippocampal subfields volumetric trajectories over time. Models were adjusted by age, sex, AD disease status, years of education and total hippocampal volume. Disease and sex status‐specific trajectories dependent on genetics predisposition were assessed by including an interaction term.

Results

Significant hippocampal subfield volume reductions were observed, with more pronounced atrophy in MCI and AD participants [Figure 1A]. High genetic predisposition to AD was associated with accelerated atrophy in various subfields [Figure 1B]. MCI individuals with high genetic predisposition showed more severe atrophy in several subfields, with sex‐related differences observed, particularly in women [Figure 2]. Notably, these effects were non‐significant when excluding APOE variants. Further functional analyses pinpointed CSF pQTLS of the APOE gene and APOE‐e4 carriership status as primary drivers [Figure 3].

Conclusions

Our findings underscore the significance of genetic predisposition, especially functional APOE variants, in understanding AD progression and sex‐specific trajectories. The results reveal varying atrophy patterns across disease stages, offering crucial insights for refining AD detection and tailoring interventions for more effective management.
AI‐derived endophenotypes are causally associated with Alzheimer's disease
Authors: Wen Junhao , Toga Arthur W. , Davatzikos Christos
Published: January 2025

Background

Brain morphology changes due to both natural aging and various pathological conditions. We used magnetic resonance imaging (MRI) and artificial intelligence (AI) to derive three brain age gaps (Wen et al., 2023b) [gray matter (GM), white matter (WM), and functional connectivity (FC)‐BAG] for brain aging and 9 dimensional neuroimaging endophenotypes (Wen et al., 2023a) [DNE: Alzheimer's disease (AD)1‐2, autism spectrum disorder (ASD)1‐3, schizophrenia (SCZ)1‐2, and late‐life depression (LLD)1‐2) for disease heterogeneity (a.k.a., subtypes). We applied genome‐wide association study (GWAS) summary statistics of the 3 BAGs, 9 DNEs, and two AD case‐control studies (Lambert et al., 2013; Wightman et al., 2021) to decipher the potential causality between these AI‐derived endophenotypes and AD (Fig. 1).

Method

We investigated whether the 3 BAGs and 9 DNEs (AD1‐2, ASD1‐3) were causally linked to AD using a bi‐directional two‐sample Mendelian randomization implemented in the TwoSampleMR R package (Hemani et al., 2018) with five different estimators. No individual data were used. The GWAS summary statistics of the 3 BAGs and 9 DNEs were performed using the UK Biobank data publicly available at https://labs.loni.usc.edu/medicine. The AD summary statistics are obtained at https://pgc.unc.edu/for‐researchers/download‐results/ for Wightman et al. and at https://gwas.mrcieu.ac.uk/ for Lambert et al., excluding the UK Biobank participants.

Result

We identified potential causal relationships from AD2, characterized by medial temporal lobe atrophy, to AD [P‐value=1.74x10‐4, OR (95% CI) = 1.25 (1.11, 1.40), number of SNPs=7], and AD to WM‐BAG [P‐value=7.18x10‐5, OR (95% CI) = 1.04 (1.02, 1.05), number of SNPs=13] (Fig. 1). Regarding the latter, our sensitivity check indicated the absence of apparent outlier SNPs or horizontal pleiotropy (Verbanck et al., 2018) (Egger estimator intercept: ‐2.22x10‐3±3.87810‐3, P‐value=0.57). All five estimators demonstrated consistent causal effects. The funnel plot displayed no noticeable asymmetry. Most IVs exhibited positive effects on AD, with three showing a negative association. Additionally, leave‐one‐out analyses indicated that no single IV dominated this causal relationship (Fig. 2).

Conclusion

This investigation revealed a causal association between two AI‐derived endophenotypes and AD. These endophenotypes could be used to identify individuals at high risk of developing AD and select populations in future AD clinical trials.
Alzheimer’s disease APOE neuropathology‐based score, amyloid, and ptau polygenic scores' association with amyloid PET positivity
Authors: Hammad Yazan , Deming Yuetiva , Morse Jacob , Grover Ethan , Bendlin Barbara B. , Betthauser Tobey J.
Published: January 2025

Background

APOE is the greatest genetic risk factor for AD, however, other smaller genetic effects are often ignored. In this work, endophenotype‐informed polygenic scores (PGS) that exclude the APOE region were tested along with a separate, previously published, APOE neuropathology‐based score (APOEscore). The APOEscore serves as a more nuanced quantification of APOE genetic risk that considers the effects of the different haplotypes. PGS and APOEscore were compared to amyloid positivity, determined via PET imaging, which is used as a measure for AD risk and progression.

Methods

Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with genetic data and Florbetapir (18F‐AV‐45) amyloid PET summary SUVR (whole cerebellum reference region) values were included in analyses. Amyloid positivity (A+) was defined as SUVR > 1.11. PGS were calculated using the weights from genome‐wide association studies (GWAS) of CSF Aß42 (amyloid‐PGS) or ptau181 (ptau‐PGS), after excluding the APOE region (±500kb). APOE effects were accounted for using the APOEscore that was calculated following Deming et al (2023).

Results

1094 participants (618 A+) were included in the analyses (Table 1). The APOEscore was significantly associated with A+ after accounting for sex and age at scan (OR = 2.931, P = 6.38e‐45; Table 2). The amyloid‐PGS was also significantly associated with A+ (OR = 0.492, P = 0.026), whereas the ptau‐PGS did not quite reach significance (OR = 3.218, P = 0.054). After adding the APOEscore, the effect of amyloid‐PGS on A+ remained but did not quite reach significance (OR = 0.515, P = 0.072) and ptau‐PGS was not significant (OR = 1.845, P = 0.375).

Conclusion

These results validate the utility of the APOEscore with PET amyloid as well as the potential value of including non‐APOE genes in quantifying the genetic risk for amyloid accumulation and AD. The significant association between amyloid‐PGS and A+, and near significance after adding the APOEscore, demonstrates the existence of additional genetic effects outside of APOE that have an impact on amyloid accumulation. While the ptau‐PGS did not reach significance, possibly due to sample size, the OR (3.218) was greater in magnitude than the amyloid‐PGS (1/OR = 2.033). Future work will explore these relationships in other cohorts and with other PET AD biomarkers.
Image‐derived phenotypes in the AMYPAD Prognostic and Natural History Study
Authors: Pieperhoff Leonard , Lorenzini Luigi , Tranfa Mario , Padrela Beatriz E , Ritchie Craig W , Boada Mercè , Marquié Marta , Scheltens Philip , Vandenberghe Rik , Hanseeuw Bernard J , Martinez‐Lage Pablo , Payoux Pierre , Stephens Andrew W. , Buckley Christopher , Farrar Gill , Jessen Frank , Gispert Juan Domingo , García David Vállez , Mutsaerts Henk‐Jan , Collij Lyduine E. , Wink Alle Meije , Barkhof Frederik
Published: January 2025

Background

The Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) Prognostic & Natural History Study (PNHS) is a prospective longitudinal PET cohort of over 1,500 non‐demented individuals from 10 parent cohorts across Europe. We provide an overview of ongoing efforts to curate and integrate magnetic resonance imaging (MRI) multimodal images across sites and to extract biologically meaningful information (i.e., image‐derived phenotypes; IDPs) in this early AD population. Data will be made available on the ADDI platform (fair.addi.ad‐datainitiative.org).

Method

Imaging protocols included core (T1w, T2w, T2*, FLAIR) and advanced (rs‐fMRI, SWI, DWI, and ASL) MRI sequences. Figure 1 provides an overview of the different acquisitions, their corresponding pipelines, and the obtained IDPs. For T1w images, we computed regional volumes and thickness values using FreeSurfer v7.1.1 (surfer.nmr.mgh.harvard.edu/). Morphometric similarity networks were computed using MIND (github.com/isebenius/MIND). White matter hyperintensity volumes were obtained from FLAIR images using Bayesian Model Selection (BaMoS). With rs‐fMRI, mean functional connectivity of canonical networks were extracted using FSL MELODIC and dual‐regression analyses after preprocessing with fMRIPrep v23.0.1 (fmriprep.org). Diffusion MRI scans were processed with QSIprep v0.16 (qsiprep.readthedocs.io) to compute tract‐based spatial statistics and tractograms to build structural connectivity matrices. Finally, cerebral blood flow and the spatial coefficient of variation were computed from ASL images using ExploreASL (github.com/ExploreASL). Statistical harmonization was performed using RELIEF (github.com/junjypark/RELIEF).

Result

Baseline and follow‐up characteristics of the 1537 subjects with available T1w are described in Table 1. Raw and statistically harmonized variants of 380 core and 298 advanced IDPs were calculated. Figure 2 shows the distribution of hippocampal volumes per site before and after statistical harmonization, and their relation with participants' age (R2raw=0.179, R2harmonized=0.422). Considering recent developments in the field, the AMYPAD PNHS aims to include additional IDPs associated with vascular health, such as perivascular spaces and other glymphatic system‐related markers.

Conclusion

We present the pipeline built for MRI harmonization and feature extraction of the AMYPAD PNHS dataset. The extracted IDPs can help identify novel imaging outcomes, support the development of disease progression models for the preclinical stages of AD, and provide a reference point for future studies to promote replicability and robustness of findings.
Brain arteriolosclerosis is linked to lower gray matter volume in community‐based older adults
Authors: Tomash Ana , Tazwar Mahir , Yasar Md Tahmid , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos
Published: January 2025

Background

Brain arteriolosclerosis is characterized by the thickening of vessel walls and arteriolar stenosis and is one of the primary pathologies of cerebral small vessel disease. Arteriolosclerosis is linked to lower cognitive and motor function, as well as an elevated risk of dementia. This study aimed to investigate the association of brain arteriolosclerosis with regional gray matter volumes in a large number of community‐based older adults.

Method

Data from ex‐vivo MRI and detailed neuropathological evaluation were collected from older adults (N=882) participating in four longitudinal, clinical‐pathologic cohort studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Figure 1A). Cerebral hemispheres from all participants were obtained at autopsy and imaged ex‐vivo with a multi‐echo spin‐echo sequence (ME‐SE) on 3T clinical MRI scanners approximately one month postmortem. The acquired voxel size was 0.6mm × 0.6mm × 1.5mm, and the scan time was approximately 30 minutes. The gray and white matter were segmented in the ex‐vivo MRI data. Subsequently, the gray matter underwent further division into 42 cortical and subcortical regions using multi‐atlas segmentation. The volume of each region was measured and normalized by the participant’s cerebral hemisphere volume. Following ex‐vivo MRI, a detailed neuropathologic assessment was performed on pathologies including arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts, Alzheimer's pathology, Lewy bodies, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), and hippocampal sclerosis (Fig. 1B). For statistical analysis, linear regression was employed to explore the association of brain arteriolosclerosis with regional gray matter volumes (normalized by cerebral hemisphere volume) controlling for all other neuropathologies (Fig. 1B), demographics (age at death, sex, years of education), postmortem intervals, and scanner (Fig. 1A).

Result

More severe brain arteriolosclerosis was associated with lower volume in several gray matter regions, including medial orbitofrontal, superior frontal, pericalcarine, cuneus, and lateral occipital areas, independently of the effects of other neuropathologies (Figs. 2, 3).

Conclusion

This study demonstrated that brain arteriolosclerosis is associated with lower volume in multiple gray matter regions independently of the effects of other vascular or neurodegenerative pathologies.
[18F]SMBT‐1 PET can visualize the spatial distribution of reactive astrogliosis in patients with neurodegenerative dementias
Authors: Okamura Nobuyuki , Hiraoka Kotaro , Kobayashi Ryota , Tomita Naoki , Ishiki Aiko , Mesfin Berihu , Wu Yingying , Harada Ryuichi , Kikuchi Asuka , Takeda Kazuko , Kikuchi Akio , Furukawa Katsutoshi , Watabe Hiroshi , Mugikura Shunji , Kawakatsu Shinobu , Ishii Kenji , Nihashi Takashi , Kato Takashi , Furumoto Shozo , Tashiro Manabu
Published: January 2025

Background

Reactive astrogliosis refers to functional and morphological changes in astrocytes that occur with neuronal damage in numerous neurological conditions. PET tracers targeting monoamine oxidase B (MAO‐B) are used to visualize reactive astrogliosis in the living brain. [18F]SMBT‐1, a MAO‐B selective PET tracer, was developed by modifying the chemical structure of [18F]THK5351. This study investigates the changes in [18F]SMBT‐1 binding in the brains of patients with Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD).

Method

The study involved 85 subjects, including healthy controls (HCs), subjects with mild cognitive impairment (MCI), patients with AD dementia, and FTLD including behavioral variant frontotemporal dementia (bvFTD) and semantic dementia (SD). To compare the regional standardized uptake value ratio (SUVR) values between disease groups, 30‐minute dynamic scans were conducted 60 minutes after administration of [18F]SMBT‐1. The cerebellar white matter was used as a reference region for calculating the SUVR values. PiB PET or flutemetamol PET was performed to confirm the existence of amyloid‐ß pathology in the brain.

Result

[18F]SMBT‐1 binding in the cerebral cortex was elevated in amyloid PET‐positive HC, MCI, and AD patients compared to amyloid PET‐negative subjects. The amount of SMBT‐1 binding in the neocortex correlated with changes in cognitive function of HC and MCI subjects. In addition, a distinct spatial pattern of [18F]SMBT‐1 retention was observed in patients with bvFTD and SD, consistent with areas of brain atrophy in the frontal and temporal lobes.

Conclusion

Distinctive patterns of [18F]SMBT‐1 binding were observed in the neocortex of AD and FTLD, indicating its usefulness for the differential diagnosis of dementia. The study also implies that reactive astrogliosis is present before dementia onset, associated with amyloid‐ß accumulation and cognitive decline.
Short‐term Sirolimus Treatment Increases Cerebral Blood Flow in Asymptomatic APOE4 Females Determined by 3T MRI
Authors: Neher Caitlin M. , Khegai Oleksandr , Overschmidt Jessica , Cassani Joanne , Xing Xin , Flemister Abeoseh , Green Stefan J. , Kurt Mehmet , Beversdorf David Q. , Xu Feng , Grinstead John W. , Balchandani Priti , Altes Talissa A. , Lin Ai‐Ling
Published: January 2025

Background

Apolipoprotein e4 allele (APOE4) is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD) with females having higher risk than males. Compared with non‐carriers, cognitively normal, middle‐aged APOE4 carriers have lower cerebral blood flow (CBF) decades before clinical symptoms appear. Early intervention to protect CBF would be critical for APOE4 carriers to mitigate AD progression. We have shown in APOE4 mice that Rapamycin (a.k.a. Sirolimus), a FDA‐approved mTOR‐inhibitor, can restore CBF. Here, in the first human study, our goal is to determine whether the findings translate to human APOE4 carriers by measuring CBF with MRI.

Method

The study was performed at the University of Missouri. Low dose Sirolimus (1 mg/day) was given for 4 weeks to two middle‐aged, cognitively normal APOE4 females (45‐65 yrs; MOCA>28). APOE status was determined by oral swabs. 3T MRI‐based pseudo‐continuous arterial spin‐labeled (PCASL, 1.7x1.7x4mm resolution) images were acquired at four time‐points: baseline (pre‐treatment), 2nd and 4th week into treatment, and washout (2 weeks post‐treatment). PCASL data was processed with FSL BASIL toolbox and regionally analyzed using FreeSurfer segmentation of T1‐weighted images.

Result

Average values of CBF (ml/100g/min) increased in all areas of investigation. When compared to baseline values, we observed an average 34.8±2.1% increase in washout CBF in the cortex across subjects (Fig. 1). Within the cortex, there was an average increase of 41.5±8.9, 28.2±6.2, 37.4±1.7, and 33.1±0.3% in the frontal, parietal, temporal and occipital lobes, respectively. White matter CBF showed a similar trend, increasing by 33.7±4.9% across subjects from baseline to washout (Fig. 2). Smaller AD‐associated regions were evaluated and also showed CBF improvement: the entorhinal cortex showed a 25.1±4.3% increase, while the hippocampus and amygdala showed a 21.4±1.1 and 23.6±9.8% increase, respectively (Fig. 3). No side effects were observed, and no changes in blood glucose and HbAc1 levels were found in the participants.

Conclusion

Short‐term Sirolimus treatment can effectively increase CBF for asymptomatic APOE4 females, who have the highest risk for AD. Future work will include APOE4 males, increase the sample size and compare CBF with non‐carriers (e.g., APOE3/APOE2). Restoration of CBF may pave a way to mitigate or prevent AD developments for APOE4 carriers.
Understanding cognitive deficits in memory clinic patients with mixed disease by combining plasma markers and advanced diffusion MRI
Authors: Dewenter Anna , Dehsarvi Amir , Steward Anna , Biel Davina , Pescoller Julia , Zhu Zeyu , Wagner Fabian , Gross Mattes , Nuscher Brigitte , Roemer Sebastian Niclas , Buerger Katharina , Janowitz Daniel , Ewers Michael , Tiedt Steffen , Dichgans Martin , Brendel Matthias , Franzmeier Nicolai
Published: January 2025

Background

Memory clinic patients typically present with Alzheimer’s disease (AD) and cerebral small vessel disease (SVD) to varying degrees. Therefore, it is crucial to determine the etiology of cognitive deficits for facilitating patient‐centered treatment in memory clinics. Plasma biomarkers (ptau217, Glial Fibrillary Acidic Protein [GFAP], Neurofilament light chain [NfL]) and fixel‐based advanced diffusion MRI markers (fiber density, fiber‐bundle cross‐section) show potential towards disentangling AD‐ and SVD‐related brain changes (Dewenter et al., Brain, 2023). However, their predictive power in understanding heterogeneous and SVD/AD‐specific cognitive deficits in memory clinic patients remains incomplete. We assessed i) how plasma‐based and fixel markers explain AD‐typical and SVD‐typical cognitive deficits and ii) their interrelation to uncover disease‐specific mechanisms.

Method

We included n = 76 in‐house memory clinic patients with Simoa‐based plasma ptau217, GFAP and NfL assessments, comprehensive neuropsychological testing (CERAD‐plus battery) and 3T MRI. Global white matter hyperintensity (WMH) volume and average skeletonized mean diffusivity (MD) were included as well‐established SVD markers. AD severity was probed through plasma ptau217 and cortical thickness of the pre‐established AD signature ROI. Advanced diffusion MRI was used to assess fiber density and fiber bundle cross‐section of key white matter tracts (Fig. 1A).

Result

Using linear regression, increased ptau217, reduced cortical thickness in AD signature ROI and fiber‐bundle cross‐section were highly associated with impaired episodic memory, i.e. a typical AD‐related symptom (Fig.1B, Fig.2A). In contrast, GFAP and NfL increases and reductions in MSMD and fiber density were associated with executive dysfunction, a typical sign of SVD‐related cognitive impairment (Fig.1B, Fig.2A). Additionally, fiber density was associated with GFAP and NfL levels, while fiber bundle‐cross section, a macroscopic marker of tract atrophy, was not associated with any of the plasma markers (Fig.2B).

Conclusion

Ptau217 displayed high sensitivity and specificity for AD‐typical memory impairment, whereas GFAP and NfL were associated with SVD‐typical processing speed and executive impairment. Additionally, fiber density, a pre‐established imaging marker for SVD, was associated with GFAP and NfL. This highlights the effectiveness of these markers in distinguishing and characterizing SVD and AD in memory clinic patients and emphasizes the importance of considering concomitant SVD in patients with elevated GFAP and NfL levels.
Type 2 diabetes and Alzheimer's disease share common cortical neurodegenerative patterns
Authors: Motaghi Mahboubeh , Potvin Olivier , Duchesne Simon
Published: January 2025

Background

Type 2 diabetes (T2D) is a prevalent health condition associated with cognitive impairment and dementia. T2D induces adverse effects not only on the pancreas but also on the liver, kidneys, muscles, fat cells, and, notably, the brain. Both T2D and Alzheimer's disease (AD) exhibit associations with neurodegeneration, yet the extent of their shared patterns of brain atrophy remains poorly understood, potentially indicating common pathways. The primary objectives were to assess the similarity between neural degeneration patterns in T2D and AD and to identify commonalities between these two diseases.

Method

We employed linear models to compare neurodegeneration patterns linked to T2D and AD. A total of 43,172 participants from the United Kingdom Biobank (UKBB) (3,479 with T2D) and 8,378 from ADNI (871 with AD) were included in our study. We selected Free Surfer‐derived cortical thickness measures extracted from T1‐weighted MRI, age, sex, and blood biomarkers of T2D. The age range for UKBB was 40‐70 years, while for ADNI, it was 55‐97 years. We filtered data for individuals aged 55 and older, normalized features, and created age‐ and sex‐matched groups. We then created cortical atrophy maps using linear regression models for each group. Comparison of the AD and T2D maps was performed using permutation‐based tests accounting for spatial autocorrelation.

Result

Our findings revealed similar patterns of neural degeneration in T2D and AD brain maps, particularly in the frontal, parietal, temporal, and occipital lobes, suggesting shared neuroanatomical alterations. Statistically significant overlap was observed in atrophy patterns between AD and T2D patients. T2D individuals exhibited greater atrophy in brain regions affected in AD, such as the hippocampus. Permutation analysis indicated no significant difference between the impact of T2D and AD on brain regions, supporting the notion that T2D is a substantial risk factor for AD.

Conclusion

This study enhances our understanding of the similarities in how T2D and AD impact the brain, highlighting the potential connection between these conditions. Further research is warranted to explore underlying mechanisms and implications for clinical interventions.
Feasibility of detecting Amyloid burden in preclinical Alzheimer's disease with quantitative magnetization transfer MRI
Authors: Mao Andrew , Flassbeck Sebastian , Marchetto Elisa , Rusinek Henry , Assländer Jakob
Published: January 2025

Background

Magnetization transfer (MT) MRI is sensitive to the presence of macromolecules, including amyloid‐beta, and previous work suggests that it may be useful for discriminating patients with Alzheimer's disease (AD) from healthy controls. In this study, we investigated if quantitative MT (qMT) is capable of detecting the amyloid concentration in a preclinical cohort.

Method

We recruited 14 subjects with a clinical dementia rating of 0 from NYU's ADRC cohort (7 male, mean age 74, 6 amyloid‐negative). An experimental 12 min qMT technique with an effective 1.24 mm isotropic resolution was used to obtain 6 parameter maps describing an unconstrained 2‐pool qMT model (Figure 1). MPRAGE and FLAIR images were acquired at 1 mm isotropic, rigid‐body registered to the qMT maps and used to perform Freesurfer‐based cortical parcellation. [18F]Florbetaben (FBB) images acquired within the preceding 24 months were rigid‐body registered to the qMT maps and used to compute average measurements across each cortical lobe for each hemisphere at 50% of the cortical thickness. Pearson's correlation coefficients were computed for all 6 qMT parameters with respect to FBB SUVR values. Amyloid‐positive and negative groups were compared using one‐way ANOVA tests. 5 Desikan‐Killiany ROIs containing substantial artifacts in the qMT maps were excluded from all analyses, though some imaging artifacts remain.

Result

The exchange rate between the two spin pools and the macromolecular pool's longitudinal relaxation rate were found to be both negatively correlated with amyloid concentration and significantly decreased in amyloid‐positive subjects most prominently within the temporal lobe (Figs.2–3). The former is consistent with previous reports in more advanced AD stages, but the latter has not previously been reported as its value is fixed in most qMT methods. However, we observed no significant changes in the macromolecular pool size—which encompasses both myelin and amyloid‐beta—with increasing amyloid burden.

Conclusion

MT MRI may be a promising tool for monitoring amyloid accumulation without the need for contrast agents or radiotracers. A larger cohort and a further optimized qMT sequence are needed to validate these preliminary findings.