bluuebunny/crossref_metadata_2025 huggingface dataset:
New in vitro tools to investigate the role of microglia in neurodegeneration
Authors: Erlebach Lena , Welzer Marc , Bühler Anika , Miely Daniela , Schwarz Niklas , Panagiotakopoulou Vasiliki , Haesler Lisa M. , Lambert Marius , Obermüller Ulrike , Beschorner Natalie , Koch Henner , Neher Jonas J. , Wuttke Thomas , Hedrich‐Klimosch Ulrike , Jucker Mathias , Kronenberg‐Versteeg Deborah
Published: December 2023

Background

Human induced pluripotent stem cells (iPSCs) have transpired as an attractive tool to investigate neurological diseases. And while immune cells, and in particular microglia, have emerged as important players in many neurological and in particular in neurodegenerative diseases, it remains a challenge to fully recapitulate an in vivo‐like phenotype ex vivo. This is due to the fact that microglial identity is shaped by the neural tissue environment.

Method

We have now developed a chimeric brain slice culture system, where we engraft iPSC‐derived microglia onto mouse (and human) organotypic brain slice cultures. Brain slice cultures offer the advantage that many aspects of the complex cytoarchitecture of the mature/aged living brain, including cortical layering, columnar organization and electrophysiological properties can be preserved over several weeks.

Result

We found that iPSC‐derived microglial precursors integrate and differentiate well in the brain slice cultures, with morphology, network characteristics and functional responses reminiscent of human microglia. Gene expression profiling of iPSC‐derived microglia revealed enhanced maturation over time. Upon induction of neurodegenerative disease pathology in these slice cultures, the iPSC‐derived microglia show transcriptional changes converging towards those observed in patients with neurodegenerative disease pathology.

Conclusion

This system is a novel cellularly complex tool allowing to dissect the dynamics and molecular mechanisms of microglial genetic risk factors of many neurological diseases, while preserving experimental amenability to test therapeutic approaches in a human(ized) system.
Amyloid Reduction: Donanemab Perspective
Authors: Sims John R.
Published: December 2023

Background

Methods

Result

Conclusion
Integrative gene expression studies on the path to precision medicine in Alzheimer’s and related disorders
Authors: Ertekin‐Taner Nilufer
Published: December 2023

Background

Genetic studies in Alzheimer’s disease and related disorders (ADRD) revealed numerous disease risk loci many of which reside in noncoding regions. To translate these discoveries to precision medicine therapies and biomarkers, integrative multi‐omics studies especially combining gene expression and disease phenotypes are necessary.

Method

In this presentation, we will review existing and emerging approaches in the discovery of functional disease risk variants, pathways and key disease molecules in ADRD via integrating multi‐omics and disease phenotypic data using computational systems biology followed by experimental validation.

Results

Integrative genome‐wide association studies (GWAS) of ADRD risk, ADRD‐related phenotypes, gene expression and epigenetic factors such as methylation nominate disease variants and pinpoint risk mechanisms. Large scale differential gene and co‐expression network analyses discovered novel disease pathways unique to or shared between different ADRD. Experimental validations of these findings in model systems yielded high confidence molecular perturbations in ADRD.

Conclusion

ADRD is characterized by molecular perturbations in myriad pathways including vascular, synaptic, immune, myelination and many others that are revealed through integrative multi‐omics studies in well‐characterized human cohorts and prioritized through experimental model systems. These molecules serve as candidate precision medicine therapeutic targets and biomarkers.
APOE‐dependent and ‐independent polygenic pathways determining early Alzheimer’s Disease pathological changes in CSF and MRI
Authors: Lorenzini Luigi , Collij Lyduine E. , Tesi Niccoló , Ingala Silvia , Sudre Carole H , Wolz Robin , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Chetelat Gael , Ritchie Craig W , Gispert Juan Domingo , Mutsaerts Henk‐Jan , Altmann Andre , Tijms Betty M. , Wink Alle Meije , Visser Pieter Jelle , Barkhof Frederik
Published: December 2023

Background

Little is known about the genetic factors and downstream molecular pathways determining individual variability in fluid and imaging biomarkers associated with Alzheimer’s disease(AD). We studied polygenic risk scores (PRS) and pathway‐specific PRS in relationship with AD fluid and imaging biomarkers, in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort.

Method

EPAD inclusion criteria were age>50 and Clinical Dementia Rating = 0.5 (n = 1886, Table 1). AD‐PRS was based on 85 previously identified loci, including and excluding APOE (PRSAPOE, PRSnoAPOE)[1]. Using gene‐variant and variant‐pathway mapping[2], six pathway‐specific PRSnoAPOE were identified:1) immune‐activation, 2) signal‐transduction, 3) inflammatory‐response, 4) migration, 5) amyloid‐production, and 6) clearance. Linear models were used to assess the relationship of all PRS with fluid AD biomarkers, including Aß1‐42, p‐Tau181, and t‐tau; and several imaging biomarkers, including hippocampal volume, global and lobar white matter hyperintensities (WMH) volumes, fractional anisotropy (FA) in 14 regions of interest from diffusion tensor imaging, and 10 resting‐state network connectivity from functional MRI. Models were adjusted for age, sex, site, and multiple comparisons.

Result

Models’ coefficients are reported in Table 2. PRSAPOE was significantly associated with decreased Aß1‐42, and increased p‐Tau181 and t‐Tau. PRSnoAPOE showed a weaker, but still significant, negative association with Aß1‐42 levels, and a significant positive association with p‐Tau181 and t‐Tau. Aß1‐42 was only significantly associated with the migration, amyloid, and clearance pathways, while all pathways were significantly positively associated with p‐Tau181 and t‐Tau. Hippocampal volume was only significantly associated with PRSAPOE. Regarding WMH load, PRSAPOE showed a positive association with global, frontal periventricular, and parietal deep lobes. Furthermore, the clearance pathway was related to WMH load in all regions, most strongly in periventricular areas. Only the migration pathway was related to increases in FA in the splenium, body, and genu of the corpus callosum. Only the PRSAPOE was related to reduced functional connectivity (FC) in the default mode, control, and visual networks.

Conclusion

We show that genetic risk beyond APOE facilitates the manifestation of AD related pathologies. Moreover, clearance and migration pathways were associated with neuroimaging measures of white matter integrity, while FC and hippocampal volume were associated with overall AD genetic risk.
Novel CSF tau biomarkers can be used for disease staging of sporadic Alzheimer’s
Authors: Salvadó Gemma , Horie Kanta , Barthélemy Nicolas R. , Vogel Jacob W , Binette Alexa Pichet , Chen Charles D. , Gordon Brian A. , Benzinger Tammie L.S. , Holtzman David M. , Morris John C , Palmqvist Sebastian , Stomrud Erik , Janelidze Shorena , Ossenkoppele Rik , Schindler Suzanne E. , Bateman Randall J. , Hansson Oskar
Published: December 2023

Background

Staging Alzheimer’s disease (AD) allows for the identification of key milestones and inflection points in the disease course. However, most current in vivo disease staging methods rely on costly and low‐accessible measures such as PET. Our objective was to generate and evaluate a staging model based on multiple cerebrospinal fluid (CSF) biomarkers.

Method

We created a staging model using the Subtype and Stage Inference (SuStaIn) algorithm in 426 participants covering the whole AD spectrum (Table 1) by evaluating CSF Ab42/40 and 5 CSF tau markers: the proportion of tau phosphorylated at three threonine residues (pT205/T205, pT217/T217, and pT231/T231), and the concentrations of microtubule‐binding region of tau at residue 243 [MTBR‐tau243] and total‐tau [mid‐domain containing T212‐221]). We investigated associations between CSF stages and cross‐sectional and longitudinal changes in amyloid and tau pathologies, neurodegeneration and cognition using linear regression models. ROC curves were used to identify the optimal stage for predicting positivity in imaging biomarkers and to separate AD vs non‐AD cognitive symptoms. We also tested the relative risk of progression from cognitively unimpaired or MCI to AD‐type dementia using Kaplan‐Meier curves and Cox‐proportional Hazard models. Creation of the model and cross‐sectional analyses were replicated in an independent cohort (n = 222, Table 1).

Result

SuStaIn revealed that only one subtype was present and that five CSF biomarkers (ordered: Ab42/40, pT217/T217, pT205/T205, MTBR‐tau243, T212‐221) were sufficient to create an accurate disease staging model (Fig.1A‐B). Increasing stages (0‐5) were associated with increased abnormality in other AD‐related biomarkers (Fig.1C). In both cohorts, stage = 2 accurately predicted amyloid‐PET positivity (AUC = 0.89), stage = 4 predicted tau‐PET (AUC = 0.94) and neurodegeneration positivity (AUC = 0.81). In the main cohort, stage = 2 separated non‐AD from AD‐related cognitive impairment (AUC = 0.96). Longitudinal changes for several AD‐biomarkers by stages are presented in (Fig.2A). Higher stages (4‐5) at baseline were associated with higher hazard ratios (HR) of progressing to AD‐type dementia (CU&MCI: HR = 4.6[2.0,10.9], MCI: HR = 3.5[1.5,8.1], Fig.2B‐C).

Conclusion

Our results suggest that the AD continuum can be accurately staged with a single CSF sample, which may be useful in the clinical setting for patient management but also as a tool in clinical trials for selection and monitoring of study participants.
Discerning neurodegenerative and aging genetic influences on hippocampal subfields trajectories in the Alzheimer’s disease continuum
Authors: Vilor‐Tejedor Natalia , Evans Tavia E , Genius Patricia , Rodríguez‐Fernández Blanca , Rodrigo Albert , Navarro Arcadi , Gispert Juan Domingo , Adams Hieab H.H.
Published: December 2023

Background

Hippocampal atrophy is one of the most characteristic biomarkers of Alzheimer’s disease (AD), and its genetic basis, as well as that of its distinct subfields, is of current interest. However, hippocampal subfields have so far only been assessed largely unrelated to brain atrophy, and the majority of studies were focused on general population samples, explicitly excluding diagnosed patients. In this study, we evaluated whether hippocampal subfields trajectories are a suitable endophenotype to discern between neurodegenerative and aging genetic influences in the Alzheimer’s continuum.

Method

The dataset includes AD patients (N = 113), mild cognitive impairment (N = 426), and control normal (CN) (N = 272) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Individuals were evaluated with 3T MRI at baseline and every 6 months for a total of 96 months. Hippocampal subfields were extracted using longitudinal processing within FreeSurfer(6.0). We used longitudinal mixed‐effect models with random intercept for individuals to investigated the association between hippocampal subfields volumetric changes and genetic predisposition to AD, Parkinson’s disease, frontotemporal dementia (neurodegeneration), as well as intrinsic and extrinsic epigenetic clock acceleration and telomere length (biological aging). Models were adjusted by age, sex, AD‐stage and total hippocampal volume. Disease status‐specific trajectories were also assessed.

Result

Genetic predisposition to biological aging (driven by genetic predisposition to telomere length) was significantly associated with subfield changes in presubiculum (β = ‐11.2, p = 4.1e‐04), parasubiculum (β = ‐4.4, padj = 4.4e‐04), molecular layer (β = 5.9, padj = 2.0e‐04), dentate gyrus (DG) (β = 5.79, padj = 4.4e‐04), CA4 (β = 7.2, padj = 4.4e‐05), and HATA (β = ‐1.7, padj = 0.027). Genetic predisposition to neurodegeneration (driven by predisposition to AD) was associated with volumetric changes in CA3 (β = 4.4, p = 0.047). In stratified models, we observed significant volumetric changes due to genetic predisposition to neurodegeneration in controls (CA1, CA4, DG, parasubiculum, molecular layer). In MCI (subiculum regions and CA4) and AD (hippocampal fissure, molecular layer and DG), volumetric changes were mostly associated with genetic predisposition to biological aging processes.

Conclusion

We showed differential genetic mechanisms associated with hippocampal subfield trajectories that were specific to Alzheimer’s disease stage. These results may help elucidate new biological mechanisms in the course of the disease as well as discern additional molecular mechanisms related to neurodegeneration and aging.
Brain MRI diffusion abnormalities associated with arteriolosclerosis pathology
Authors: Tomash Ana , Tazwar Mahir , Yasar Md Tahmid , Zhang Shengwei , Evia Arnold M , Schneider Julie A , Arfanakis Konstantinos
Published: December 2023

Background

Brain arteriolosclerosis is one of the main pathologies of cerebral small vessel disease. It involves the thickening of the vessel wall and stenosis of arterioles causing lower cognitive and motor function, and higher odds of dementia. This work intends to explore the independent association of brain arteriolosclerosis with diffusion abnormalities in the white matter (WM) of community‐based older adults.

Method

Participants comprised community‐dwelling older adults (N = 175) from four 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) (Fig.1A). Whole brain 3D T1w MPRAGE, T2w FLAIR, and diffusion‐weighted MRI (2×2×2mm3, b = 1,000s/mm2 for 40 diffusion gradient directions, and 6 b = 0s/mm2 volumes) data were acquired in‐vivo using 3T MRI scanners. The fractional anisotropy (FA) and trace maps were transformed to the space of the IIT Human Brain Atlas v.5.0 and projected onto the WM skeleton of the IIT atlas. Following a participant’s death, the extracted brain underwent a detailed evaluation by a neuropathologist. Assessed neuropathologies included arteriolosclerosis, Alzheimer’s pathology, LATE‐NC, gross and microscopic infarcts, atherosclerosis, and cerebral amyloid angiopathy (Fig.1B). Linear regression was used in voxels of the WM skeleton to test the association of FA or trace with the severity of arteriolosclerosis controlling for all other neuropathologies, white matter hyperintensities (WMH), demographic variables (age at scan, sex, years of education), antemortem interval to imaging, and scanner. The statistical analyses were carried out using FSL’s PALM tool with 5,000 permutations and threshold‐free cluster enhancement. The significance level was set at p<0.05, after family‐wise error rate (FWER) correction for multiple testing.

Result

Arteriolosclerosis score was associated with lower FA (Fig.2) and higher trace (Fig.3) of the diffusion tensor throughout the brain in multiple WM regions, even in areas typically free of WMH. Other neuropathologies or the effects of WMH on diffusion characteristics had no impact on these relationships.

Conclusion

The current study showed that, regardless of the impact of other neuropathologies or visible WMH, brain arteriolosclerosis in older persons is associated with diffusion abnormalities that extend throughout the WM.
Temporal lobe function during memory encoding in older individuals prior to the onset of cognitive impairment
Authors: Beason‐Held Lori L , Shafer Andrea T , Calcagno Nicole , Kitner‐Triolo Melissa , Resnick Susan M.
Published: December 2023

Background

Previous studies have shown that resting state brain function begins to change in the years leading up to the development of cognitive impairment. This study examines temporal lobe function during memory encoding approximately 2.5 years before the onset of cognitive impairment in Baltimore Longitudinal Study of Aging (BLSA) participants.

Method

BLSA participants with subsequent memory impairment (Subsequently Impaired (SI), n = 22, mean age = 83.6, time to impairment = 2.5 ± 1.1 SD years post‐scan) and age, sex, and education matched cognitively normal participants (Cognitively Normal (CN), n = 64, mean age = 84.9) performed a face‐scene encoding task during fMRI scanning. Group differences in task performance and brain activation patterns were examined during encoding trials they later remembered, and trials they later forgot during the recognition phase of the task.

Result

The SI group performed more poorly than the CN group during the recognition phase of the task. Both CN and SI activated the occipitotemporal visual pathway during memory encoding. Yet relative to CN participants, the SI group showed decreased activation of the hippocampus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus during encoding of face‐scene pairs. This decreased activation was seen during both encoding of pairs they later remembered and pairs they forgot during recognition.

Conclusion

Both memory dysfunction and decreased temporal lobe activity during encoding begin before the onset of clinically evident cognitive impairment. In the SI group, the decreased temporal lobe activation was seen regardless of whether they later remembered or forgot the face‐scene pairs during the recognition task. This suggests that those who go on to develop impairment have an overall weaker functional response in temporal lobe regions during memory encoding. Further examination of the functional connectivity of these regions may help to determine if differences in brain network characteristics are related to subsequently remembered or forgotten visual stimuli during encoding. This work was supported by the Intramural Research Program of the NIH, National Institute on Aging.
Plasma biomarkers across the spectrum of Alzheimer’s and Parkinson’s disease: Association with cortical thickness and cognitive dysfunction
Authors: Coughlan Gillian T , Zhukovsky Peter , Sanchez Erlan , Grady Cheryl , Munoz Douglas , Black Sandra E. , Buckley Rachel F. , Masellis Mario
Published: December 2023

Background

Plasma biomarkers of phosphorylated‐tau(p‐tau), astrocytosis and axonal damage offer a reliable means of identifying and measuring multiple pathological processes in‐vivo. How these biomarkers are associated with cortical brain structure and cognition within, and across, disorders is unclear. Leveraging the Ontario Neurodegenerative Disease Research Initiative, we examined the cross‐sectional association between plasma biomarkers, cortical thickness, and multi‐domain cognition.

Method

290 participants diagnosed with AD or PD (in accordance with clinical guidelines) and healthy controls (HC) were included (MeanAge = 68.96;[41% women; 35% APOE4carriers]). Four groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 121), ii)PD with MCI or dementia(PDMCI/PDD;N = 78), iii)PD with normal cognition(PD‐NC;N = 43) and HC(N = 44; Table1). Plasma measures of p‐tau181‐UGOT, Neurofilament light chain (NfL) and GFAP, alongside FreeSurfer‐derived cortical thickness were included. A neuropsychological battery was administered. All models were adjusted for age, sex, and education.

Result

There was an effect of diagnostic group on global cortical thickness, with PD‐NC, ADMCI/ADD and PDMCI/ADD exhibiting a significant reduction relative to HC(Fig1A). Regional patterns of brain atrophy were significantly associated in ADMCI/ADD and PDMCI/ADD(Fig1B). Across groups, p‐tau181, GFAP and to a lesser extent NfL, were associated with cortical thinning, particularly in lateral temporal and medial parietal regions (Fig2A). Unlike global thickness, ADMCI/ADD and PDMCI/PDD, but not PD‐NC, showed reduced thickness in the regions associated with p‐tau181, GFAP and NfL (Fig2B). Diagnostic group*GFAP/NfL/ptau181 interactions were not significant. Mediation analysis showed the cortical thinning in lateral temporal and medial parietal regions mediated between 33% to 40% of association between p‐tau181 and delayed memory. Similarly, thinning in these areas mediated 22% to 33% of the relationship between GFAP and executive function(Fig2C).

Conclusion

We conclude that there is a similar pattern of gray matter loss in MCI/Dementia due to AD and PD. Higher concentrations of plasma p‐tau181 and GFAP are associated with poorer memory and executive function, in part through cortical thinning in lateral temporal and medial parietal regions. In conclusion, pathological processes related to the deposition of amyloid and tau, as well as astrogliosis, may co‐exist across cognitively impaired individuals with AD and PD. This is consistent with autopsy findings showing that AD pathology is present in 33‐60% of PD patients.
An exploratory pilot study on diffusion MRI measurement of cortical microstructural neurodegeneration for the assessment of dementia in a Japanese hospital setting
Authors: Ridgway Gerard R , Nakajima Takashi , Torso Mario , Valotti Michele , Hardingham Ian , Ehsan Omar , Chance Steven A
Published: December 2023

Background

The use of diffusion MRI (dMRI) to assess cortical microstructure has demonstrated promise for measuring neurodegeneration in Alzheimer’s disease (PMID:33174658, PMID:36281682) and frontotemporal dementia (PMID:32641807, PMID:34686217) using retrospective research datasets. The ultimate translation of research findings to clinical practice requires prospective studies in hospital settings. A pilot study at the National Hospital Organization, Niigata, was designed and successfully delivered.

Method

The study was registered on Oct 5th 2021 (jRCT1032210367). Scanning took place between Oct 13th 2021 and June 30th 2022, on a 1.5T Philips Ingenia. MRI data was transferred using a secure cloud gateway (Cimar). A total of 10 healthy controls (HC), 10 Alzheimer’s disease (AD) patients, and 5 frontotemporal dementia (FTD) patients were recruited. Structural (3D T1‐weighted) and dMRI (2mm isotropic, 32 directions at b = 1000 s/mm2) scans were used to calculate cortical mean diffusivity and three neuropathologically‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+). Metrics were also summarized over AD signature regions (Ridgway et al., CTAD 2022).

Result

Of the n = 25 cases, 18 had clear clinical diagnoses after neurological and radiological assessment, while 7 were more complex (including focal bleeding, focal ischemia, meningioma, supra‐sellar tumour). Characteristics are given in Table 1. Figure 1 plots two whole‐brain measures: PerpPD+ and AngleR. A threshold of PerpPD+ > 1.325 has 100% sensitivity to the 8 clear AD cases, with 86% specificity for 7 controls vs AD. Results were less clear for FTD using whole‐brain measures alone. The Cohen’s d effect size for clear AD versus clear HC was 2.82 using whole‐brain PerpPD+. Using signature regions (Figure 2b) improved separation to d = 3.08 for PerpPD+, compared to d = 1.87 for the cortical thickness signature (Figure 2a).

Conclusion

The pilot study demonstrated practical feasibility and good performance for distinguishing AD from HC using cortical diffusivity measures acquired at the 1.5T field‐strength common in hospitals in Japan. Future work will investigate FTD signature regions. A larger multicentre study assessing diagnostic accuracy using additional AD biomarkers is warranted.
MK‐6240 tau‐PET in an Aβ‐enriched sample from the 1946 British birth cohort
Authors: Coath William , Markiewicz Pawel J , Modat Marc , Scott Catherine J , Malone Ian B , Arstad Erik , Awais Ramla , Sander Kerstin , Weston Philip SJ , Thomas David L , Dickson John , Schöll Michael , Ourselin Sebastien , Richards Marcus , Fox Nick C , Cash David M , Schott Jonathan M
Published: December 2023

Background

We investigated imaging biomarkers of Aß and neurodegeneration in relation to tau‐PET Braak stage in a preclinical birth cohort.

Method

Cognitively normal individuals enrolled in Insight 46, the neuroimaging sub‐study of the MRC National Survey of Health and Development (1946 British birth cohort), were scanned on combined PET/MR with [18F]florbetapir Aß‐PET at age ∼70 years and again at ∼73 years. A sub‐sample enriched for Aß (Aß+; Centiloid> = 13, hole cerebellum reference) is currently being assessed with [18F]MK‐6240 tau‐PET at age ∼76 years. For this interim analysis, tau‐PET images (90‐110 minutes post‐injection) were co‐registered with T1‐weighted MRI. Anatomical areas were parcellated on the T1 to form Braak regions. Standard uptake value ratios (SUVRs) were calculated using an inferior cerebellar grey reference without partial volume correction. Tau‐PET positivity (Tau+) was defined using Gaussian mixture modelling in each region. Participants were assigned to Tau‐, Braak I‐II, III‐IV or V‐VI groups based on the most advanced Tau+ region. Group differences in baseline Aß (Centiloids), Aß accumulation (Centiloids/year) and hippocampal atrophy rate (%/year) were investigated with Mann‐Whitney U tests.

Result

Analysis included 80 individuals with tau‐PET data (Table 1), 45% of the sample were Aß+ by age 73. Three individuals did not conform to the Braak stage hierarchy (orange triangles, Figure 1). No Aß‐ individuals were Tau+ beyond Braak I. Figure 2 shows baseline Aß, Aß accumulation and hippocampal atrophy rates for Braak stage groups for participants who had data at all timepoints (N = 78). Tau+ individuals (in any Braak region) had significantly higher baseline Aß than Tau‐ individuals. Rate of annual Aß accumulation was higher for Braak III‐IV and Braak V‐VI compared to Tau‐ individuals. Hippocampal atrophy rate was elevated for Braak V‐VI compared to Tau‐, and Braak III‐IV was borderline significant.

Conclusion

In this preliminary analysis, tau‐PET positivity beyond Braak I was restricted to individuals who were Aß+ three years prior. Participants with elevated tau aged 76 had increased Aß at age 70. Increased rates of hippocampal atrophy were occurring at least three years prior to tau scanning in individuals with advanced tau pathology. These findings will be updated as more data is acquired.
Lineage and geometry of MRI‐visible perivenous and periarterial spaces in white matter confirmed on immunohistochemical microscopy
Authors: Schwartz Daniel , Roese Natalie E , Hurworth Justin , Lahna David , Wall Rachel C , Kaye Jeffrey A , Woltjer Randy L , Silbert Lisa C
Published: December 2023

Background

MRI‐visible perivascular spaces (mrPVS) in the brain, typically found in white matter and assumed to be pathologically enlarged though historically considered a benign finding, have been more recently associated with normal aging as well as with various disease states, including traumatic brain injury, sleep apnea, Alzheimer’s Disease (AD), Parkinson’s Disease, and cerebral amyloid angiopathy. One putative cause for their pathological enlargement has been damage to the parenchyma surrounding the PVS, bounded by the astrocytic endfoot, caused by an increase in vascular pressure or pulsatility. Arteries are more pulsatile than veins, and thus it is expected that mrPVS, presumed to be enlarged, will be predominately around arteries. This pre and post mortem MRI + immunohistochemistry (IHC) study sought to clarify the lineage and spatial distribution of PVS visible at the resolution of MRI in aged individuals who were cognitively normal (C), mildly cognitively impaired (MCI), had clinical signs of dementia and mixed AD and vascular disease at pathology (AD/VD), and had pathology‐confirmed AD only (AD).

Method

Detailed imaging and IHC acquisition, as well as MRI and IHC processing and registration methods, can be found at [https://pubmed.ncbi.nlm.nih.gov/36343095/ and https://pubmed.ncbi.nlm.nih.gov/36054513/]. Each MRI was inspected for PVS by an experienced rater (JH) and trichrome and smooth muscle actin (SMA) IHC of the corresponding vessels were judged to be arteries or veins based on SMA positivity and morphology (DLS).

Result

35 mrPVS over 19 subjects’ post mortem MRIs were unequivocally identified on trichrome and SMA. Of these, 23 surrounded arteries (SMA+, Fig. 1), and 12 surrounded veins (faint/thin/uneven SMA, Fig. 2). Mean distance (range) to the cortical ribbon from mrPVS surrounding arteries and veins were 2.8mm[0‐8mm] and 5.4mm[2‐14mm], respectively.

Conclusion

PVS large enough to be visible on MRI are more frequently arterial if nearer the cortical ribbon; mrPVS nearer the ventricle are more likely to be collecting veins. As collecting veins nearer the ventricles and arterioles in cortex tend to have higher pulse pressures, this finding is congruent with the hypothesis that PVS may enlarge as a result of higher vascular pressures common in older age and cerebrovascular disease.
Longitudinal trajectories of myelin loss in the context of Alzhiemer’s disease biomarkers, glial activation, and APOE4
Authors: Stephenson Henry G. , Kohli Akshay , Kecskemeti Steven R , Rubinski Anna , Ewers Michael , Alexander Andrew L , Deming Yuetiva , Ma Yue , Van Hulle Carol A. , Langhough Rebecca E , Jonaitis Erin M. , III Douglas C Dean , Ulland Tyler K. , Chin Nathaniel A. , Okonkwo Ozioma , Betthauser Tobey J , Asthana Sanjay , Kollmorgen Gwendlyn , Carboni Margherita , Wild Norbert , Carlsson Cynthia M , Johnson Sterling C , Blennow Kaj , Zetterberg Henrik , Bendlin Barbara B
Published: December 2023

Background

Lower measures of myelin have been associated with abnormal levels of AD biomarkers and APOE4 carriage. However, most human studies have been cross‐sectional, leaving the relationship between AD and myelin changes unclear. The purpose of this study was to determine the association between AD pathology, APOE4, glial activation, and longitudinal changes in quantitative R1 (qR1), a marker sensitive to myelination obtained via MPnRAGE MRI.

Method

Participants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and Wisconsin Alzheimer’s Disease Research Center (ADRC) were selected based on available longitudinal MPnRAGE, clinical diagnosis, and APOE genotyping (N = 446). A subset (N = 141) included those with available baseline CSF (AB42/40, pTau181), and gliosis markers (sTREM2, GFAP, YKL40) measured using a robust prototype assay as part of the Roche NeuroToolKit research platform (Roche International). Longitudinal mean qR1 was estimated from white matter regions from the ICBM‐DTI‐81 atlas. In the overall sample, linear mixed effects models predicting regional qR1 (FDR‐corrected) with random intercepts and slopes were estimated controlling for sex, age centered within‐subjects (agec), age averaged within‐subjects (agegm), cognitive impairment, and APOE4 carriage as covariates. Two‐way interactions between impairment and APOE4 with agec were tested in the overall sample as were moderating effects of CSF amyloid‐positivity, pTau181, and gliosis markers on agec in the CSF sample.

Result

In the overall sample, older agec, agegm, and female sex were associated with lower qR1 in a majority of tracts indicating substantial longitudinal declines in qR1 over time and lower qR1 with advanced age and female sex. Sex, impairment, and APOE4 did not show significant agec interactions. Likewise, none of the CSF biomarkers moderated the effect of agec in the CSF subsample.

Conclusion

While aging is robustly associated with longitudinal demyelination as potentially indexed by qR1, these rates do not appear to be moderated by AD pathology, cognitive impairment, APOE4, or glial activation in early disease. Given the capacity for re‐myelination in the context of injury, longitudinal studies are critical for parsing myelin and AD relationships. Established associations between myelin and AD risk may reflect later disease processes, particularly in samples more enriched for tau pathology.
Effects of biomarker timing on preclinical cognitive trajectories and tau PET accumulation
Authors: Cody Karly Alex , Langhough Rebecca E , Janelidze Shorena , Christian Bradley T. , Johnson Sterling C , Hansson Oskar , Betthauser Tobey J
Published: December 2023

Background

The timing of AD biomarker positivity may be important for defining optimal anti‐amyloid therapy windows for secondary prevention. This work characterizes the AD biological cascade and investigates biomarker onset timing and associations of timing with preclinical cognitive decline and tau PET accumulation using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP).

Method

WRAP participants (N = 172; mean(SD) age at last plasma = 69.4(6.6) years; 159 unimpaired, 9 MCI, 3 dementia, 1 impaired non‐AD) with available plasma pTau217, amyloid PET, and longitudinal cognitive assessments were included. Plasma pTau217 was quantified using an immunoassay on the Meso Scale Discovery platform (Lilly Research Laboratories). Amyloid burden was quantified using cortical 11C‐PiB DVR (cerebellum GM reference region). Positivity thresholds were defined using group‐based trajectory modeling applied to participants with longitudinal (≥2) biomarker observations (Ptau217, n = 162; PiB, n = 155). Sampled iterative local approximation (SILA) was used to model longitudinal PiB and pTau217 trajectories and estimate biomarker onset ages. Biomarker timing groups were defined as: PiB(‐)/pTau217(‐); coincident (PiB(+) and pTau217(+) onsets within 2 years of each other); PiB(+) first; or pTau217(+) first. We used a linear mixed effects model (random intercept and age‐related slope; unstructured covariance) to investigate the impact of biomarker timing group on cognitive decline measured by a three‐test Preclinical Alzheimer’s Cognitive Composite (PACC‐3). In a subset with tau PET (n = 120), we assessed regional tau burden (18F‐MK‐6240 SUVRs; 70‐90min, inferior cerebellar GM reference region) relative to plasma pTau217(+) and PiB(+) timing.

Result

In the PiB(+)/pTau217(+) subset (n = 60; 35%), PiB(+) onset generally preceded pTau217(+), but with considerable heterogeneity in this timing (Figure 1A‐H). Older age at PiB(+) onset was associated with shorter time to pTau217(+) onset (Figure 1G‐H). In PACC‐3 analyses, post‐hoc analyses of the significant biomarker timing group*age interaction showed fastest decline in the pTau217(+) first group (Figure 2). Both PiB(+) and pTau217(+) durations predicted MK‐6240 accumulation; ∆AICc indicated better fit with pTau217(+) time (Figure 3).

Conclusion

In this mostly preclinical sample, the timing of PiB(+) and plasma pTau217(+) were differentially associated with cognitive decline and tau PET accumulation. These preliminary findings suggest secondary AD prevention with anti‐amyloid therapy may be most beneficial before pTau217 onset.
Plasma biomarkers of Alzheimer´s disease in the continuum of dementia with Lewy bodies
Authors: Diaz‐Galvan Patricia , Przybelski Scott A. , Algeciras‐Schimnich Alicia , Lesnick Timothy G. , Schwarz Christopher G. , Senjem Matthew L. , Gunter Jeffrey L. , Jack Clifford R. , Min Paul H , Jain Manoj K. , Miyagawa Toji , Forsberg Leah K. , Fields Julie A. , Savica Rodolfo , Graff‐Radford Jonathan , Ramanan Vijay K , Jones David T. , Botha Hugo , St Louis Erik K , Knopman David S. , Graff‐Radford Neill R , Ferman Tanis J , Petersen Ronald C. , Lowe Val J. , Boeve Brad F. , Kantarci Kejal
Published: December 2023

Background

Patients with dementia with Lewy bodies (DLB) may have Alzheimer´s disease (AD) pathology. Plasma biomarkers of beta‐amyloid (Aß), phosphorylated tau (pTau), and neurodegeneration are sensitive to AD neuropathologic changes in AD dementia. While these plasma biomarkers are well tested in the AD continuum, their performance for concomitant AD pathology in the DLB continuum is still unclear.

Method

We included patients with isolated REM sleep behavior disorder (iRBD; n = 15), with mild cognitive impairment with Lewy bodies (MCI‐LB; n = 37), and with DLB (n = 70) from the Mayo Clinic Alzheimer’s Disease Research Center. Cognitively unimpaired individuals (CU; n = 100) included from the Mayo Clinic Study of Aging were balanced on age and sex. A panel of plasma biomarkers of Aß40, Aß42, p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) measures was obtained. We calculated the ratio of plasma Aß40/42. Lower Aß40/42 indicates increased Aß pathology. Plasma Aß40, Aß42, GFAP, and NfL were measured using the Simoa® Neurology 4‐Plex E Advantage kit and pTau‐181 was measured with the Simoa® pTau‐181 Advantage V2 kit. Both were run on a Quanterix HD‐X analyzer. AD imaging biomarkers were assessed on PET using Pittsburgh compound B (PiB) for Aß and 18F‐Flortaucipir for tau.

Result

Higher levels of plasma GFAP were observed in the MCI‐LB (p = 0.014) and DLB (p<0.001) groups compared to CU (Figure). DLB patients also showed higher levels of plasma pTau181 (p<0.001) and NfL (p<0.001). Higher amyloid and tau PET standardized uptake value ratio (SUVr) in the DLB continuum were associated with higher levels of plasma p‐tau181, NfL, and GFAP (p<0.001). After accounting for age, plasma Aß40/42 did not correlate with amyloid or tau PET SUVr.

Conclusion

In the DLB continuum, abnormal levels of GFAP in plasma can be detected as early as the prodromal stages of the disease. Plasma pTau181 reached abnormal levels in the DLB stage. Higher plasma GFAP, NfL, and p‐tau181 are associated with higher amyloid and tau PET SUVr in the DLB continuum. Plasma biomarkers have the potential to contribute to screening and early diagnosis in the DLB continuum, which has implications in designing new treatments.
Using Natural Language Processing to identify psychiatric symptoms related to Alzheimer’s disease: a novel tool to enhance molecular brain research in Alzheimer’s disease
Authors: Vogelgsang Jonathan , Jiang Weiqian , Dan Shu , Vempati Sangeetha , Chatigny Michael , Abston Joshua , Durning Peter , McCoy Thomas , Klengel Torsten , Berretta Sabina
Published: December 2023

Background

Neuropsychiatric symptoms (NPS), such as anxiety, depression, or agitation, are common across different stages of Alzheimer’s disease (AD). However, their molecular course is still poorly understood. While post‐mortem brain research provides a unique source to study brain‐specific molecular changes, clinical characterization of post‐mortem brain donors is challenging and primarily subject to case‐control designs. Here, we present a novel approach to post‐mortem brain donor characterization using natural language processing (NLP).

Method

We analyzed electronic health records (HER) of 92 brain donors (46 males, 46 females, mean age 81.9 years, B&B 0 ‐ VI) using NLP‐based NIMH Research Domain Criteria (RDoC) quantification. Individual RDoC scores were regressed to their neuropathological findings or RNAseq data from two independent brain regions, BA32 and insula.

Result

Neuritic plaques (NP) in all four cortices show a high association with RDoC “cognition”, controlled for age and sex (frontal: ß = 0.38, p < 0.001; parietal: ß = 0.35, p < 0.001; temporal: ß = 0.37, p < 0.001; occipital: ß = 0.37, p < 0.001). These findings align with prior clinicopathological correlation studies where cognitive examinations were performed within one year before death (Nelson et al., J Neuropathol Exp Neurol, 2012). At pFDR<0.05, we identified 492 differentially expressed genes (DEGs) in the insula and 333 DEGs in the BA32. We have further built a model regressing individual RDoC levels against their DEGs in the two brain regions. In each domain, we observed a cluster of genes that is up‐ or downregulated in relation to their RDoC score (higher/lower domain burden). In addition, we saw that the majority of DEGs are RDoC‐specific. 223 DEGs were uniquely related to one domain (170 DEGs in the insula and 53 DEGs in BA32), while a total of 211 DEGs were associated with at least two domains (151 DEGs in the insula and 60 DEGs in BA32).

Conclusion

NLP‐based analysis of RDoC can be applied to post‐mortem case collections to phenotype brain donors and show promising associations with neuropathology or RNAseq data that can be used to discover novel molecular pathways related to psychiatric symptoms.
Fine semantic segmentation of hands for human functional pattern recognition in IADLs using deep learning
Authors: Babatope Eyitomilayo Yemisi , Acosta‐Franco Jesus Alejandro , García‐Vázquez Mireya Saraí , Ramírez‐Acosta Alejandro Álvaro
Published: December 2023

Background

Alzheimer’s Disease (AD) is an irreversible degenerative brain disease and the most common cause of dementia, in the elderly population (age 65 and above) although people younger may develop the disease (Clemmensen, 2020). AD is characterized by impairment in behavior and cognition which eventually obstruct the Instrumental Activities of Daily Living (IADL) (Kumar, 2022). Researchers have predicted functional capacity by assessing IADL as they are strongly associated with cognitive impairment. With the availability of big data and public repositories of multimedia data such as images and videos, artificial intelligence algorithms have been used in classifying and making informed decisions that could help in disease prediction and monitoring. In the context of early diagnosis of Alzheimer, researchers have worked with machine learning techniques applied to neuroimaging for AD classification (Lama, 2021). Researchers and practitioners often use Activity of Daily Living to monitor independent‐living senior citizens’ self‐care ability, wellness status, and disease progression (Zhu, 2021). Automating the assessments of IADL will ease the evaluation of functional and cognitive function and strengthen the prediction of AD.

Method

Our work approaches the timely detection and diagnosis of AD by exploring the deficiency in hand dexterity and visuospatial skills while performing IADL using egocentric videos. Therefore, in this work, we propose a fine semantic segmentation of hands, optimizing the predictions at the level of the relationship between pixels in a deep learning method. We trained the optimized RefineNet‐Pix convolutional neural network, obtaining a higher accuracy in the segmentation of semantic maps of hands.

Result

With the optimization of RefineNet‐Pix we obtained an accuracy higher than 87.9% (Urooj, 2018) in the semantic segmentation of hands. By integrating the RefineNet‐Pix results to the base model for human functional pattern recognition, we obtain an accuracy higher than 74% with respect to the base model (Yemisi, 2022).

Conclusion

The optimized RefineNet‐Pix model segments pixel‐wise the hand regions in egocentric videos, providing hand motion information that can be used to classify impairment based on human functional patterns. Optimization of these models is a way forward in building a technological device for the support of Alzheimer’s diagnosis.
Cognitive functioning predicts learning and performance of syncopated rhythms in healthy aging adults
Authors: Colverson Aaron
Published: December 2023

Background

Rhythmic music making may be beneficial for maintenance of healthy executive functioning and processing speed throughout the aging process. However, little is known about how engagement with rhythmic music making associates with healthy executive functioning and processing speed. This study aimed to determine the predictive potential of learning and performance of rhythms upon performance in executive functioning and processing speed tasks.

Method

This study involved a cross‐sectional, non‐randomized within subjects design, defined by a rhythmic musical activity (RMA), and executive functioning (EF) and processing speed (PS) tasks. The RMA involved thirty progressively syncopated rhythms, operationalized via three learning trials and a performance trial. The EF and PS tasks included multiple subtests of the Weschler Adult Intelligence Scale (WAIS) Working Memory and Processing Speed Indices (WMI & PSI), and Trail Making Parts A&B.

Result

Healthy younger (ages 18‐35) and elderly (ages 55‐89) individuals provided informed consent and participated (N = 60; 46 female; 78.3% Caucasian). Learning and performance of syncopated rhythms between age groups significantly predicted scores on the WAIS PSI (t = 2.227/2.101, p = 0.030/0.040) and Trails A&B (t = ‐3.431/‐4.155, p = 0.003/<0.001; t = ‐3.636/‐4.256, p = <0.001/<0.001). Only rhythm learning predicted scores on WAIS WMI (t = 2.821, p = 0.007), with a trend shown for rhythm performance (t = 1.934, p = 0.059).

Conclusion

This study is one of few to show relationships between rhythm perception and executive functioning in healthy aging. The results suggest the potential value of rhythmic music making upon maintenance of healthy executive functioning and processing speed throughout the aging process. A longitudinal study involving a control group and a larger sample size may enhance the findings of this study. Additionally, application to the Alzheimer’s disease and related dementias populations may provide comparative evidence to the healthy aging population.
Impact of midlife intake of flavonoid‐rich fruits on dementia risk in the Framingham Heart Study
Authors: Lyu Chenglin , Jacques Paul F , Doraiswamy P. Murali , Gurnani Ashita S , Au Rhoda , Hwang Phillip H
Published: December 2023

Background

Consumption of foods with high flavonoid content may be protective against dementia in older adults, but it is unclear whether this relationship is consistent earlier in life. We investigated the relationship between consumption of flavonoid‐rich fruits in midlife and risk of dementia, including Alzheimer’s disease (AD).

Method

1,642 participants from the Framingham Heart Study Offspring cohort who were aged 45‐59 years and did not have prevalent dementia at Exam 5 (1991‐1995), and had a valid food frequency questionnaire data were included. Intake of 12 fruit items with high flavonoid content or are important contributors to overall flavonoid intake at Exam 5 were examined. Total fruit intake was calculated by summing intake of each fruit item. Diagnoses of all‐cause dementia and AD dementia were adjudicated by a multi‐disciplinary consensus committee through 2019. Cox models were used to evaluate the association between higher intake (>30th percentile) versus lower intake (≤30th percentile) of total fruit consumption, as well for each fruit item, and incident dementia, adjusting for demographic, behavior and lifestyle, dietary, genetic, and clinical factors.

Result

The sample was, on average, 52 years of age, 53% female, and had 14 years of education, with an average follow up time of 24 years in the study. Higher intake of total fruits was associated with decreased risk of all‐cause dementia (HR = 0.56; 95% CI = 0.32 – 0.98), but not with AD dementia. Decreased risk of all‐cause dementia was associated with higher intake of apples or pears (HR = 0.47; 95% CI = 0.27 – 0.81), and oranges (HR = 0.55; 95% CI = 0.32 – 0.95). Higher intakes of apples or pears (HR = 0.50; 95% CI = 0.25 – 1.00), and oranges (HR = 0.43; 95% CI = 0.22 – 0.85), were also associated with decreased risk of AD dementia. Sex modified the association between total fruit intake in midlife and dementia risk (HRfemale = 0.46; 95% CI = 0.21 – 0.97; HRmale = 0.65; 95% CI = 0.27 – 1.60).

Conclusion

Greater consumption of flavonoid‐rich fruits in midlife, particularly apples or pears, as well as oranges, were significantly associated with reduced dementia risk.