bluuebunny/crossref_metadata_2025 huggingface dataset:
Age‐related tau‐PET uptake and its downstream effects extend beyond the medial temporal lobe in cognitively normal older adults
Authors: Wuestefeld Anika , Berron David , Binette Alexa Pichet , van Westen Danielle , Stomrud Erik , Mattsson‐Carlgren Niklas , Strandberg Olof , Smith Ruben , Palmqvist Sebastian , Glenn Trevor , Hansson Oskar , Wisse Laura EM
Published: December 2022

Background

Amyloid‐beta (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe (MTL). However, there is evidence that age‐related Aβ‐independent tau pathology is present outside the MTL (Kaufman et al., Acta Neuropathol, 2018). We examine tau deposition determined by positron emission tomography (PET) in regions typically involved earlier/later in AD and downstream effects on neurodegeneration and cognition in cognitively unimpaired older adults and a low‐Aβ subgroup.

Methods

We included 488 adults (40‐91 years; low‐Aβ: n=355, 65.2±11.5 years) from the BioFINDER‐2 study. MTL volumes (dentate gyrus, subiculum (SUB), cornu ammonis 1) and thickness (entorhinal cortex, Brodmann areas (BA)35/36, and parahippocampal cortex) were obtained, using Automated Segmentation for Hippocampal Subfields packages for T1‐ and T2‐weighted magnetic resonance images. Thickness of early/late neocortical AD‐regions (anterior cingulate, precuneus/posterior cingulate (PPC), orbitofrontal, inferior parietal cortex; and middle frontal, lateral occipital, and precentral/postcentral gyrus) was determined using FreeSurfer. [18F]RO948‐ and [18F]flutemetamol‐PET standardized uptake value ratios (SUVRs) were calculated for local tau and global/local Aβ. Aβ status was determined using Aβ‐PET or cerebrospinal fluid Aβ‐42/40 ratio. Global cognition was measured using delayed word‐list recall, trail making test B, and animal fluency.

Results

Increasing age was associated with higher tau‐PET SUVRs primarily in MTL/frontal/parietal regions. A significant association between age and local tau‐PET remained even when including Aβ‐PET as a mediator (Fig. 1).

Age and local tau‐PET, but not Aβ‐PET, where negatively associated with structure in most examined regions (Figs. 2‐3). Age‐structure associations were serially mediated via tau‐PET in regions with early AD pathology (SUB/BA35/PPC). Also, in the low‐Aβ subgroup, tau‐PET mediated the age‐structure (SUB/BA35/PPC) associations (Fig. 3D). Finally, the age‐global cognition relationship was serially mediated via MTL tau‐PET and subiculum volume, even when including global Aβ‐PET as additional mediator (Fig. 4).

Conclusion

We observe partially Aβ‐independent associations between age and tau‐PET signal across the neocortex. Interestingly, partially Aβ‐independent tau‐PET signal appears to mediate the age‐structure associations in and outside the MTL (PPC), also in the low‐Aβ group, and the age‐MTL structure‐cognition associations. This potentially provides in vivo support for Primary Age‐related Tauopathy downstream effects on structure, beyond the MTL, and cognition.
Cerebrovascular injury markers explain the effect of systemic vascular risk on cognitive decline in older adults with lower amyloid burden
Authors: Shirzadi Zahra , Yau Wai‐Ying Wendy , Rabin Jennifer S. , Buckley Rachel F. , Properzi Michael J , Fu Jessie Fanglu , Hsieh Stephanie , Thibault Emma G. , Mojiri‐Forooshani Parisa , Goubran Maged , MacIntosh Bradley J. , Black Sandra E. , Price Julie C , Johnson Keith A. , Sperling Reisa A. , Chhatwal Jasmeer P. , Schultz Aaron P.
Published: December 2022

Background

Systemic vascular risk is a well‐established contributor to late‐life cognitive decline, yet the mechanism is not completely understood. We investigated whether neuroimaging‐based measures of vascular injury (white matter hyperintensity (WMH) volume, Peak width of Skeletonized Mean Diffusivity (PSMD), and relative cerebral blood flow (rCBF)) could explain the effect of systemic vascular risk on cognitive decline using longitudinal data from the Harvard Aging Brain Study.

Method

We used the Framingham Heart Study cardiovascular disease risk score (FHS‐CVD) as an index of systemic vascular risk. We extracted WMH from structural MRI (https://hypermapp3r.readthedocs.io/) and PSMD from diffusion MRI (http://www.psmdmarker.com). We performed kinetic modeling on dynamically‐acquired PiB‐PET data to extract 1) amyloid burden as the distribution volume ratio (PiB‐DVR) and 2) relative tracer delivery (PiB‐R1 via MRTM reference‐tissue analysis as a proxy of rCBF). Global cognition was assessed using Preclinical Alzheimer Cognitive Composite (PACC).

We considered two linear mixed effect models to examine whether cerebrovascular injury markers could explain the FHS‐CVD effect on PACC change over time: 1) FHS‐CVD on PACC change controlling for age, sex, years of education, and PiB‐DVR; 2) the previous model including WMH, PSMD, and PIB‐R1. Analyses were stratified by high (PiB+) and low (PiB‐) baseline amyloid burden.

Result

Figure 1 illustrates the relationships between demographics and neuroimaging measures at baseline. Table 1 shows the demographics and study information. We observed a significant effect of FHS‐CVD on PACC change (PiB‐: t=‐3.9, p<0.001 (Table 2); PiB+: t=‐2.6, p=0.008). When the cerebrovascular injury markers were included in the model, the effect of FHS‐CVD was reduced in the PiB‐ group while PSMD and PiB‐R1 explained PACC change (Table 3; Figure 2). The second model fit was significantly better than the first model (L.ratio= 25.9, p<0.001). The effects remained significant after controlling for gray matter volume. In contrast, cerebrovascular injury measures did not explain the effect of FHS‐CVD on PACC change in the PIB+ group.

Conclusion

These results demonstrate that cerebrovascular injury largely explains the effect of systemic vascular risk on cognitive decline in older adults with lower amyloid burden suggesting mechanisms by which a higher systemic vascular risk impacts brain function.
Multi‐modal biomarkers improve prediction of memory function in cognitively unimpaired older adults
Authors: Trelle Alexandra N , Tran Tammy T , Wilson Edward N. , Deutsch Gayle , Sha Sharon , Andreasson Katrin I. , Carr Valerie A , Kerchner Geoffrey A. , Mormino Elizabeth C. , Wagner Anthony D
Published: December 2022

Background

Identifying biomarkers that predict current and future cognition may improve estimates of Alzheimer’s disease risk among cognitively unimpaired older adults (CU). In vivo measures of amyloid and tau protein burden and task‐based functional MRI measures of core memory mechanisms, such as the strength of cortical reinstatement during remembering, have each been linked to individual differences in memory in CU. This study assesses whether combining CSF biomarkers with fMRI indices of cortical reinstatement improves estimation of memory function in CU, assayed using three unique tests of hippocampal‐dependent memory.

Method

Participants were 157 CU (90F, aged 60‐88 years, CDR=0) enrolled in the Stanford Aging and Memory Study (SAMS). Cortical reinstatement was quantified using multivoxel pattern analysis of fMRI data collected during completion of a paired associate cued recall task. Memory was assayed by associative cued recall, a delayed recall composite, and a mnemonic discrimination task that involved discrimination between studied ‘target’ objects, novel ‘foil’ objects, and perceptually similar ‘lure’ objects. CSF Aβ42, Aβ40, and p‐tau181 were measured with the automated Lumipulse G system (N=115). Regression analyses examined cross‐sectional relationships between memory performance in each task and a) the strength of cortical reinstatement in the Default Network (comprised of posterior medial, medial frontal, and lateral parietal regions) during associative cued recall and b) CSF Aβ42/Aβ40 and p‐tau181, controlling for age, sex, and education. For mnemonic discrimination, linear mixed effects models were used to examine the relationship between discrimination (d’) and each predictor as a function of target‐lure similarity.

Result

Stronger cortical reinstatement was associated with better performance across all three memory assays. Age and higher CSF p‐tau181 were each associated with poorer associative memory and a diminished improvement in mnemonic discrimination as target‐lure similarity decreased. When combined in a single model, CSF p‐tau181 and Default Network reinstatement strength, but not age, explained unique variance in associative memory and mnemonic discrimination performance, outperforming the single‐modality models.

Conclusion

Combining fMRI measures of core memory functions with protein biomarkers of Alzheimer’s disease significantly improved prediction of individual differences in memory performance in CU. Leveraging multimodal biomarkers may enhance future prediction of risk for cognitive decline.
Amyloid PET in the Lewy Body disease continuum
Authors: Diaz‐Galvan Patricia , Przybelski Scott A. , 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 , St Erik K , Knopman David S. , Graff‐Radford Neill R. , Ferman Tanis J , Petersen Ronald C. , Lowe Val J. , Boeve Bradley F. , Kantarci Kejal
Published: December 2022

Background

β‐amyloid plaques, a pathological hallmark of Alzheimer’s disease, are common in dementia with Lewy bodies (DLB). However, little is known about when β‐amyloid levels increase throughout the Lewy body disease (LBD) continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD), to a stage of mild cognitive impairment‐Lewy bodies (MCI‐LB), and finally DLB. Our objective was to investigate β‐amyloid deposition throughout the LBD continuum, as well as the influence of sex and APOE ε4 status, as potential factors contributing to Alzheimer’s disease pathological changes.

Method

Patients with iRBD (n=24), MCI‐LB (n=62), and DLB (n=82) from the Mayo Clinic Alzheimer’s Disease Research Center and Center for Sleep Medicine were included. β‐amyloid levels were measured by Pittsburgh compound B (PiB) PET and global cortical standard uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared to each other and to cognitively unimpaired individuals (CU; n=100) balanced on age and sex from the Mayo Clinic Study of Aging (MCSA). Clinical groups were compared using ANCOVA after adjusting by age.

Result

MCI‐LB and DLB patients had significantly higher global cortical PiB SUVR than CU participants, while PiB SUVR in iRBD patients was comparable to that of CU participants (Figure 1). DLB patients also had significantly higher global cortical PiB SUVR compared to iRBD patients (p=0.004). In MCI‐LB and DLB, global cortical PiB SUVR was higher in APOE ε4 carriers compared to APOE ε4 non‐carriers (p<0.001), and women had higher global cortical PiB SUVR compared to men (p=0.024).

Conclusion

In this cross‐sectional study, β‐amyloid pathology gradually increased throughout the clinically defined LBD continuum. Whereas β‐amyloid levels are comparable to cognitively unimpaired individuals in iRBD, a significant elevation in β‐amyloid levels coincides with cognitive impairment observed in MCI‐LB and DLB. Specifically, women and APOE ε4 carriers tend to have higher β‐amyloid levels than men and APOE ε4 non‐carriers. These findings have important implications for targeting patients within the LBD continuum, who may benefit from amyloid modifying therapies.
Problems using structural MRIs from the oldest‐old, and some solutions: Lessons learned from The 90+ Study and ADNI
Authors: Woodworth Davis C. , Nguyen Hannah L. , Li Janice X. , Nguyen Katelynn M. , Greenia Dana E. , Kawas Claudia H. , Corrada Maria M. , Sajjadi S. Ahmad
Published: December 2022

Background

The oldest‐old (≥85 years) have the highest rates of dementia. However, because of pronounced brain atrophy, standard neuroimaging programs face unique challenges in this cohort. Here, using data from both The 90+ Study and Alzheimer’s Disease Neuroimaging Initiative (ADNI), we report the prevalence of errors when processing brain MRIs from oldest‐old participants using standard approaches and present some strategies for ameliorating these issues.

Method

First, we analyzed image quality issues and segmentation errors (FreeSurfer) for the last available scans by age‐groups (oldest‐old, ≥85 years, vs younger‐old, <85 years) in ADNI. Second, we evaluated the utility of an age‐specific template (the 90+ T1w Template) for realigning MRIs from the oldest‐old compared to a standard template (Montreal Neurological Institute T1w template, MNI) using linear and nonlinear registration (FSL) and evaluating alignment quality using visual and deformation (Jacobian) measures for oldest‐old participants in both The 90+ Study and ADNI. Lastly, we evaluated whether stringent preprocessing (bias field removal, denoising, brain extraction, intensity normalization using Computational Anatomy Toolbox (CAT12)) helped reduce FreeSurfer segmentation errors in frontal, parietal, and temporal regions in MRIs from the oldest‐old. Comparisons were performed using Chi‐square tests.

Result

In ADNI data (Table‐1), MRIs from oldest‐old participants (∼10% of cohort) were around twice as likely to have image quality issues (20% vs 13%, P<0.001) and brain segmentation errors (45% vs 29%, P<0.001) compared to younger‐old participants. Figure‐1 shows a histogram of image quality issues and segmentation errors, which become more common with greater age. Compared to the MNI template, MRIs from participants aged 90 and older from both The 90+ Study (N=163, Table‐2) and ADNI (N=75) had fewer registration errors (∼5% vs ∼23%, P<0.001 for all) and less severe deformation when using the 90+ T1w Template (Figure‐2). Our proposed preprocessing pipeline (see Figure‐3 for example) roughly halved segmentation errors in the oldest‐old (P<0.001 for all regions, Figure‐4).

Conclusion

Our results show that adapting pipelines specifically for processing brain MRIs of oldest‐old participants minimizes errors, enabling more effective use of neuroimaging to study neural correlates of neurodegeneration and dementia in this important portion of our aging population.
Imaging and fluid biomarkers predictive of progression from mild cognitive impairment to dementia
Authors: Jannati Ali , Gomes‐Osman Joyce Rios , Tobyne Sean , Bates David , Pascual‐Leone Alvaro
Published: December 2022

Background

Dementia is a growing socioeconomic and medical problem that affects increasing portions of the population, with a prevalence that doubles every 5 years after the age of 65. Alzheimer’s disease (AD; 60–80%) and frontotemporal lobar degeneration (FTLD; 5–10%) constitute two of the most common causes of dementia. The first symptoms appear during an initial clinical phase referred to as mild cognitive impairment (MCI). Each year, 8–15% of patients with MCI develop clinical dementia. Identifying biomarkers predictive of progression from MCI to dementia will enable initiation of disease‐modifying treatments at a stage where clinical symptoms of dementia are still limited. We investigated the predictive utility of imaging and fluid biomarkers of AD and FTLD including ß‐amyloid plaques and neurofibrillary tangles composed of hyperphosphorylated tau in positron emission tomography (PET), cerebrospinal fluid (CSF), and MRI for predicting progression of MCI to dementia.

Method

Mixed‐effects logistic regressions were conducted in the National Alzheimer's Coordinating Center (NACC) dataset (n=222–2,462) to investigate the predictive utility of abnormally elevated amyloid or tau on PET (PET‐amyloid, PET‐tau), abnormally low amyloid in CSF (CSF‐amyloid), abnormally elevated CSF tau (CSF‐tau), AD or FTLD pattern in FDG‐PET (FDG‐AD, FDG‐FTLD), hippocampal atrophy in MRI, and MRI evidence for FTLD (MRI‐FTLD). Potential covariates including age at baseline, gender, education, apolipoprotein E genotype, and number of follow‐up visits were included in the regression models.

Results

PET‐amyloid (OR=5.80), MRI‐FTLD (OR=4.46), hippocampal atrophy (OR=4.22), CSF‐tau (OR=3.49), and FDG‐AD (OR=2.91) were the strongest predictors (p‐values<=0.001), followed by FDG‐FTLD (OR=2.71), and CSF‐amyloid (OR=2.21) (p‐values<0.027). Among patients with available imaging AD biomarkers (n=500), PET‐amyloid (OR = 3.31) and hippocampal atrophy (OR = 3.12) were independent and comparably strong predictors. Among patients with available fluid AD biomarkers (n=214), CSF‐tau was a significant predictor of MCI progression (OR=2.48, p=0.035), whereas CSF‐amyloid was not (OR=1.71, p=0.21).

Conclusion

PET‐amyloid, hippocampal atrophy, and CSF‐tau were the strongest predictors of progression of MCI to AD. MRI evidence was a stronger predictor than FDG‐PET for progression of MCI to FTLD. Imaging and fluid biomarkers provide complementary prognostic factors for forecasting the trajectory of clinical outcome among patients with MCI.
Microglial activation might protect against accumulation of Aβ and tau aggregates over time in non‐demented Aβ‐positive individuals
Authors: Pereira Joana B , Janelidze Shorena , Binette Alexa Pichet , Strandberg Olof , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Stomrud Erik , Hansson Oskar
Published: December 2022

Background

The past years have seen a turning point in the view of the impact of microglia in Alzheimer’s disease (AD). In particular, the activation of soluble TAM receptors and the TREM‐2 dependent transition from a homeostatic to a disease‐associated microglia stage 2 state (DAM2) seem to play relevant roles in AD. However, a comprehensive analysis of microglial‐associated biomarkers and their associations with longitudinal accumulation of amyloid‐β (Aβ) and tau aggregates in humans has not been performed yet.

Method

We determined the baseline levels of DAM2‐associated biomarkers (sTREM2, LPL, CST7, SPP1, CSF1), TAM receptors (AXL, Mer) and their ligand (Gas6) in the cerebrospinal fluid (CSF) of non‐demented individuals from the Swedish BioFINDER‐2 cohort. All subjects underwent longitudinal Aβ (18F‐flutemetamol) and tau (18F‐RO948) positron emission tomography (PET). Linear mixed effects models were employed to test whether the microglial markers predicted longitudinal amyloid and tau PET changes, while adjusting for relevant covariates and multiple comparisons.

Result

Higher levels of DAM2 markers, TAM receptors and their ligand were associated with slower global Aβ‐PET accumulation over time in Aβ‐positive participants (p<0.05), in contrast to SPP1, which was associated with faster Aβ‐PET deposition (p=0.012). Moreover, higher levels markers associated with TAM receptors and DAM2 microglia were associated with slower longitudinal tau‐PET accumulation in the neocortex (p<0.01) in Aβ‐positive subjects with evidence of tau pathology. The associations with longitudinal tau remained significant after adjusting for Aβ‐PET changes indicating they were independent of amyloid.

Conclusion

These findings suggest that markers associated with DAM2 and TAM might mitigate the accumulation of amyloid and tau aggregates in individuals with Aβ as well as both Aβ and tau pathology, respectively. These findings have important implications for future clinical trials using microglial drugs in isolation or in combination with anti‐Aβ and anti‐tau therapies for AD.
Developing early vulnerable area aggregates for PET detection of beta‐amyloid based on young and middle‐aged adults from the Framingham Heart Study
Authors: Thibault Emma G. , Farrell Michelle E. , Beiser Alexa S , Becker Alex , Satizabal Claudia L , Jacobs Heidi I.L. , DeCarli Charles S. , Hanseeuw Bernard , Killiany Ronald J , Sperling Reisa A. , Seshadri Sudha , Johnson Keith A.
Published: December 2022

Background

As Alzheimer’s clinical trials shift earlier and earlier in the disease process, current global PET measures of beta‐amyloid (Aβ) positivity may be insufficient for detecting the earliest Aβ deposits. Regional PET measures may better detect the earliest deposits. Previous efforts to identify early‐accumulating regions have inferred which regions may be most vulnerable based on older adults. Our aim was to identify early vulnerable areas by looking earlier in the lifespan.

Method

235 clinically‐normal adults ages 33‐74 from the Framingham Heart Study (FHS) underwent one time‐point of dynamic Pittsburgh Compound B (PIB) PET (Tab.1). PIB was regionally quantified in Desikan regions using distribution volume ratio (DVR, cerebellar reference). Linear and quadratic (Age + Age2) models were run to determine association of age with region of interest (ROI) PIB DVR, and ROIs with significantly increasing DVRs were selected for the generation of candidate early vulnerable area (EVA) aggregates. Multiple aggregate EVA DVRs (EVA2‐EVA11) were generated by sequential addition of regions in rank order of descending Age2 estimate. EVA positivity was derived from both full‐sample GMM and <45 sample mean+2SD thresholds. Finally, EVA aggregates were tested using an independent cohort of older adults from the Harvard Aging Brain Study (HABS) that were imaged under an identical protocol (n=250, ages 50‐92), computing sensitivity and specificity of each aggregate at baseline to predict progression to global PIB positivity 3 years later.

Result

Of 35 Desikan regions each evaluated on the left and right, 11 emerged as quadratic age relationships (p<0.05; Fig.1) and were used to generate EVA aggregates (Fig.2). Independent validation in baseline global PIB‐ individuals from HABS indicated EVA9 and EVA10 best predicted future accumulation (Fig.3). GMM‐based thresholds provided excellent specificity (SP=1.0) but weak sensitivity (SE=0.41) to predict progression to global PIB positivity 3 years later, while the more liberal mean+2SD thresholds improved sensitivity but decreased specificity (SE=0.88, SP=0.88).

Conclusion

Utilizing lifespan data from FHS, we identified a set of early vulnerable regions that are predictive of future accumulation in an independent sample of older adults. These findings are potentially useful in identifying the earliest deposits of Aβ for use in clinical trial design.
Identifying lifestyle factors that promote brain resilience in ApoE4 carriers
Authors: Haddad Elizabeth , Javid Shayan , Zhu Alyssa H , Nir Talia M , Gadewar Shruti , Gari Iyad Ba , Lam Pradeep , Gupta Arpana , Thompson Paul M , Jahanshad Neda
Published: December 2022

Background

Apolipoprotein (ApoE) E4 (e4) carriers are at increased risk for Alzheimer’s disease (AD) (Strittmatter, 2012), which is often characterized by accelerated hippocampal atrophy and cognitive decline after 65 (Reinvang, 2013). However, not all e4 carriers develop AD. In those at heightened genetic risk, it is important to evaluate lifestyle factors that might slow brain aging, and delay dementia onset. Poorer sleep quality, physical activity, and diet have been associated with several AD‐related processes ‐ including increased beta‐amyloid burden, decline in vascular integrity, reduced glucose metabolism, and neuronal dysfunction (Mander 2017, Radak 2010, Sezgin 2014). Smoking (Durazzo, 2014) and excessive alcohol consumption (Venkataraman, 2017) have also been shown to promote AD pathology and risk. Moreover, social contact and education may enhance cognitive reserve (Livingston, 2020). Here, we investigated the role of these factors in promoting structural brain resilience in a population susceptible to AD from the UK Biobank (UKB; Miller, 2016).

Method

UKB participants over age 65 with e3e4 or e4e4 genotype were included (1415M, 1355F). A novel deep learning method (Lam, 2020) was used to calculate predicted brain age (a machine‐learning estimate of a person’s age from their brain MRI). Participants were labeled as resilient if their predicted age was 3+ years younger than their actual age. Lifestyle factors evaluated may be found in Table 1. Association rule learning (Agrawal, 1993) using the mlxtend python library was used to identify sets of factors most often associated with resiliency.

Result

604/2770 of the e4 carriers were labeled as resilient (Figure 1). The antecedent set with the highest likelihood (42%) of being associated with resiliency included following the ideal recommendations for physical activity, infrequent alcohol consumption, averaging at least 7 hours of sleep/night, participating in leisure/social activities, and never having smoked. These measures also appeared in other likely antecedent sets (Table 2).

Conclusion

We identified several lifestyle factors that may promote resilience to brain aging in those at elevated risk for AD. We aim to replicate our findings using a larger dataset with brain age calculated, and train sex‐specific models as well as testing them in people of more diverse ancestry.
Capturing Morphometric Patterns of Alzheimer's Disease Progression with a TV‐L1 Ordinal Machine Learning Model
Authors: Zhao Yuji , Gutman Boris A
Published: December 2022

Background

The most common neurodegenerative disease, Alzheimer’s disease (AD) constitutes about two thirds of cases of dementia overall [1]. Mild cognitive impairment (MCI) is considered to be a transitional stage between aging and AD [2]. This general AD staging information and ample MCI data motivate a further investigation on the subcortical shape analysis incorporating MCI data in AD study. We therefore designed a novel logistic regression model to explore more morphometric patterns associated with the disease progression of AD.

Method

In this study, we used T1‐weighted MRI data of 225 controls, 398 MCI patients and 195 AD patients from the ADNI‐1 dataset. We designed an ordinal logistic regression model [3] regularized by total variation (TV) and L1 penalization term [4]. Unlike the binary or conventional multi‐class classifiers, our TV‐L1 ordinal classifier is capable of sparse‐spatially utilizing ordinal morphometric features to learn potential ordinal patterns and predict normal control, MCI and AD all at once in a single model. We extracted vertex‐wise thickness features in 7 subcortical regions [5] and trained our model with all 14 regions of interest (ROI) across the whole brain. To evaluate the performance and find the optimal hyper‐parameters in our classification task, we computed the precision, recall score and f‐score with a 4‐fold cross‐validation (CV) grid search. For comparison we also trained a TV‐L1 logistic regression model binary classifiers for controls and AD.

Result

Table 1 shows the confusion matrix, precision, recall score and f‐score. Based on the 4‐fold CV, the average precision and recall score for control, MCI and AD are 0.457 and 0.443 respectively. The weights map of the trained TV‐L1 logistic regression model is shown in Figure 1, and that of the TV‐L1 ordinal classifier in Figure 2.

Conclusion

By designing an TV‐L1 ordinal logistic regression machine learning model, we performed a shape feature‐based classification for controls, MCI and AD with f1 score substantially above chance across all three AD stages. The trained weights map reveals subtle morphometric patterns associated with the disease progression from a cognitively normal state to MCI and eventually AD stage. This could potentially provide more insights for clinical studies of AD.
Dopaminergic and noradrenergic integrity are differentially associated with late‐life memory performance
Authors: Dahl Martin J , Bachman Shelby L , Dutt Shubir , Düzel Sandra , Lindenberger Ulman , Kühn Simone , Werkle‐Bergner Markus , Mather Mara
Published: December 2022

Background

Age‐related deficits in dopaminergic neuromodulation play a key role in determining memory decline. Facilitated by technical advancements, recent research has also implicated noradrenergic neuromodulation in shaping late‐life memory development. However, investigations disentangling the contribution of the two neuromodulators to the neurobiological basis of human cognitive aging are scarce.

Method

We collected high‐resolution magnetic resonance imaging (MRI) data of the dopaminergic substantia nigra–ventral tegmental area and the noradrenergic locus coeruleus of 320 younger and older adults at two time points (T1, T2; ∼1.9 years delay). The imaging protocol included three scans sensitive for the substantia nigra–ventral tegmental area and locus coeruleus—a Fast‐Spin‐Echo [FSE] sequence, and a Magnetization‐Transfer sequence, acquired once with a dedicated magnetic saturation pulse [MT+] and once without, resulting in a proton‐density like image [MT–]. We aggregated the information shared across imaging modalities by estimating multimodal latent factors expressing dopaminergic and noradrenergic integrity.

Participants also completed a comprehensive cognitive battery at three time points (T1, T2, T3), including tests of fluid intelligence, episodic and working memory. We used structural equation modeling to evaluate cross‐sectional associations of substantia nigra–ventral tegmental area and locus coeruleus integrity with late‐life cognition. In a second set of models, we probed longitudinal changes in substantia nigra–ventral tegmental area and locus coeruleus integrity (T1–T2) and used them to predict participants’ future cognitive performance (at T3).

Result

Cross‐sectionally, we found differential associations of dopaminergic and noradrenergic nuclei with late‐life cognition. While locus coeruleus integrity was related to better episodic memory across several memory tasks, substantia nigra–ventral tegmental area integrity was related to working memory performance. Moreover, consistent with a largely shared biosynthesis of the neuromodulators, dopaminergic and noradrenergic nuclei were positively related. Longitudinally, we found that older age was associated with more‐negative change in substantia nigra–ventral tegmental area and locus coeruleus integrity (T1–T2). Importantly, changes in locus coeruleus integrity reliably predicted future episodic memory performance (at T3).

Conclusion

These findings support the utility of in‐vivo indices for catecholaminergic integrity and highlight differential roles of dopaminergic and noradrenergic neuromodulation in late‐life cognitive decline.
Neuroinflammation is associated with the rising of early Alzheimer’s disease pathology in amyloid‐negative elderly
Authors: Wang Yi‐Ting , Bezgin Gleb , Tissot Cécile , Lussier Firoza Z , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Arias Jaime Fernandez , Kang Min Su , Rahmouni Nesrine , Rosa‐Neto Pedro
Published: December 2022

Background

Amyloid‐β (Aβ) and tau are the two well‐recognised pathological hallmarks of Alzheimer’s disease (AD). In the recent decades, increasing evidence supports neuroinflammation as one of the earliest pathomechanistic alterations throughout the AD continuum. However, little is known about the spatial and temporal patterns of neuroinflammatory processes based on AD pathological status. Furthermore, it also remains elusive how longitudinal change of neuroinflammation affects cerebral amyloid and tau load in the trajectory of AD.

Method

We examined a total number of 122 subjects (mean age= 65.6 years, 66.4% women, 33.1% APOEɛ4 carriers) from the TRIAD cohort at McGill University Research Centre for Studies in Aging. Neuroinflammation, cerebral Aβ load and tau deposition were assessed with positron emission tomography (PET) radiotracers [11C]PBR28, [18F]AZD4694 ([18F]NAV4694) and [18F]MK6240 respectively. Amyloid‐β positivity was determined by a cortical composite [18F]NAV4694 SUVR threshold of 1.55, based on previously published method. Voxelwise analyses were performed to evaluate the relationships between cerebral amyloid load and neuroinflammation. A subgroup of 42 subjects who had underwent two‐year follow‐up PET scans were used to study how the longitudinal change of neuroinflammation affects other AD hallmarks.

Result

At early stages of amyloid pathology, we found a positive linear relationship between neuroinflammation and amyloid load. Voxelwise analyses also revealed a stronger association between amyloid and neuroinflammation among the Aβ‐negative subjects. Longitudinally, the increase of neuroinflammation was linked to the accumulation of cerebral amyloid and tau in Aβ‐negative subjects.

Conclusion

Neuroinflammation was associated with amyloid at early stages of amyloid pathology. In addition, elevation of neuroinflammation was associated with the increase of amyloid and tau accumulation in Aβ‐negative subjects.
Plasma Markers of Neurodegeneration Associated with Postoperative Delirium in an Older Elective Arthroplasty Population
Authors: Sweeney Aoife , Passmore Anthony Peter , Beverland David , McGuinness Bernadette , McAuley Daniel F , Mawhinney Tim , O'Brien Seamus , Schott Jonathan M , Heslegrave Amanda , Zetterberg Henrik , Cunningham Emma L
Published: December 2022

Background

Postoperative delirium (POD) is associated with subsequent cognitive decline. It is not yet clear to what extent that is because delirium indicates underlying neurodegeneration.

Method

An observational cohort study of postoperative delirium (POD) in an elective arthroplasty population recruited 315 individuals aged over 65, without a diagnosis of dementia. Blood was sampled pre‐operatively at the time of anaesthesia and on day 1 postoperatively. Following surgery, delirium was assessed daily on days 1‐3 postoperatively. Stored plasma was analysed for markers of inflammation and neurodegeneration. Statistical analysis was carried out to determine associations of these markers with POD.

Result

Those who developed POD (n = 44) had statistically significantly lower preoperative plasma amyloid‐beta 1‐40 (Aβ40; p=0.01) and postoperative day one plasma Aβ42/40 ratio (p=0.02) compared to participants who did not develop POD. A change in postoperative plasma neurofilament light (NFL), a marker of axonal degeneration, relative to preoperative NFL was associated with POD (p=0.028). POD was also associated with a statistically significantly change in postoperative plasma phosphorylated tau181 (pTau181) relative to preoperative levels (p<0.001).

Conclusion

Development of POD in an older population without a diagnosis of dementia is associated with both i) preoperative plasma markers in keeping with neurodegeneration and ii) a different pattern of postoperative change in plasma markers of neuronal damage compared to people who did not develop POD. This suggests that i) people, without a pre‐existing diagnosis of dementia, who develop POD after elective arthroplasty surgery are more likely to have underlying neurodegeneration and ii) participants developing POD have a different neuronal response to peri‐operative insults than participants who do not develop POD.
Cerebral Small Vessel Disease and Gait Speed in Older Adults without Dementia
Authors: Vazquez Juan P , Verghese Joe , Allali Gilles , Barzilai Nir , Milman Sofiya , Blumen Helena M
Published: December 2022

Background

Disturbances in gait have been found to be predictors of dementia and mobility disability in older adults. The relationship between cerebral small vessel disease (CSVD) and gait speed during simple (normal pace walking; NPW) and complex walking (walking‐while talking; WWT) conditions are not well understood. The current study examined the relationship between CSVD (as assessed as white matter hyperintensities and lacunes), NPW and WWT in older adults without dementia.

Methods

NPW and WWT speeds were measured in 113 older adults (46.9% female, 53.1%% male, mean age=78.6±6.3) without dementia enrolled in the LonGenity study. Using an established rating system, white matter hyperintensities (WMH) and lacunes of presumed vascular origin were quantified from Fluid Attenuated Inversion Recovery (FLAIR) images from the same participants. Linear regression models adjusted for age, gender, global health, cohort, and estimated total intracranial volume were used to examine the association between NPW and DTW velocity and markers of CSVD.

Results

Number of WMH in both the basal ganglia and the temporal lobes were associated with slower NPW velocity in our adjusted models (β=‐3.274 cm/s p=.047, β=‐3.113 cm/s p=.048, respectively). Number of frontal lobe WMH was associated with slower NPW velocity in our unadjusted model (β=‐3.316 cm/s p=.017) but not in the adjusted model (β=‐1.521 cm/s p=.262). WMH were not found to be significantly associated with WWT velocity. Lacunes of presumed vascular origin were not found to be significantly associated with neither NPW or DTW velocity. Significant interactions between measures of CSVD and gender, age, or cohort were not found in our models.

Conclusion

Gait is a complex task requiring the integration of both cognitive and motor function across different brain regions. We find here that higher CSVD burden as measured by the presence of WMH in the basal ganglia and temporal lobes are independently associated with slower normal gait velocity. Interestingly, no such association was seen with WWT, a task requiring a higher cognitive load. Further studies are needed to establish temporality of these lesions with declines in gait velocity. Doing so may show utility of CSVD imaging markers as predictors of gait disturbances and dementia.
Roadmap to implementation of a fully automated blood‐based biomarker test to facilitate diagnosis and treatment in early Alzheimer’s disease
Authors: Carboni Margherita , Suridjan Ivonne , van der Flier Wiesje M. , Monsch Andreas U. , Burnie Nerida , Baldor Robert , Sabbagh Marwan N. , Vilaseca Josep , Cai Dongming , Quevenco Frances‐Catherine , Golebiewska Ewelina , Lah James J.
Published: December 2022

Background

Routine implementation of a fully automated blood based biomarker (BBBM) will expand access to diagnosis and initiation of disease modifying therapies (DMTs) in Alzheimer’s disease (AD). This analysis explores current obstacles in the AD diagnostic pathway, the unmet need for a BBBM test to facilitate referral decisions, and barriers to BBBM testing.

Method

Data are from quantitative (n=1,694 physicians) and qualitative (n=186 healthcare professionals/payers) surveys in US/China/UK/Germany/Spain and two Advisory Boards (US/Europe). Primary care physicians (PCPs) and specialists (neurologists/geriatricians/psychiatrists) were represented.

Result

From the quantitative survey, between 17.8% (China) and 83.5% (France) patients with cognitive impairment present first to primary care, with the rest presenting directly to secondary care. 73% PCPs use cognitive assessment alone for referral, with 35% using laboratory results. Confirmatory testing with positron‐emission tomography (PET) or cerebrospinal fluid (CSF) analysis is rare in the primary care setting. PCPs request PET and CSF for 8% and 12% patients, respectively, compared with 40% and 36% for specialist neurologists. Most centers use local guidelines to decide CSF/PET referral. 31% of patients diagnosed with AD underwent CSF/PET. Time to clinical diagnosis varies between countries and pathways, from 14 weeks in primary care to 29 weeks for patients referred to a specialist.

The Advisory Board considered a minimally‐invasive, patient‐friendly BBBM with high negative predictive value (NPV > 90%) and moderate positive predictive value for Ab positivity could act as triage, excluding patients not needing confirmatory testing, while freeing capacity and allowing timely intervention for all others. The BBBM test would be useful in primary and secondary care, although payer coverage in primary care may limit its immediate use. In secondary care, the BBBM test could reduce unnecessary/invasive amyloid testing, and streamline the diagnostic pathway.

Conclusion

An easy‐to‐use, minimally invasive BBBM test that detects amyloid pathology could be used with other tests/assessments to guide further diagnostic procedures or onward referral, reducing time to diagnosis and allowing timely access to potential DMTs. BBBMs have potential to be a first biomarker test, providing early‐stage information on underlying pathophysiology.
Novel Diagnostic 64Cu PET Imaging Agents for Alzheimer’s Disease
Authors: Mirica Liviu M
Published: December 2022

Background

Metal radiotracers exhibit beneficial properties that can improve in vivo positron emission tomography (PET) imaging over traditional radionuclides, such as longer half‐lives, facile last‐stage radiolabeling steps, and the potential for dual imaging‐therapy applications. Among such radionuclides, 64Cu exhibits a longer half‐life (t1/2 = 12.7 h) that allows for later PET imaging times and the ability to distribute 64Cu imaging agents to facilities that do not have an on‐site cyclotron.

Method

The employed approach uses a bifunctional chelator with two Aβ‐interacting fragments that dramatically improves the Aβ‐binding affinity and lipophilicity for favorable blood‐brain barrier (BBB) penetration, while the use of optimized‐length spacers between the Cu‐chelating group and the Aβ‐interacting fragments further improves the in vivo Aβ‐binding specificity and brain uptake of the corresponding 64Cu PET imaging agent.

Result

Herein, we report to a novel molecular architecture for 64Cu PET imaging agents that show appreciable in vivo brain uptake and exhibits high specific affinity for beta‐amyloid aggregates, leading to the successful PET imaging of amyloid plaques in the brains of 5xFAD mice versus those of WT mice.

Conclusion

64Cu PET imaging agents can be used for in vivo imaging of beta‐amyloid aggregates.
The relationship between cerebrospinal fluid neurofilament light protein biomarker and cortical thinning across the spectrum of Alzheimer’s disease
Authors: Yadlapalli Vineetha , Sharp Elizabeth , Oh Hwamee
Published: December 2022

Background

Alzheimer’s disease (AD) is an age‐related neurodegenerative disease pathologically characterized by beta‐amyloid plaque accumulation and tau‐protein neurofibrillary tangles in the brain. Recent research has sought to identify additional potential biomarkers for earlier detection and treatment of the disease, including one such protein named cerebrospinal fluid neurofilament light protein (CSF NfL). Despite CSF NfL’s essential contributions to forming the neuronal cytoskeleton and supporting neuroaxonal function, the roles of CSF NfL in longitudinal AD progression and AD‐related neurodegeneration remain to be elucidated. This study examined the relationships between baseline CSF NfL levels and cortical gray matter atrophy along the spectrum of AD on a longitudinal scale over the span of two years.

Method

We included 179 study subjects (mean age = 74.21; 90 Females) with 60 cognitively normal (CN) individuals, 63 patients with late mild cognitive impairment (LMCI), and 56 AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Baseline CSF NfL measures and demographic data were downloaded from the ADNI study. Structural magnetic resonance imaging (MRI) scans from three time points (baseline, year 1, year 2) were processed and analyzed using FreeSurfer longitudinal analysis pipelines to compute percent changes in gray matter thickness for Year 1 (Y1) and Year 2 (Y2) compared with baseline, respectively.

Result

Baseline CSF NfL was positively associated with greater cortical thinning across all study subjects, which were more pronounced in Y2. This relationship between baseline CSF NfL and cortical thinning remained the same in the AD diagnosis group. For the LMCI diagnosis group, there was no clear trend between baseline CSF NfL measures and percent changes in cortical thickness. Interestingly, a positive association between baseline CSF NfL value and percent changes in cortical thickness was observed in the CN diagnosis group at Y1, especially in the left hemisphere.

Conclusion

CSF NfL may contribute to the disease progression potentially through cortical atrophy and has an ability to predict cortical thinning over the short period of time. Longitudinal follow‐up analyses are warranted to incorporate its trajectory into the A/T/N classification system.
Associations Between Age, Hippocampal Volume, and Spatial Working Memory in Periadolescent Children: Preliminary Findings from the PRANK Study
Authors: Sexton Jennifer N , Ramirez Meghan K , Phipps Connor J , Heller Abi , Behm Lillian , Zatkalik Abigail L , Nickolas Kristen , Maerlender Arthur C. , Phatak Vaishali S , Cramer Justin A. , Blair James , Murman Daniel L , Warren David E
Published: December 2022

Background

During childhood development, particularly the periadolescent epoch, significant changes in cognition and brain structure are known to occur. The development of spatial working memory (SWM), for example, continues throughout the teenage years. The hippocampus is necessary for normal SWM, as seen by the substantial memory deficits seen in patients with Alzheimer's disease (AD) and their associated hippocampal pathology. It is hypothesized that vulnerability to AD could be modulated by early brain development, so understanding the developmental relationship between hippocampal volume (HV) and SWM would provide a key baseline for comparison of different trajectories. Our ongoing study, Polygenetic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK; R01 AG064247), measures brain structure/function, cognitive abilities, and Alzheimer’s polygenetic risk score in periadolescent children (age 8‐13). Here, we report preliminary data from PRANK measuring the association between HV, age, and SWM.

Method

Using preliminary data from the PRANK project, we investigated the association between SWM, age, and HV. Our sample included children (N=80, age 8‐13 years), recruited from the community and tested at University of Nebraska Medical Center; demographics were consistent with the recruitment area. SWM was measured using the Spatial Working Memory task between errors term from the Cambridge Neuropsychological Battery. Structural MRI data were collected using a 3T Siemens Prisma instrument. HV was measured using automated segmentation in Freesurfer.

Result

SWM was associated with age, r(80) = ‐.334, p = .002, such that older children showed fewer spatial working memory errors than younger children. HV was not significantly associated with SWM, controlling for age, r(77) = ‐.027, p = .813. However, the direction of the relationship between HV and SWM (larger HV associated with fewer SWM errors) was consistent with previous literature (Faridi et al., 2015).

Conclusion

These preliminary results suggest that increasing age is associated with better SWM in typical childhood; findings for HV were non‐significant. We anticipate that our study’s full sample will provide appropriate statistical power to test the association of SWM with HV. In future efforts, we will investigate this association as it relates to polygenic risk for Alzheimer’s disease and whether these results generalize to children with Down syndrome.
Comprehensive H2O Molecules Regulation via Deep Eutectic Solvents for Ultra‐Stable Zinc Metal Anode
Authors: Li Ming , Wang Xuanpeng , Hu Jisong , Zhu Jiexin , Niu Chaojiang , Zhang Huazhang , Li Cong , Wu Buke , Han Chunhua , Mai Liqiang
Published: December 2022

The corrosion, parasitic reactions, and aggravated dendrite growth severely restrict development of aqueous Zn metal batteries. Here, we report a novel strategy to break the hydrogen bond network between water molecules and construct the Zn(TFSI)2‐sulfolane‐H2O deep eutectic solvents. This strategy cuts off the transfer of protons/hydroxides and inhibits the activity of H2O, as reflected in a much lower freezing point (<−80 °C), a significantly larger electrochemical stable window (>3 V), and suppressed evaporative water from electrolytes. Stable Zn plating/stripping for over 9600 h was obtained. Based on experimental characterizations and theoretical simulations, it has been proved that sulfolane can effectively regulate solvation shell and simultaneously build the multifunctional Zn‐electrolyte interface. Moreover, the multi‐layer homemade modular cell and 1.32 Ah pouch cell further confirm its prospect for practical application.