bluuebunny/crossref_metadata_2025 huggingface dataset:
Determinants of enlarged perivascular spaces (ePVS) on MRI: The Florida Vascular Imaging Phenotypes (FL‐VIP) Study of AD risk
Authors: Rundek Tatjana , Brutto Victor Del , Goryawala Mohammed , Saporta Anita Seixas Dias , Merritt Stacy S. , Camargo Christian , Agudelo Christian , Ariko Taylor , Dong Chuanhui , Loewenstein David , Duara Ranjan , Haq Ihtsham U.
Published: February 2022

Background

PVS are fluid filled compartments surrounding small intracerebral vessels. They are conduits for fluid transport, exchange, and waste clearance. Their relationship to cardiovascular markers is unknown. We tested whether ePVS counts are affected by vascular risk factors and comorbidities.

Method

We analyzed nondemented subjects’ brains from the FL‐VIP (comprised of 1Florida ADRC participants with available high quality 3T MRI). ePVS were defined as parenchymal hypo/hyperintensities of <3 mm seen on a single axial T1, T2 or FLAIR section through the basal ganglia (BG) and centrum semiovale (CSO). ePVS were defined as parenchymal hyperintensities <3 mm and graded as 0 (none), 1 (<10), 2 (11‐20), 3 (21‐40), and 4 (>40). The side with highest ePVS count was graded. BG and CSO scores were summed to yield a 0‐8 total. Generalized linear models were used to estimate ePVS score associations with demographics, vascular risk factors, and vascular comorbidities (VASCom score).

Result

Of 228 non‐demented participants (mean age 72±8 years; 61% women, 60% Hispanic, mean education 15±4 years, 33% ApoE4 carriers), 59% were hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. ePVS scores ranged from 0‐7 (mean 2.5±1.4), 0‐4 for BG (mean 1.3±0.7) and CSO (mean 1.2 ±0.9). Majority of subjects (73%) had a total ePVS score greater than 1. In unadjusted analysis, BG ePVS were correlated with age (r=0.27, P<0.001), hypertension (r=0.19, p=0.008), MI/CHF/Angina (r=0.14, P=0.03), and coronary bypass (r=0.20, P=0.004). CSO ePVS were correlated with age (r=0.23, P=0.0005), obesity (r=‐0.15, p=0.03), and dyslipidemia (r=‐0.14, P=0.04). In multivariable stepwise regression analyses, BG ePVS were associated with age (β=0.024 per year, p=0.0001), being Hispanic (OR=0.21, P=0.035), coronary bypass (OR=0.70, p=0.025), and hypertension (OR =0.17, p=0.079). CSO PeVS were associated with age (β=0.028 per year, P<0.001) and dyslipidemia (OR=‐0.31, P=0.02).

Conclusion

ePVS were more prevalent with aging, greater vascular risk burden, and Hispanic origin. Hypertension, cardiovascular disease and prior coronary bypass surgery were associated with ePVS in BG, but not in CSO. BG ePVS may be an important marker of small vessel disease linking vascular burden and cognitive impairment.
Genetic and environmental influences on Alzheimer’s disease neuroimaging signatures
Authors: Williams McKenna E. , Gillespie Nathan A. , Dale Anders M. , Elman Jeremy A. , Eyler Lisa T. , Fennema‐Notestine Christine , Hagler Donald J. , McEvoy Linda K. , Neale Michael C. , Panizzon Matthew S. , Sanderson‐Cimino Mark E. , Franz Carol E. , Kremen William S.
Published: February 2022

Background

Composite scores of MRI‐based brain morphometry, commonly termed ‘Alzheimer’s disease (AD) signatures,’ have demonstrated associations with AD symptom severity and progression to AD. Our group recently showed that two AD signatures, a cortical thickness/volume and mean diffusivity (MD) signature, aid prediction of progression to mild cognitive impairment among cognitively normal adults in their 50s. Genetic and environmental influences on these signatures, and whether the signatures capture unique AD‐related variance, remains unclear.

Method

Participants were from the Vietnam Era Twin Study of Aging (age=56.18, SD=2.61). Our previously published thickness/volume signature, a novel MD signature using the same regions and weights as the thickness/volume signature, and an MRI‐based measure of predicted brain age (ns=310‐502) were used in trivariate twin models to determine the relative influence of genetic and environmental factors on each phenotype. Correlations were examined to determine if the latent genetic and environmental influences overlap among the three phenotypes.

Result

Heritability estimates were similar for the signatures and predicted brain age (0.68‐0.71). Phenotypic correlations ranged from ‐0.47 to 0.27. Genetic correlations were: 0.33 [95% CI: 0.19,0.47] (thickness/volume signature and predicted brain age); ‐0.55 [95% CI: ‐0.66,‐0.42] (MD signature and predicted brain age); and ‐0.36 [95% CI: ‐0.51,‐0.20] (thickness/volume and MD signatures).

Conclusion

Both AD brain signatures are highly heritable. However, despite very similar heritability estimates among the three phenotypes, genetic correlations demonstrated that the two AD signatures are not redundant with each other or with a measure of predicted brain age. The results suggest that each AD signature captures some unique genetic variance, including genetic influences that are distinct from genetic influences on general brain aging.
Tracing individual trajectory of longitudinal tau spreading in deep latent space
Authors: Kim Sohee , Cho Hanna , Lee Wha Jin , Kim Sung‐Woo , Lyoo Chul Hyoung , Seong Joon‐Kyung
Published: February 2022

Background

Alzheimer’s disease (AD) usually appears in mid‐60s (Late‐Onset AD, LOAD), but also rarely appears in patients younger than 65 (Early‐Onset AD, EOAD), while showing distinct features. Tau shows high correlation with AD prognosis and can be detected through positron emission tomography (PET) scan. Tau data mapped into a low dimensional latent space will help detect longitudinal change pattern along AD spectrum. Furthermore, fitting tensors using individual line segments will enable us to track individual tau trajectory in the latent space.

Method

We recruited 74 healthy controls, 75 mild cognitive impairment patients, and 38 AD patients with two PET scans ([18F]Flortaucipir for tau and [18F]Florbetaben for Aβ) with two‐year follow‐up. We used standardized uptake value ratios (SUVRs) for tau PET data. All patients’ tau data went through autoencoder and principal component analysis, pretrained using baseline (BL) tau data. Using only amyloid positive AD patients’ BL – follow‐up (FU) line segments, we fit tensors and tracked individual trajectories in the latent space using a tensor tracing algorithm.

Result

In the 2‐dimensional latent space the points dispersed toward the upper‐ and right‐side as the disease deteriorated. Reconstructed SUVR maps showed tau accumulation pattern of EOAD through x‐axis, such as tau spreading in temporal, prefrontal, and parietal lobes. Reconstructed map of 1st quartile group in y‐axis showed tau spreading dominance in parietal lobe and 4th quartile group showed dominance in prefrontal, temporal lobe. Each patient’s trajectory, predicted based on the latent space, showed reconstructed map following individual tau accumulation pattern. In addition, EOAD tau spreading trajectory tend to precede LOAD tau spreading trajectory.

Conclusion

We decomposed high dimensional tau accumulation pattern into 2 independent components through deep‐learning methods. X‐axis showed EOAD tau accumulation pattern and y‐axis was divided into LOAD tau accumulation pattern and non‐prefrontal dominant pattern. In addition, tensor fitting of the longitudinal vector field enables us to find individual tau spreading trajectories which can be used to predict future and past spreading. Even though this study was done using only one factor, tau, it has the potential to be expanded to other factors such as amyloid or neurodegeneration data.
Networking analysis for neuroimaging and genetic markers in Alzheimer's disease
Authors: Moon Seok Woo
Published: February 2022

Background

This paper examines late‐onset dementia‐related cognitive impairment and neuroimaging‐genetics biomarker association using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data archive.

Method

The demographics of the 1,026 ADNI 1, ADNI GO and ADNI 2 arms of the ADNI study included participants ages 65 to 85, 266 normal CN’s (CDR=0, Male:138, Female:128), 572 mild cognitively impaired MCI’s (CDR=0.5, Male:227, Female:245), and 188 AD patients (CDR=0.5/1, Male:102, Female:86).

The extracted AD‐related imaging and genetic markers were employed in a subsequent network analysis. We used Plink, to model the genetics data, and the Pipeline environment, to develop an end‐to‐end neuroimaging‐genetics data analysis protocol that identified the neuroimaging associations with SNPs and the clinical diagnosis. The expected significant correlations between the SNPs and the neuroimaging phenotypes were confirmed using neuroimaging genetics networking analyses.

Genotype dosage data for AD‐associated SNPs were extracted from the imputed ADNI genetics dosage data using sample‐major additive coding. 29 such SNPs were selected (Jansen, et al., 2019) that meet a minor allele frequency threshold (MAF>0.5%).

Result

There were 9 ROIs (7 thicknesses, 1 volume, and 1 gauscurve) which were associated with 6 genomic markers in the level of ‘p<0.001’ in the CN cohort. There were 43 ROIs (31 thicknesses, 11 volume, and 1 pct) which were associated with 5 genomic markers in the level of ‘p<0.001’. There were 10 ROIs (9 thicknesses and 1 volumes) which were associated with 3 genomic markers in the level of ‘p<0.0001 in the MCI cohort. There were 3 ROIs (1 thicknesses, 1 volume, and 1 pct) which were associated with 3 genomic markers in the level of ‘p<0.001’ in the AD cohort. The 29 genes were influencing on the 200 neuroimaging markers with some networking patterns using WGCNA R‐package for the CN, MCI and AD groups, even though we could not find any networking the 29 genes themselves.

Conclusion

Structural brain changes are important indicators of dementia progression. Network analysis pairing morphometric biomarkers with genetic indicators allows investigation of clinical and phenotypic associations that facilitate deep systematic understanding of genetic and environmental influences on aging and cognitive decline.
Individual variability in the cortical distribution of elevated 18F‐flortaucipir uptake in posterior cortical atrophy
Authors: Katsumi Yuta , Eckbo Ryan , Putcha Deepti , Wong Bonnie , Quimby Megan , McGinnis Scott M. , Touroutoglou Alexandra , Dickerson Brad C.
Published: February 2022

Background

Accumulating evidence supports the relevance of the localization of tau pathology, as measured with 18F‐flortaucipir (FTP) PET imaging, for characterizing clinical phenotypes of Alzheimer’s disease (AD), including posterior cortical atrophy (PCA). The present study investigated the degree to which the cortical distribution of elevated FTP uptake varies across individual patients with PCA, with the goal to identify regions of heightened vulnerability to tau pathology in this population. Based on available PET imaging evidence and using a systems neuroscience approach, we hypothesized that the majority of PCA patients would exhibit elevated FTP uptake in the visual and dorsal attention networks of the brain, consistent with impairments in basic and higher‐order visual processing characteristic of this syndrome.

Method

15 patients with PCA underwent FTP PET imaging. Individual FTP standardized uptake value ratio (SUVR) maps were partial volume corrected and projected to template cortical surface space. These individual SUVR maps were converted to Z‐score maps using data obtained from 24 age‐matched healthy control subjects, then binarized at Z > 1.5. Percent overlap maps were created based on the individual binarized Z‐score maps. A parcellation of the cerebral cortex into seven canonical intrinsic functional networks was used to characterize the spatial topography of elevated FTP uptake.

Result

100% of PCA patients showed elevated FTP uptake in brain regions including bilateral superior parietal lobule, area MT, and importantly, bilateral frontal eye fields, which are key nodes of the dorsal attention network. In more than 80% of patients, elevated signal was also observed bilaterally in the occipital, parietal, and temporal areas that are nodes of the visual, frontoparietal, and default mode networks, with more circumscribed and variable involvement of prefrontal cortex.

Conclusion

The results support the hypothesis that tau pathology in PCA universally affects the key nodes of the dorsal attention network consistent with visuospatial and visuomotor deficits commonly observed in PCA, including oculomotor apraxia (impaired voluntary control of eye movements). In addition to the nearly universal involvement of visual association networks, key nodes of default mode and frontoparietal control networks likely subserve other cognitive deficits that are common but more variable in PCA.
Determining the efficacy of non‐pharmacological interventions to manage neuropsychiatric symptoms of dementia in residential aged care settings: A systematic review of systematic reviews
Authors: Koch Jana , Amos Jessica , Mortby Moyra E
Published: February 2022

Background

Non‐pharmacological interventions such as music, physical activity, and reminiscence provide a cost‐effective and safe approach to managing neuropsychiatric symptoms in neurocognitive disorders. While much research has focused on evaluating the efficacy of individual non‐pharmacological interventions used to manage neuropsychiatric symptoms and inform best practice, they have struggled to provide clear results and recommendations. A possible explanation for the lack of clear results may be the failure of previous studies to examine the efficacy in specific population settings (e.g. residential aged care vs. community settings). This systematic review of systematic reviews evaluates the efficacy of non‐pharmacological interventions used to manage neuropsychiatric symptoms in the context of residential aged care settings only.

Method

A systematic review of systematic reviews was conducted. PubMed/Medline, Embase, Cochrane Library and Web of Science were searched for eligible reviews in December 2019 and February 2020. Two authors independently screened title and abstracts, and assessed full‐text reviews for eligibility. The quality of systematic reviews was appraised with ‘AMSTAR‐2: A Measurement tool to assess systematic reviews’. Narrative summaries were created to group findings by intervention domains.

Result

From 1362 systematic reviews identified, 26 met the inclusion criteria and were included. Of these, 10 focused on person tailored interventions, six on sensory stimulation interventions, three on environmental interventions, three on exercise interventions and four on other interventions. Quality ratings identified reviews to be of mostly moderate quality (73%). The majority of reviews report positive results, but effects were not always statistically significant. Tailored interventions that included music and social elements appeared to be most beneficial for depressive symptoms and mood. Furthermore, outcome measures and intervention protocols were highly heterogenetic across interventions.

Conclusion

This systematic review of systematic review highlights the importance of considering intervention settings when evaluating the efficacy of non‐pharmacological interventions in neurocognitive disorders across studies. The findings suggest that in this setting, combining different types of interventions and tailoring them to the personal experiences of the resident is recommended. Use of a more standardized approach for outcome measures is vital in order to accurately assess intervention efficacy and allow for comparison of intervention approaches.
Electrophysiological brain functional network alterations associated with hippocampal volume in healthy and pathological aging
Authors: Torres Lucia , Cuesta Pablo , Fernández Ricardo Bruña , Vilca Brenda Chino , Dolado Alberto Marcos , Fuertes Miguel Yus , Arrazola Juan , Fernandez Alberto , Verdejo Juan , Maestú Fernando , Higes Ramón López
Published: February 2022

Background

The early detection of Alzheimer disease is currently one of the main worldwide scientific goals. Estructural biomarkers, such as cortical deterioration and medial temporal lobe atrophy (MTLa), are well known and deeply studied. The relation of these structural changes with brain connectivity could help to understand the consequences of neurodegeneration in brain functioning, with the ultimate goal of explaining cognitive impairment. Magnetoencephalogram (MEG) quantitative analysis is a precise, non‐invasive tool to evaluate changes in bioelectrical activity of the brain. Therefore, it brings us the opportunity to study disruption of functional brain networks associated with changes in MTLa volume, as assessed with structural MRI.

Method

We recruited 376 healthy elders and 130 mild cognitive impairment patients (MCI) (aged from 61 to 85) from the “Hospital Universitario San Carlos” and the Center for elders at the Chamartín District, all located in Madrid, Spain. All of them underwent a neuropsychological evaluation, MRI assessment, and MEG recordings. The MCI diagnosis was established according to the NIA‐AA criteria. None of the participants exhibited a history of psychiatric or neurological disorders (other than MCI). We used a completely data‐driven approach to evaluate the relationship between functional connectivity (FC) and the hippocampal volume.

Result

Our main finding was an augmented theta band functional connectivity (FC) in right temporal (RTemp) areas associated with lower hippocampal volume, and we found this FC signature to correlate negatively with memory performance. Furthermore, the average theta FC of this area differed significantly between groups, although the original relationship remained significant for each group independently. Finally, we performed a seed‐based analysis targeting the original right temporal region and found that the modulation of the theta FC was driven by connections to 1) superior frontal and 2) contralateral temporal areas.

Conclusion

The results depict a clear FC pattern that seems to be associated with both healthy and pathological aging. This MEG signature may be useful as a non‐invasive biomarker for the progressive subcortical degeneration that occurs along aging, both healthy and pathological. Furthermore, it is also related with cognitive performance, especially with memory functioning.
Comparison of diffusion weighted, imaging‐derived, fractional anisotropy with a novel MRI contrast‐weighted ratio method for measuring myelin in older adults at risk for Alzheimer’s disease
Authors: Price Lauren Rose , Deardorff Rachael , Wu Yu‐Chien , McDonald Brenna C. , West John D. , Risacher Shannon L. , Saykin Andrew J.
Published: February 2022

Background

MRI measures sensitive to myelin integrity have been investigated as potential AD biomarkers. T1‐weighted/T2‐weighted ratio is a simple yet informative measure, but many cohorts have transitioned to only T1‐weighted and T2‐weighted Fluid Attenuated Inversion Recovery (FLAIR) acquisitions. We previously obtained similar results using FLAIR instead of T2 (T1w/T2FLAIRw). Our goal now is to compare T1w/T2FLAIRw to fractional anisotropy (FA) from diffusion weighted imaging (DWI).

Method

Pearson’s correlations of T1w/T2FLAIRw and FA values of hippocampal white matter (WM) integrity were calculated in two independent cohorts acquired on different scanners: Cohort 1 (21 CN; 7 SCD; 20 MCI; 4 AD) and Cohort 2 (40 CN; 43 SCD; 45 MCI; 20 AD). Image‐processing algorithms were designed in‐house, building on previous methods and implemented using SPM12 and FSL dtifit. Diagnostic group differences were assessed in both cohorts using one‐way ANOVA and independent sample T‐tests with Tukey correction.

Result

Cohort 1 demonstrated significant correlation of WM integrity values between methods in the left hippocampus (p=.002) and approached significance in the right (p = .074). Between‐group analyses showed significant differences in left hippocampal WM between cognitively unimpaired (CU [CN and SCD]) and cognitively impaired (CI [MCI and AD]) groups, with follow‐up tests showing differences between CN and AD patients in both methods. Right hippocampal T1w/T2FLAIRw ratio values showed significant differences between CU and CI, though no significant diagnostic group differences. Right hippocampal FA values were not significant.

Cohort 2 demonstrated significant bilateral correlation between imaging methods (p < .001), with bilateral significant differences between CU and CI groups in both methods. CN and MCI right hippocampal values were significantly different from each other in both methods. Box plots demonstrated clear similarities in patterns of diagnostic profile between methods.

Conclusion

A similar overall pattern was observed across the T1w/T2FLAIRw and DWI‐FA methods. This may reflect myelin disruption although further studies are needed to address source of signal differences on imaging. Differences in FA effect sizes for the hippocampus across samples and scanners merits further exploration.
White matter fiber density for vocabulary better maintained than fluid abilities in aging
Authors: Gazes Yunglin , Li Ruiyang , Mensing Ashley , Babukutty Reshma S. , Noofoory Diala , Nazario Geneva Hidalgo , Langfield Christopher , Sakhardande Jayant , Lee Seonjoo
Published: February 2022

Background

Aging research has repeatedly shown that crystallized abilities, cognitive processes reliant on learned knowledge, are well preserved well into old age. On the other hand, fluid abilities, processes that are not knowledge‐dependent, show decline as early as the third decade of life. It is still unclear what mechanism enables the two starkly contrasting aging trajectories to exist all within the same brains.

Method

From the Reference Ability Neural Network (RANN) study, 181 participants (age=51.2±17.2, 101females) with both baseline and 5‐year follow‐up diffusion weighted imaging data were included in the current analysis. Based on fMRI activation data, the set of brain regions were derived that are associated with performance of each of four cognitive abilities: vocabulary, processing speed, episodic memory, and reasoning. Using these regions as seeds, white matter tracts connecting the brain regions for each ability were extracted and used to calculate the mean fiber density associated with each ability. Three models, linear, partial linear, and quadratic were performed to model the longitudinal changes in fiber density for each ability. Mixed effect regression was used to test whether vocabulary, the only crystallized ability, shows more gradual decline than white matter for the other three abilities, which were all fluid abilities. The non‐linear trend of age was modeled using B‐splines with the knot point selection based on Bayesian information criteria (BIC).

Result

Consistent with cross‐sectional results reported in Gazes et al. 2020, mean fiber density for white matter tracts associated with the vocabulary ability was shown to follow a slower decline with age than that for the three fluid abilities – processing speed [F(2,1251)=57.5, p<.001], episodic memory [F(2,1251)=5.32, p<.001), and reasoning [F(2,1251)=4.05, p<.001]. Figure 1 shows the age‐related trajectory modeled with quadratic trend, which was the best fitting model based on BIC values. Vocabulary, in purple, clearly demonstrates a shallower decline than the other three abilities for fiber density.

Conclusion

This study demonstrated that longitudinal changes in the microstructural integrity of white matter tracts are better preserved for vocabulary, a crystallized ability, than that for the three fluid abilities, suggesting that preservation of white matter contributes to the maintenance of crystallized abilities with age.
Employing the Moca‐T (telephone) as a means of cognitive screening in a rural, ethnically diverse population during Covid‐19 restrictions
Authors: Wiese Lisa Ann Kirk , Williams Ishan Canty , Schoenberg Nancy E , Galvin James E , Lingler Jennifer H
Published: February 2022

Background

Rural, ethnically diverse older adults face a heightened risk of Alzheimer’s disease and related dementias (ADRD), but experience disparities in dementia education, detection, and treatment. The Covid‐19 pandemic struck during a rural, faith‐based outreach to address this gap. In‐person research activities were redesigned to employ a telephone approach.

Method

The revised research question targeting a rural community of 89% African American, Hispanic, and Haitian Creole residents was adapted to “Is the telephone an effective method for a) increasing AD knowledge, and b) detecting cognitive risk, in a rural underserved setting?” Faith‐based health educators, trained using online Alzheimer’s Association resources, contacted church congregants who responded to announcements during virtual worship services. Participants completed a measure of basic dementia knowledge (BKAD; Wiese et al., 2020), and MoCA‐T with a cut point of 11 indicating need for referral (Nasreddine, 2019) .

Result

Of the estimated 120 persons across five churches who received an invitation, 75% (n = 90) participated in dementia education and memory screening via telephone. Dependent samples t‐test showed a significant increase in dementia knowledge: t(89) = ‐6.3, p < .001), and paired samples pre/post; t(24) = ‐2.23, p = < 004). Of the 60 who completed cognitive screening using the MoCA‐T, 15 (25%) were found to be at risk for memory impairment. Twelve (80%) of the 15 participants assessed as being at risk did follow‐up with their provider.

Conclusion

Rural residents were willing to participate in telephone‐based health‐seeking activities during quarantine, and the Moca‐T was useful in identifying cognitive risk.
Predicting memory in preclinical AD from resting‐state functional connectivity
Authors: Fountain‐Zaragoza Stephanie , Heshung Liu , Jensen Jens H. , Helpern Joseph A. , Benitez Andreana
Published: February 2022

Background

Emerging research suggests that patterns of brain functional connectivity can be used to predict clinical features and disease states. Individuals across the Alzheimer’s Continuum exhibit alterations in connectivity across various brain networks (Contreras et al., 2019). However, less is known about functional changes during the preclinical stage and whether those changes are associated with cognitive test performance. This study sought to identify functional connectivity characteristics that track with episodic memory, one of the earliest cognitive changes observed in the disease course (Mortamais et al., 2017), among cognitively unimpaired older adults with and without brain amyloid deposition.

Method

n = 51) and ‐negative group (AB‐, n = 89). Resting‐state data were submitted to a pipeline for creating individual‐specific functional parcellations that account for variability in brain topology (Wang et al., 2015). Functional connectivity was used to predict demographically‐adjusted memory factor scores (Besser et al., 2018; Kiselica et al., 2020) in each group. Predictive models were generated using ridge regression and 50 iterations of 10‐fold cross‐validation. Prediction accuracies (i.e., Spearman rank correlations between predicted and observed scores) from the median performing models are reported.

Result

Median prediction accuracy was r
s = 0.40 (IQR = .063) in the AB+ group and r
s = 0.11 (IQR = .059) in the AB‐ group. Although the two groups did not differ on memory scores, the resulting networks were topologically distinct (Fig. 1). Qualitative visual review showed that the AB+ networks were predominantly comprised of inter‐network connections, whereas the networks in the AB‐ group appeared more circumscribed. In the AB+ group, the majority of connections predicting better memory were frontoparietal inter‐network connections, a pattern suggestive of compensatory hyper‐connectivity.

Conclusion

Individual‐specific patterns of resting‐state functional connectivity can be used to predict episodic memory in the preclinical stages of the Alzheimer’s Continuum. These results suggest that the presence of beta‐amyloid is associated with less network segregation, potentially reflecting early disease‐related network disruption even prior to the emergence of clinical symptoms.
The interactive effect of MCI subtype and white‐matter hyperintensity load on the expression of large‐scale neurofunctional networks
Authors: De Marco Matteo , Vettore Martina , Pallucca Claudia , Bendini Matteo , Gallucci Maurizio , Venneri Annalena
Published: February 2022

Background

Mild Cognitive Impairment (MCI) is a condition with a large degree of clinical heterogeneity. A major classification is that between 'amnestic' and 'non‐amnestic' patients. It is known that large‐scale neural networks differ between these two subtypes. White‐matter‐hyperintensities (WMH) load may contribute to affecting the efficiency of these networks. It is unknown, however, whether WMH burden influences the expression of major brain networks in a similar way in both amnestic and non‐amnestic MCI. We thus hypothesised that an interactive effect on brain networks would exist between MCI subtype and WMH load.

Method

One‐hundred‐and‐twenty‐three MCI patients were included in this study, retrospectively selected from our internal Ageing Database and the Treviso Dementia Registry initiative. They all completed an MRI protocol inclusive of resting‐state fMRI and neuroanatomical acquisitions. FLAIR scans were processed with the ‘Lesion Segmentation Tool’ to quantify global WMH volume (i.e., lower vs. higher). Resting‐state scans were preprocessed and denoised with the CONN toolbox and an independent component analysis was run to extract five major large‐scale networks: default‐mode, salience, left‐right frontoparietal and visual. Subtype‐by‐WHM load ANOVAs were run to test for significant interactions for each of the five inferential models, controlling for major confounding factors.

Result

Significant interactions were found in two models only. Within the salience network having a lower WMH load was associated with stronger connectivity in the right insula significantly more among amnestic patients. Within the left frontoparietal network, having a lower WMH load was associated with stronger connectivity in the right frontoinsular cortex significantly more among amnestic patients, and in the left mediotemporal lobe significantly more among non‐amnestic patients.

Conclusion

The interplay of two important clinical variables such as MCI subtype and WMH load has a significant effect on the expression of two large‐scale brain networks that sustain stimuli selection and integration and executive control. This pattern is expressed in alignment with clinical symptoms of subtypes. WMH load contributes to down‐regulating the efficiency of large‐scale brain networks in a way that is dependent on MCI subtype and aligned with vulnerability of each subtype. This is an important element of prognostic utility.
Validation of locus coeruleus histological reconstructions to MRI
Authors: LaMore Tia , Chen Yuheng , Li Song , Tonsun Duygu , Otaduy Maria , Heinsen Helmut , Alegro Maryana , Grinberg Lea T.
Published: February 2022

Background

The Locus coeruleus(LC) is one of the first sites of tau aggregation and suffers from dramatic volume loss early on. Due to the shrinking of the LC preceding the onset of clinical symptoms of AD by decades, a precise understanding of the neurobiological correlates of MRI signal may turn LC neuroimaging into an early non‐invasive staging biomarker for AD. Though there are many efforts to image the LC in‐vivo, first, it is vital to confirm postmortem validation of the MRI signal. In this study, we are attempting to validate postmortem histological reconstructions of the LC to its corresponding postmortem MRI reconstructions, voxel‐to‐voxel.

Method

We used a pipeline developed in‐house employing brainstem processing, staining, and computer‐based algorithms for 2D and 3D registration to reconstruct the histological volume of the brainstem with structural detail. This pipeline allows for precise alignment of histology‐based cytoarchitectural 3Dreconstructions (Fig. 1A) of the brainstem to its 7T‐MRI counterpart (Fig. 1B). Photoshop and Freeview were used to manually segment the LC in digital images of cross sections of the brainstem labeled with Nissl staining (Fig. 2), to generate 2D LC masks in all 4 cases. We then registered the stained cross sections and their corresponding LC masks to the cross sections’ blockface to correct for any deformation of tissue during the staining process. We applied Freeview commands to reconstruct the 3D brainstems and their 3D LC masks. We registered the resulting 3D reconstruction and LC mask to matching MRI coordinates, enabling voxel‐to‐voxel comparisons. We will continue to demonstrate the value of our pipeline in regards to validating neuroimaging methods in AD with these structural masks of the postmortem LC registered to the MRI counterpart in 3 more cases.

Result

The histological 3D LC masks were registered onto the parallel 3D MRIs. In Freeview, we plan to run correlation analysis with an output of dice coefficient ranging from 0‐1, with a coefficient of 1 translating to the voxels of the LC masks and the MRI signal overlapping exactly.

Conclusion

Our pipeline enables voxel‐to‐voxel correlation analysis between histology and MRI scans for validation of LC neuroimaging. Current finalization of 3 other cases is ongoing.
The relationship between cortical grey to white matter signal contrast (GWC) and tau pathology in atypical AD
Authors: Flaherty Ryn , Krivensky Samantha , Brickhouse Michael , Carvalho Nicole , Eckbo Ryan , Salat David H , Dickerson Brad C. , Touroutoglou Alexandra , Putcha Deepti
Published: February 2022

Background

Grey to white matter signal intensity ratio (GWC) has been studied as a novel metric of integrity and as a marker of neurodegeneration in Alzheimer’s disease (AD). Regions with reduced GWC co‐localize with regions of cortical atrophy in AD (Salat et al. 2011; Salat et al. 2009). Cortical atrophy in AD robustly colocalizes with tau pathology measured using tau PET ligands (Putcha et al. 2019). For this study, we hypothesized that GWC co‐localizes with tau pathology and shows greater sensitivity to tau pathology than cortical atrophy across the atypical phenotypic spectrum of AD.

Method

We studied 29 amyloid‐positive atypical AD patients, including 16 patients with posterior cortical atrophy (PCA), 10 with logopenic variant primary progressive aphasia (lvPPA), and 3 with an amnestic dysexecutive presentation. Whole‐cortex maps of GWC and cortical atrophy were generated for each individual using FreeSurfer. Tau PET (18F‐Flortaucipir) signal was projected for each individual to the cortical surface using PETsurfer. Eta squared (η2) was computed to determine the spatial overlap of each measure of neurodegeneration (GWC, cortical atrophy) with tau PET signal for each subject and then averaged across the whole group.

Result

Both GWC and cortical atrophy revealed a pattern of neurodegeneration consistent with AD, including in medial parietal, lateral parietal, and posterior lateral temporal cortices. Lower GWC was also observed in several regions beyond the areas of cortical atrophy in patients including in bilateral dorsolateral and dorsomedial prefrontal cortices. Supporting our hypothesis, there was greater spatial overlap between the GWC and tau PET maps (η2 = 0.30) compared to cortical atrophy and tau PET maps (η2 = 0.24; t=4.49, p=0.0001).

Conclusion

While both measures of neurodegeneration (GWC, cortical atrophy) showed a high degree of spatial overlap with tau PET signal across our sample of atypical AD participants, we conclude that GWC, a novel MRI‐derived biomarker of neurodegeneration in AD, correlates more strongly with AD‐related tau neuropathology than traditional cortical atrophy measures. This suggests that GWC could be a sensitive biomarker of AD‐related tissue changes that may represent neuronal injury or neurodegeneration. Further work is needed to establish how GWC tracks with tau pathology over time.
Brainstem volume is negatively associated with amyloid deposition in the Framingham Heart Study
Authors: Jacobs Heidi I.L. , O’Donnell Adrienne , Satizabal Claudia L. , Hanseeuw Bernard , Thibault Emma G. , Koijs Daniel , Sanchez Justin S. , Buckley Rachel F. , Yang Qiong , Sperling Reisa A. , Johnson Keith A. , Beiser Alexa S. , Seshadri Sudha
Published: February 2022

Background

The brainstem consists of various nuclei that accumulate tau early in the Alzheimer’s disease (AD) trajectory. Previous studies discovered the genetic loci linked to brainstem volume, revealing genetic overlap with several neurological disorders, including AD. We aimed to investigate whether the volume of distinct parts of the brainstem are related to AD pathology, amyloid or tau, and whether this effect is modified by APOE genotype. Finally, we evaluated whether genetic variants related to total brainstem volumes are related to AD‐pathology by aggregating previously reported genetic loci into a brainstem polygenic risk score.

Method

We included 267 individuals from the Framingham Heart Study who underwent 3T MRI, Flortaucipir (n=238) and PiB‐PET imaging on Siemens HR+ or GE‐Discovery GE PET cameras(mean age: 54 (SD:8) years, 51% male; 24% APOE‐E4; Figure 1). Subregional brainstem volumes were quantified using FreeSurfer 6.0 and adjusted for total cranial volume. Regional FTP‐PET, neocortical PiB‐PET signal were referenced to cerebellar grey and partial volume corrected (PVC). We performed several hierarchical regressions: 1) to associate each brainstem volume to neocortical PiB and tau in temporal lobe regions 2) to examine interactions between PiB and brainstem volumes on tau and 3) interactions between APOE and brainstem volume on tau. We then examined whether the brainstem polygenic risk score was associated with AD‐pathology. Covariates included age, sex and PET‐camera.

Result

In both the PVC and non‐PVC analyses, lower medulla and pons volumes were consistently associated with greater neocortical PiB binding (Figure 2). Midbrain volume was at trend‐level negatively associated with inferior temporal and amygdala tau. No other associations were observed with tau. We observed no interactions between brainstem volumes and PiB or APOE on regional tau. The brainstem polygenic risk score was not associated with AD‐pathology (Figure 3).

Conclusion

Lower brainstem volume, in particular medulla and pons, is associated with amyloid deposition in a cohort of middle‐aged individuals. There is no evidence for associations with known brainstem loci, suggesting that these associations may occur via different or indirect pathways, or that lower brainstem volumes may be a reflection of overall disease progression and neurodegeneration.
Long‐term progression of amyloid and tau biomarker profiles: Four‐year follow‐up imaging study
Authors: Cho Hanna , Baek Min Seok , Kim Han‐Kyeol , Lee Jae Hoon , Chun Joong‐Hyun , Ryu Young Hoon , Lyoo Chul Hyoung
Published: February 2022

Background

To investigate long‐term progression of amyloid (A) and tau (T) image‐based biomarker profiles in a cohort with wide range of cognitive status.

Method

In 273 participants [96 cognitively unimpaired (CU), 106 mild cognitive impairment (MCI), and 71 AD dementia (DEM)] who completed 18F‐florbetaben and 18F‐flortaucipir PET studies for visit 1 (V1), 167 participants (62 CU, 68 MCI, and 37 DEM) completed visit 2 (V2) PET studies at two years, and subsequently 66 participants (23 CU, 33 MCI, and 10 DEM) completed visit 3 (V3) PET studies at about four years (mean 4.5 years) after the V1 study. A/T biomarker profiles were determined by using the cut‐off standardized uptake value ratios of composite regions most vulnerable to each pathology.

Result

5.6% (5/90) of participants converted from A‐ to A+ at V2 and 18.5% (5/27) at V3. Likewise, 4.2% (5/118) of participants converted from T‐ to T+ at V2 and 17.4% (8/46) at V3. In comparison with lower conversion rate from T‐ to T+ in the A‐T‐ participants [2.3% (2 A‐T+ / 86 A‐T‐) at V2 and 7.4% (2 A+T+ / 27 A‐T‐) at V3], A+T‐ participants exhibited higher conversion rate from T‐ to T+ [9.4% (3 A+T+ / 32 A+T‐) at V2 and 31.6% (6 A+T+ / 19 A+T‐) at V3].

Conclusion

Positive conversion of A/T biomarkers occurs steadily throughout the long‐term period. Compared to A‐ individuals, positive conversion of T biomarker occurs four times more frequently in A+ individuals.
Effect of comprehensive, individualized, person‐centered management (CI‐PCM) on psychotropic medication usage in advanced Alzheimer’s persons in a 28‐week randomized controlled trial
Authors: Kenowsky Sunnie , Shao Yongzhao , Bao Jia , Torossian Carol , Dafflisio Gianna , Vedvyas Alok , Reisberg Barry
Published: February 2022

Background

Behavioral and Psychological Symptoms of Dementia (BPSD) are burdensome and disturbing for caregivers and persons living with Alzheimer’s disease (AD). They are also a primary cause of institutionalization of Alzheimer’s persons. Physicians use psychotropic medications to treat the BPSD of AD. Many of these medications have deleterious consequences as evidenced in part by their black box warnings. We published results of a 28‐week, clinician‐blind, randomized, controlled trial of our CI‐PCM program in moderate‐to‐severe, community‐residing, Alzheimer’s persons receiving memantine (Reisberg…Kenowsky, Dement Geriatr Cogn Disord, 2017). The BPSD were examined using the Behavioral Pathology in Alzheimer’s Disease‐Frequency Weighted severity scale, which showed significant benefit in the CI‐PCM subject group at week 28 (p<0.05).

Methods

We examined the magnitude of usage of psychotropic medications used to treat BSPD in subjects from our 2017 study who were randomized to receive Usual Community Care (UCC) or the CI‐PCM Program. Psychotropic medications used to treat other conditions were excluded. Subjects were evaluated at baseline and weeks 4, 12 and 28. We examined the ratio of daily psychotropic medication usage in the two groups. Psychotropic medications were compared by examining the percent of the maximum daily dosage of each medication taken cumulatively throughout each study observation period from week 4 to week 28. The Wilcoxon rank sum test was used to analyze the difference between the two groups.

Results

At baseline, the group randomized to UCC consumed significantly more psychotropic medication than subjects randomized to the CIPCM program (p<0.05). Because there was a significant difference between groups at baseline, we analyzed usage in comparison with baseline (see figure 1). The UCC subjects used more psychotropic medication on a per day average relative to baseline from week 4 to week 28 than the CI‐PCM subjects (p<0.01). The total amount of psychotropic medication taken, in comparison with baseline, was significantly lower in CI‐PCM subjects from weeks 4 to 28 (p<0.0001).

Conclusions

CI‐PCM subjects took significantly less psychotropic medication and their BPSD symptomatology significantly improved. The CI‐PCM program is a safe, highly efficacious nonpharmacologic intervention that significantly reduces both BPSD symptomatology and psychotropic medication usage in advanced AD persons.
Tools validated for assessment of mental health and cognition in older adults of Latin America and the Caribbean: A scoping review
Authors: Miranda‐Castillo Claudia , León‐Campos María O , Molleda Pedro , Paddick Stella‐Maria
Published: February 2022

Background

The global population is ageing, with an estimated one in five people aged 60 by 2050. Latin America is one of the fastest ageing areas of the world and accurate clinical and research assessment measures of mental health in this ageing population are needed. It is not known which psychometric measures of older people’s mental health and cognition are validated in a Latin American context. This scoping review aims to address this question and outline current knowledge and research gaps.

Method

Broad search terms were defined in English then translated and adapted to Spanish and Portuguese. Databases searched included Cinahl, Medline, Embase, Scielo, Scopus, Psychinfo, EBSCO and Web of Science. Inclusion criteria were validation or adaptation studies of tools for cognitive, mental health or psychosocial outcomes in older adults, conducted in Latin America or the Caribbean 1990‐2019. Titles and abstracts were reviewed blindly against search criteria using the RAYYAN application and conflicts resolved through discussion. PRISMA guidelines were utilized for reporting. Data extraction summarised psychometric procedures (reliability, construct/criterion validity, diagnostic accuracy, factor analysis etc), setting and participants.

Results

A total of 3805 articles were identified (3075 de‐duplicated) of which 526 underwent full‐text review. In total, 337 articles meeting the review criteria were identified and data were extracted. Psychometric evaluations of 138 different tools were identified, (90.3% conducted since 2006) though 46 were evaluated twice or less. Cognitive screening measures were the most numerous (n=107 45.1%) followed by depression and quality of life. Brazil had the largest number of studies (n=135). The most frequently evaluated tools were MMSE, MOCA, Geriatric Depression Scale (GDS) and Clock Drawing Test.

Conclusion

The highest validation evidence was for cognitive measures. Most evidence relates to a small number of measures (cognition, depression and quality of life) originally developed in high‐income countries outside Latin America. The greatest evidence relates to, urban centres in Brazil.

Though a large number of validation studies have been conducted, substantial research gaps remain. The majority of tools in current use have been insufficiently validated and their utility in clinical practice across different settings in Latin America remains unclear.
Characterizing amyloid positive individuals with normal tau PET levels five years later: An ADNI study
Authors: Josephs Keith A. , Weigand Stephen D. , Whitwell Jennifer L. ,   ADNI
Published: February 2022

Background

Diagnosing Alzheimer’s disease (AD) with biomarkers requires evidence of abnormal beta‐amyloid (Aβ) and tau. Individuals that are Aβ‐positive, but tau‐negative, are considered to have AD neuropathologic change, or early AD. The objective of this study was to determine whether some Aβ‐positive but tau‐negative individuals remain tau‐negative 5‐years later and describe the characteristics of such individuals.

Method

We identified 45 individuals from ADNI who were Aβ‐positive but tau‐negative on PET more than five years after their first abnormal Aβ‐PET (Amyloid+ Low Tau, ALT group). For comparison, we identified 157 Aβ‐positive individuals that had abnormal tau‐PET within five years of their first abnormal Aβ‐PET (i.e. biomarker‐AD). Aβ‐positivity was determined by ADNI‐provided cut‐points of 1.11 for AV45 and 1.08 for florbetapir. A negative tau‐PET scan was defined using Gaussian mixture modeling.

Result

The ALT and biomarker‐AD groups were similar in terms of sex and age at the time of their first Aβ‐PET scan. However, the ALT group was characterized by a lower proportion of APOE ε4 carriers (31% versus 67%, p<0.001), a lower median centiloid (36 versus 85, p<0.001, Figure) and lower likelihood of having a dementia diagnosis at first Aβ PET (2% versus 22%, p<0.001) compared to the biomarker‐AD group. The ALT group also performed better on tests of general cognition and had larger hippocampal volume compared to biomarker‐AD (p<0.001 for all). APOE ε4 status, centiloid and hippocampal volume were all associated with increased odds of elevated tau within 5 years from baseline Aβ‐PET (Table). Within the ALT group, 19 (42%) had high centiloid (>40): these individuals did not differ from the <40 centiloid individuals in clinical diagnosis, but there was some indication of a higher APOE ε4 frequency (42% versus 23%; p=0.30).

Conclusion

Amyloid‐positive individuals can remain tau‐negative for at least five years, and without becoming demented. Baseline characteristics can help identify these ALT individuals that have a low risk of progression. These findings beg the question of whether more conservative Aβ cut‐points are required for diagnosis of individuals with a high risk of developing AD.