bluuebunny/crossref_metadata_2025 huggingface dataset:
PIB‐PET perfusion and FDG‐PET are highly correlated and similarly associated with cognitive performance
Authors: LaPoint Molly R. , Baker Suzanne L. , Landau Susan M. , La Joie Renaud , Rabinovici Gil D. , Jagust William J.
Published: December 2022

Background

Fluorodeoxyglucose PET is a useful measure of neurodegeneration in Alzheimer’s disease and aging. Because glucose metabolism and cerebral blood flow are coupled, PET measures of perfusion also detect neurodegeneration. Dynamic PET data obtained immediately following injection of highly extracted tracers can estimate relative perfusion (R1). We performed this study to examine R1 in relation to FDG PET for detection of AD and relationships to cognition.

Method

Dynamic Pittsburgh compound B (PIB) PET (0‐90 min) and FDG‐PET (30‐60 min) scans were collected in cognitively normal (CN) participants (N=109, mean age 76.2±6.4 years) and Aβ‐positive patients with MCI or dementia (N=85, mean age 65.1±9.6 years). The Simplified Reference Tissue Model 2 estimated R1 and PIB distribution volume ratios, the latter used to dichotomize CN participants by amyloid status (68 Aβ‐, 41 Aβ+). We used a standard “metaROI” composed of FreeSurfer (Desikan‐Killiany) ‐based ROIs in temporal, parietal and cingulate cortex to quantify R1 and FDG in all participants to compare R1 and FDG in the detection of between‐group differences with a one‐way ANOVA, and classification of participants with logistic regression models. Relationships between R1 or FDG and dementia severity, measured as the CDR sum of boxes, were examined in clinically impaired patients in multiple FreeSurfer‐based regions of interest.

Result

R1 and FDG were both significantly lower in patients than in CN groups (R1: F(2,191) = 70.5, p<0.000001; FDG: F(2,191) = 87.9, p<0.000001), which did not differ significantly (Figure 1). FDG and R1 were both able to distinguish between patients and CN participants similarly, with sensitivity and specificity ranging from 80‐86% (Figure 2). R1 and FDG were associated with CDR sum of boxes in a similar set of frontal, temporal, and parietal regions, although FDG associations were stronger and more extensive (Figure 3).

Conclusion

R1 and FDG perform similarly in differentiating dementia patients and controls. Relationships between FDG/R1 and cognitive performance are similar, although FDG shows more extensive associations. R1 measures obtained from dynamic PIB‐PET scans are useful indicators of neurodegeneration which can substitute for FDG in many situations.
Differential effects of comorbid Lewy body and Alzheimer’s disease pathology on regional FDG‐PET patterns
Authors: Silva‐Rodríguez Jesús , Labrador‐Espinosa Miguel , Moscoso Alexis , Schöll Michael , Mir Pablo , Grothe Michel J.
Published: December 2022

Background

In differential dementia diagnosis, an FDG‐PET pattern of pronounced posterior‐occipital hypometabolism with relative sparing of the posterior cingulate cortex (PCC) and medial temporal lobe (MTL) is indicative of an underlying Lewy body (LB) vs Alzheimer’s disease (AD) pathology. However, LB and AD pathology are often comorbid, and in patients with LB dementia the presence of AD co‐pathology correlates with a more AD‐like neurodegeneration pattern. Here we studied how concomitant LB and AD pathology affects regional FDG‐PET patterns in patients with AD dementia.

Method

The study included 52 patients from the Alzheimer’s Disease Neuroimaging Initiative autopsy cohort who had a final diagnosis of AD dementia (N=46) or amnestic mild cognitive impairment (N=6) and had an ante‐mortem FDG‐PET scan available (FDG‐PET to death interval: 3.4±2.4 years). Twenty‐one patients had autopsy‐confirmed AD without comorbid LB (‘pure‐AD’), 24 had AD with LB co‐pathology (‘AD‐LB’), and 7 had LB with no or low evidence of AD pathology (‘pure‐LB’). Pathologic groups were compared on regional FDG‐PET SUVRs, the “cingulate island sign” ratio (CISr; PCC/(precuneus+cuneus) SUVR), as well as neuropathologic ratings of substantia nigra neuron loss (SNnl). A complementary analysis assessed continuous associations of AD co‐pathology (Braak tau stage) with regional FDG‐PET SUVR and the CISr in cases with LB pathology (pure‐LB+AD‐LB).

Result

Compared to healthy controls (N=179), both pure‐AD and AD‐LB showed highly similar patterns of AD‐typical temporo‐parietal hypometabolism (Fig. 1), and neither regional FDG‐PET SUVRs, CISr, nor SNnl differed between the groups. By contrast, pure‐LB showed the expected pattern of pronounced occipital hypometabolism with relative sparing of the MTL, and CISr and SNnl were significantly higher compared to both pure‐AD and AD‐LB (p<0.05). Across cases with LB pathology, higher Braak tau stage was significantly correlated with a lower CISr (Spearman’s ρ=‐0.53, p=0.002), less occipital (ρ=‐0.37, p=0.043), and more MTL (ρ=0.36, p=0.047) hypometabolism.

Conclusion

In autopsy‐confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional FDG‐PET pattern, which may complicate in‐vivo detection of this comorbid condition. By contrast, we confirm and extend previous findings that AD co‐pathology associates with a more AD‐like neurodegeneration pattern in cases with LB pathology.
Precision estimates of Relative and Absolute Cerebral Blood Flow in Alzheimer’s disease and Cognitively Normal individuals
Authors: Heeman Fiona , Visser Denise , Yaqub Maqsood , Verfaillie Sander C.J. , Timmers Tessa , van der Flier Wiesje M. , van Berckel Bart NM , Boellaard Ronald , Lammertsma Adriaan A. , Golla Sandeep SV
Published: December 2022

Background

Alzheimer’s disease is characterized by regional reductions in cerebral blood flow (CBF) and the gold standard for measuring CBF is [15O]H2O PET. Recently, proxies of relative CBF, derived from the early distribution phase of amyloid‐β and tau tracers, have gained attention. It has been hypothesized that relative CBF is likely to have higher precision (but not accuracy) than absolute CBF, as global variations in CBF are cancelled out. The present study assessed precision of [15O]H2O PET derived relative and absolute CBF measures, and compared them with relative CBF proxies estimated from [18F]florbetapir and [18F]flortaucipir scans.

Method

Dynamic [15O]H2O, [18F]florbetapir and [18F]flortaucipir test‐retest (TRT) PET datasets were included, consisting of eleven cognitively normal (CN) individuals for [15O]H2O, four CN and five AD participants for [18F]florbetapir, and six CN and eight AD participants for [18F]flortaucipir. [15O]H2O data were analysed using the standard single tissue compartment model and [18F]florbetapir and [18F]flortaucipir using the simplified reference tissue model (SRTM). Relative CBF (i.e. K1/K1’) was derived from absolute CBF (i.e. K1 of [15O]H2O) or estimated using SRTM (i.e. R1), in all cases using cerebellar cortex as reference tissue. CBF values were obtained for 22 cortical grey matter regions and TRT variability (eq.1) was calculated for all metrics. Differences (%) between test and retest measures were assessed using Bland‐Altman analysis and TRT variability for different tracers and between diagnostic groups were compared using Wilcoxon Signed‐Rank and Mann‐Whitney U‐tests.

Result

Average differences (M±SD) between test and retest measures were small for relative measures, [15O]H2O K1/K1’:‐2.0±7.8%, [18F]florbetapir R1:‐1.7±4.1%, [18F]flortaucipir R1:‐0.1±4.2%, but somewhat larger for [15O]H2O K1:‐5.7±14.6%,(Fig.1). In case of [15O]H2O, TRT variability was lower for K1/K1’ than forK1 (p<0.001). Furthermore, [18F]florbetapir and [18F]flortaucipir derived R1 showed lower TRT variability than [15O]H2O K1/K1’ (p<0.001). Only for [18F]flortaucipir, TRT variability was higher in the AD compared with the CN group.

Conclusion

Relative CBF has higher precision than absolute CBF derived from [15O]H2O PET scans. Furthermore, relative CBF proxies derived from commonly used amyloid‐β and tau tracers appear to have an even higher precision, possibly due to the compensatory effect of extraction fraction and/or the older scanner used for [15O]H2O scans.
Polyubiquitination of Tau Increases Across Braak Stages in Alzheimer’s Disease
Authors: Lee Yoo Bin , Kramer Jack , Oh Ian , Li Song Hua , Piergies Antonia M. H. , Xue Jie , Kumar Mukesh , Spina Salvatore , Steen Judith A , Grinberg Lea Tenenholz
Published: December 2022

Background

The proteolytic ubiquitin‐proteasome system (UPS) is a main control mechanism of tau degradation in eukaryotic cells. Although the UPS is an integral regulator for tau turnover in healthy neurons, preliminary data suggests that the pathological tau in Alzheimer’s Disease (AD) is polyubiquitinated. This is an intriguing conundrum where the polyubiquitinylation of tau does not result in the degradation of the protein by the UPS. This suggests that the capacity of the UPS is limited or that the UPS is unable to degrade this form of tau. In this study, we aim to validate this potential correlation between the polyubiquitination of tau and AD, which could perhaps provide more clarity on the specific mechanisms of toxicity for AD.

Method

We examined postmortem brain tissue (inferior temporal gyrus) of 11 cases across AD neuropathological spectrum (Table 1). All slides underwent multiplex immunofluorescence for four antibodies: NeuN (neurons), FK2 (to detect polyubiquitin), T231 (ptau), and GFAP (astroglia), followed by scanning and quantification on digital slides. We quantified the percentage of neurons positive for tau (T231) and polyubiquitination (FK2) and analyzed the spearman correlation and linear regression model (LRM) corrected by age on death and sex.

Result

Cases represent a spectrum of AD stage. As expected, the proportion of neurons with tau inclusions increase along AD progression. We failed to identify neurons positive for FK2 (polyubiquitination) in the absence of tau and neurons. Moreover, we observed a direct correlation between higher Braak Stages and proportion of neurons with polyubiquitin immunoprecipitations (Figure 1, ρ = 0.89, p = 2.33e‐4).

Conclusion

Neurons with polyubiquitin immunoprecipitations increase in number along the AD continuum. These neurons tend to accumulate phospho‐tau inclusions suggesting a polyubiquitination of tau in AD. Further studies are needed to identify the mechanisms underlying the lack of tau degradation by the UPS in this situation, which could lead to treatment opportunities for AD.
Cognitive Impairment in Older Adults with Type 1 Diabetes: Longitudinal data from the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) Study
Authors: Fonseca Luciana Mascarenhas , Kanapka Lauren K , Miller Kellee M , Pratley Richard , Rickels Michael R , Chaytor Naomi S
Published: December 2022

Background

Adults with type 1 diabetes (T1D) are at increased risk for cognitive impairment, accelerated brain aging, and Alzheimer’s disease and related dementias (ADRD). However, longitudinal data on cognitive aging, cognitive impairment and ADRD in adults with T1D are still scarce. The aim of this study was to characterize cognitive impairment in a longitudinal sample of older adults with T1D.

Method

We analyzed data collected as part of the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) Study (Pratley et al., JAMA, 2020; 323(23):2397‐2406), in which 22 endocrinology practices in the United States participated. Participants with T1D ≥ 60 years of age who completed the NIH Toolbox Cognition Battery at two time points (baseline and one year follow up) were included in this study (n = 171). Cognitive impairment was classified using recommendations from Holdnack et al, 2017 (Holdnack et al., Arch Clin Neuropsychol, 2017; 32(5):574‐584).

Result

At baseline, 50% of the participants (N = 86/171) met criteria for cognitive impairment. Of those, 56% (N = 48/86) were still classified as having cognitive impairment a year later (28% of the total sample, N = 48/171). Conversely, 44% (N = 38/86) of the participants classified with impairment at baseline reverted to no impairment by a year. Of those classified as having normal cognition during the baseline assessment, 20% converted to impaired at the follow up (N = 17/85), while 80% (N = 68/85) remained normal.

Conclusion

These data indicate that caution is warranted when assessing cognition in older adults with T1D, as a large percentage of those identified as having cognitive impairment at baseline reverted to normal after a year. Serial cognitive assessment is suggested. Longitudinal research with more diverse samples of older adults with T1D is needed to better understand the clinical utility of the NIH toolbox cognition battery and other neuropsychological assessments in older individuals with T1D.
Investigation of differentially expressed proteins through neurofibrillary tangle maturation in Alzheimer’s disease using NanoString’s GeoMx Digital Spatial Profiler
Authors: Moloney Christina M. , Liu Chia‐Chen , Wickland Daniel P. , Lesser Elizabeth R. , Kachergus Jennifer , Van Blitterswijk Marka M. , Graff‐Radford Neill R. , Dickson Dennis W. , Thompson E. Aubrey , Murray Melissa E.
Published: December 2022

Background

Neurofibrillary tangles are dynamic entities with a lifespan encompassing three maturity levels: intracellular pretangles, intracellular mature tangles, and extracellular ghost tangles. Proteins are suggested to be differentially expressed throughout the tangle lifespan; however, past studies may be limited by spatial expression or number of proteins investigated. We sought to assess differences in protein expression across the tangle lifespan using GeoMxTM Digital Spatial Profiler (DSP) by NanoString, a new technology allowing for spatially derived multiplex investigation.

Method

We used DSP to measure protein expression in hippocampi from Alzheimer’s disease (n=6) and nondemented controls (n=2) using the “Human Neural Cell Profiling Core” and “Alzheimer’s Pathology” module. Regions of interest (ROIs) were classified by the major tangle maturity level recognized by a primary fluorescent conjugated tau antibody. Protein expression was normalized to the geomean of the three housekeeping genes. The tau‐positive segment was specifically analyzed for comparisons. ANOVA was used for group‐wise comparisons and t‐test using the Benjamini‐Yekutieli adjustment for multiple tests was used for pair‐wise comparisons.

Result

As expected, cytoskeletal (e.g., MAP2, Tau) and neuronal (e.g., NeuN) markers generally decreased through the neurofibrillary tangle lifespan (Figure). Markers profiled as neurodegenerative (e.g., amyloid‐β1‐42, APOE, APP) generally increased through tangle maturity levels, except for TDP‐43 which decreased. Interestingly, there was no significant difference in ubiquitin expression. Astrocytic GFAP and S100B expression was significantly increased through each maturity level. Expression of microglial‐specific markers P2RY12 and TMEM119 was significantly elevated in ghost tangles compared to mature tangles. Additional microglial/macrophage markers including Iba‐1 and CD68 were generally increased as neurofibrillary tangles matured. Interestingly, APOE expression remained low in pretangles and mature tangles before dramatically increasing in ghost tangles (Figure).

Conclusion

Our findings suggest that proteins are differentially expressed throughout the tangle lifespan and the majority followed a monotonically directed pattern. Non‐monotonically directed protein patterns may reflect the death of the neuron during the ghost tangle maturity level. Future studies will test the hypothesis that the microenvironment of the hippocampus is altered with increasing vulnerability to tangle pathology.
O‐GlcNAcylation modulates GLUT1 levels at the blood‐brain barrier
Authors: Saiyasit Napatsorn , Bauman Allison J. , Nelson Amy R.
Published: December 2022

Background

Glucose transporter 1 (GLUT1) at the blood‐brain barrier (BBB) is essential for glucose uptake into the brain. Previous studies have shown that GLUT1 levels are reduced at the BBB in Alzheimer’s disease (AD) post‐mortem brain, and perhaps explains the decreased glucose utilization observed in AD (Sweeney et al., Nat Rev Neurol, 2018). Individuals with a genetic reduction of GLUT1, known as GLUT1‐deficiency syndrome, were treated with increased blood glucose with no long‐lasting increase in brain glucose. Diabetes is a risk factor for AD and AD is sometimes referred to as Type‐3 diabetes due to elevated blood glucose levels. Taken together, these ideas provoked us to investigate connections between glucose and GLUT1 levels. Here, we tested if the glucose‐dependent post‐translational modification, O‐linked‐N‐acetylglucosaminylation (O‐GlcNAcylation), is the missing link. We hypothesized that increasing glucose concentrations will elevate O‐GlcNAcylation and decrease GLUT1 levels at the BBB. Furthermore, previous studies have shown that decreased GLUT1 levels result in reduced levels of the low‐density lipoprotein receptor‐related protein‐1 (LRP‐1) (Winkler, Nat Neurosci, 2015). Thus, we also are determining if altering glucose levels not only changes GLUT1 levels, but also other key BBB receptors implicated in AD.

Methods

Mouse brain endothelial (bEnd.3) cells were treated with vehicle (glucose 5.6 mmol), DMSO, the O‐GlcNAcase inhibitor Thiamet‐G (TMG, 1 µM), or the O‐GlcNAc transferase inhibitor OSMI‐1 (20 µM), for 24 and 48 hours. Next, the protein expression of O‐GlcNAc and GLUT1 were measured by western blot.

Results

As previously reported, TMG increased and OSMI‐1 decreased O‐GlcNAcylation at both 24 and 48 h, compared to vehicle. Notably, TMG treatment significantly reduced and OSMI‐1 increased GLUT1 expression at both time points.

Conclusion

GLUT1 levels are modulated through O‐GlcNAcylation at BBB. When blood glucose levels are high, O‐GlcNAcylation will be high, thereby reducing GLUT1 at the BBB and brain glucose uptake. This is likely a homeostatic mechanism to prevent spikes in brain glucose levels when blood sugar levels are elevated.
Dual‐tracer assessment of CBF and early amyloid uptake of Alzheimer’s disease using 15O‐water and amyloid PET
Authors: Zhao Moss , Chen Kevin , Khalighi Mehdi , Mormino Elizabeth C. , Zaharchuk Greg
Published: December 2022

Background

Reduced CBF and amyloid update measured by PET imaging have been reported among Alzheimer’s disease (AD) patients. Evidence suggested that early amyloid update may reflect the underlying CBF information. In this pilot study, we aimed to compare whether early uptake amyloid PET images can be used to estimate CBF, by comparing them with gold‐standard 15O‐water PET CBF images.

Method

Data were collected from an AD patient (female, 74 years) and a normal subject (female, 75 years) using a simultaneous 3T PET/MRI system and injection of 775 MBq of 15O‐water followed by 330 MBq of the amyloid radiotracer 18F‐florbetaben. CBF was computed by fitting the reconstructed PET data to a one‐compartment pharmacokinetic model using an image‐derived AIF. The amyloid PET data were reconstructed from time of injection to 1 and 5 minutes post‐injection yielding two short early duration uptake images, with the OSEM reconstruction parameters set as 2 iterations, 28 subsets, and a 4mm Gaussian post‐reconstruction filter. All images were transformed to the MNI‐152 2mm standard space using non‐linear registration.

Result

The figure shows the measured CBF and amyloid PET maps of the patient and normal subject. In the AD patient, a CBF deficit is present in the posterior biparietal regions (indicated by the arrows), in contrast with other regions. This characteristic CBF deficit is not seen in the normal subject.

Conclusion

With further investigation and quantification in various tracers and participant populations, using early dynamic data acquired with amyloid PET tracers could be a potential tool for measuring CBF
Distinctive age‐related longitudinal dementia progression patterns using a machine‐learning‐based MRI biomarker
Authors: Ma Da , Popuri Karteek , Wang Lei , Lockhart Samuel N. , Craft Suzanne , Gurcan Metin Nafi , Beg Mirza Faisal
Published: December 2022

Background

Dementia of Alzheimer’s type (DAT) is an age‐related neurodegenerative syndrome caused by Alzheimer’s disease. The risk of developing dementia increases with age, but also depends on disease trajectory. In this study, we aim to evaluate the effect of normal aging on the MRI‐derived dementia risk score and investigate the distinctive age‐related longitudinal dementia progression patterns among individuals with different dementia trajectories.

Method

A total of 1609 participants with multi‐timepoint neuroimaging tests and diagnoses were recruited from the ADNI. Based on their dementia trajectories, the subjects were stratified into four groups: stable normal cognition (sNC=423), stable/progressive mild cognitive impairment (sMCI=535/pMCI=321), and stable dementia of Alzheimer’s type (sDAT=330). Brain structures were automatically segmented and harmonized to control the confounding effect of sex and scanner, and feed into an extensively‐validated kernel‐based ensemble classifier to derive the score, which we termed longitudinal MR‐DAT‐Score (MRDATS). The CSF‐based biomarker was derived as the ratio between the total tau and the amyloid beta (t‐tau/Aβ1‐42). We analyzed the effect of aging on the biomarkers’ distribution of each stratified group in terms of their empirical cumulative distribution function (ECDF). We also evaluated the difference in longitudinal MRDATS progression patterns among different groups.

Result

Compared to the CSF biomarker, the MRDATS revealed a more distinctive age‐related risk increase among all stratified groups (Figure 1). In addition, the effect of aging persists across both the non‐progression groups (sNC and sMCI) and the progression groups (pMCI) except for the DAT group, where the age‐related effect is only observable for the 80‐90 years’ group. Distinctive longitudinal dementia risk progression patterns (in terms of MRDATS) were also observed for each stratified group (Figure 2). Specifically, for patients with mild cognitive impairment (MCI), distinctive patterns were observed between sMCI and pMCI across subjects across different aged populations.

Conclusion

Our study demonstrated the differential aging effect pattern as well as distinctive longitudinal patterns between AD‐progressive and non‐progressive subjects across different age groups. The results of this study emphasize the importance of disentangling the effect of aging with the disease‐driven brain atrophy patterns.
A qualitative study of older refugees’ perception and attitudes towards dementia and dementia risk reduction during the COVID‐19 pandemic
Authors: Al‐Rousan Tala , Awad Mina , Sideman Alissa Bernstein , Moore Alison A.
Published: December 2022

Background

The COVID‐19 pandemic continues to worsen economic inequality, political unrest and violence resulting in unprecedented numbers of refugees and asylees globally. Various stressors related to forced displacement may impact cognitive function as refugees age in hosting countries. However, little is known about how forced displacement impacts perceptions and attitudes towards dementia and dementia risk reduction.

Method

In‐depth interviews with 61 older refugees aged 55‐86 who were resettled in San Diego, California from Iraq and Syria, conducted between April‐December of 2021. A phenomenological long‐table approach was used to identify themes and categorize data on dementia knowledge, risk and attitudes.

Result

The mean age of participants was 64.61 (SD: 7.19), 50.82% were female, 14.75% were employed, Median income was USD $15,001 ‐ %25,000, median years since resettlement was 8 (SD7.06), 32.79% reported they could read and write English, 81.97% were Iraqis, 80.33% were married was. 16.39% have contracted COVID‐19, and 85.25% reported being more forgetful since the pandemic started. Participants' responses about their attitudes about dementia were classified into three distinctive thematic domains: fear, acceptance, and practical challenges. Participants identified fear of developing dementia and the need to improve dementia knowledge as major motivators towards adopting healthier lifestyle and health behaviors. Acceptance emerged in relationship to the following areas: 1) religious; aging mentioned in the holy books as an experience associated with feelings of humiliation and helplessness, 2) cultural; dementia as an unavoidable part of normal aging, 3) experiential; displacement and war‐related trauma increase risk of dementia. Practical challenges included the lack of age‐friendly and trauma‐informed care and services available for refugees which were identified as a major barrier for preventive, behavioral and lifestyle change.

Conclusion

These findings can be used to develop effective and refugee‐focused interventions that increase motivators and reduce barriers by tailoring interventions to refugees’ dementia risk reduction literacy and motivations to change behaviors.
Worse objective and subjective sleep‐wake metrics are associated with locus coeruleus hypopigmentation: a retrospective post‐mortem study
Authors: Van Egroo Maxime , Jacobs Heidi I.L.
Published: December 2022

Background

The brainstem locus coeruleus (LC) was recently put forward as a key nucleus to connect early sleep‐wake disruption and Alzheimer’s disease (AD) pathophysiological processes. Here, we sought to investigate the relationships between post‐mortem LC hypopigmentation, reflecting LC neurodegeneration, and retrospective subjective/objective sleep‐wake regulation metrics in two longitudinal datasets.

Method

LC pigmentation ratings were extracted from autopsy data across 517 Rush Memory and Aging Project (MAP) and 637 National Alzheimer’s Coordinating Center (NACC) cases. Actigraphy‐derived intradaily variability, an objective measure of rest‐activity rhythm fragmentation, was obtained in the MAP dataset, and subjective evaluations of sleep quality were retrieved from the NACC cohort. For both studies, sleep‐wake measures were extracted at the furthest and closest available time points, on average 6.8 y. and 2.5 y. before death, respectively. Logistic regressions adjusted for age at death, sex, race, and post‐mortem interval were used to assess whether sleep‐wake variables could predict post‐mortem LC pigmentation ratings. In the next step, additional models including AD‐related variables of APOE genotype and cortical neuropathology (amyloid‐beta and tau burden) were further performed to test for independence in the relationships between sleep‐wake measures and LC pigmentation.

Results

In the MAP cohort, higher rest‐activity rhythm fragmentation at both time points was significantly associated with greater odds of LC hypopigmentation at autopsy (Table 1). In models considering additional AD‐related variables, these relationships remained significant independently of the effects of APOE and cortical AD neuropathology (Table 1). In the NACC dataset, worse subjective sleep quality at the closest time point, but not at the furthest, was significantly linked to greater odds of LC hypopigmentation at autopsy (Table 2). Likewise, additional models indicated that this relationship is independent of APOE and cortical AD neuropathology (Table 2).

Conclusion

These findings highlight the utility of evaluating sleep and wakefulness, especially with objective measurements, to predict LC neurodegenerative processes in older populations, as far as 6.8 years before death and beyond the effects of APOE genotype and cortical AD neuropathology. Our results thus have implications for improved detection of at‐risk individuals.
Sex differences in white matter microstructure in aging and Alzheimer’s disease: A multi‐site free‐water imaging study
Authors: Archer Derek B , Shashikumar Niranjana , Jasodanand Varuna , Moore Elizabeth E. , Pechman Kimberly R. , Bilgel Murat , Beason‐Held Lori L , An Yang , Shafer Andrea T , Risacher Shannon L. , Landman Bennett A. , Jefferson Angela L. , Saykin Andrew J. , Resnick Susan M. , Hohman Timothy J. ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2022

Background

Sex differences in gray matter alterations in aging and AD have been reported, but there have been few large‐scale studies evaluating white matter microstructure. The goal of this study is to leverage multi‐site harmonized diffusion MRI data in tandem with free‐water (FW) imaging to determine the association between sex and white matter microstructure in aging and AD.

Method

The dataset used in this study leveraged cross‐sectional data from several cohorts of aging [Alzheimer’s Neuroimaging Initiative (ADNI), Baltimore Longitudinal Study of Aging (BLSA), Vanderbilt Memory & Aging Project (VMAP)]. This dataset included 1,898 participants (72±9 years, 59% female). Data was processed using standard preprocessing techniques and followed up with FW postprocessing. FW and FW‐corrected intracellular metrics of fractional anisotropy (FAT), radial diffusivity (RDT), and axial diffusivity (ADT) were then quantified within seven white matter tractography templates (see Figure 1A) and harmonized using the ComBat technique. The sex differences for each microstructural metric were then determined using a linear regression model covarying for age, diagnosis, education, and APOE‐ε4 carrier status. Secondary analyses were conducted to determine sex x diagnosis interactions on white matter microstructure.

Result

While we found no sex differences in FW, there were significant associations in all intracellular metrics. Females had significantly lower FAT in the association (pFDR=6.62x10‐10), limbic (pFDR=5.28x10‐9), motor transcallosal (TC) (pFDR=0.008), prefrontal TC (pFDR=6.34x10‐6), and projection (pFDR=4.74x10‐20) tracts and significantly lower ADT in the association (pFDR=5.23x10‐10), limbic (pFDR=1.84x10‐6), prefrontal TC (pFDR=4.41x10‐11), and projection (pFDR=5.29x10‐17) tracts. For RDT, females exhibited higher RDT in all tracts (pFDR range: 4.94x10‐16 – 0.022). Illustrations of these results can be found in Figure 1. Sex differences were compared across cohorts and were similar (Figure 2). The only significant sex x diagnosis interaction was for the projection tract RDT measure (pFDR=0.043, Figure 3).

Conclusion

This study suggests intracellular microstructural values (i.e., FAT, ADT, RDT) exhibit strong sex differences, whereby females have lower FAT/ADT and higher RDT compared to males. We also found a sex x diagnosis interaction for projection tract RDT, whereby females with AD exhibited lower RDT, but larger studies with more AD cases would be needed to further explore this finding.
White matter hyperintensities in Down syndrome: associations with demographic, genetic, fluid and imaging biomarkers of Alzheimer's disease
Authors: Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E. , Carmona‐Iragui Maria , Montal Victor , Pegueroles Jordi , Aranha Mateus Rozalem , Padilla Concepcion , Benejam Bessy , Videla Laura , Barroeta Isabel , Fernandez Susana , Altuna Miren , Giménez Sandra , González‐Ortiz Sofía , Bargalló Núria , Ribas Laia , Arranz Javier , Torres Soraya , Iulita Maria Florencia , Belbin Olivia , Camacho Valle , Alcolea Daniel , Blesa Rafael , Lleó Alberto , Fortea Juan , Bejanin Alexandre
Published: December 2022

Background

Strong associations between age, Alzheimer’s disease (AD), and vascular risk factors create challenges to delineate the specific relationships between white matter hyperintensities (WMH) and AD pathophysiology. Down syndrome (DS), a genetically determined form of AD, is not typically complicated by systematic vascular risk factors like hypertension and atherosclerosis and can therefore provide critical information in this regard. We aim to further characterize topography of WMH in DS along the AD continuum and define associations with demographic, genetic, fluid and other imaging biomarkers.

Method

In this cross‐sectional study, adults with DS from Down‐Alzheimer Barcelona Neuroimaging Initiative (DABNI) underwent a 3T‐MRI protocol, including 3D‐T1 and 3D‐FLAIR acquisitions. Gray matter (GM) volumes were computed using the CAT12 Toolbox. WMH were segmented using the lesion prediction algorithm implemented in the Lesion Segmentation Toolbox for SPM12. Segmented maps were binarized (threshold of 0.5) and WMH volumes were extracted in each brain lobe, subregions of the corpus callosum, and periventricular versus deep regions (using the standard 10mm limit from the lateral ventricles). Non‐parametric statistical tests were used to assess effects of disease severity on WMH and define associations between WMH and demographic and genetic data, CSF AD biomarkers and GM volumes.

Results

We included 116 individuals with DS (Table 1). WMH volume was higher in prodromal and demented groups for all brain regions (Fig 1). Moreover, WMH increased with disease severity such that the demented group demonstrated larger WMH volume than the prodromal group in periventricular regions, frontal and temporal lobes, and body and splenium subregions of the corpus callosum. Total WMH volume was associated with age but not sex, intellectual disability or APOE haplotype (Fig 2). Total WMH volume was negatively related to CSF Aβ42/40 ratio and positively related to CSF t‐tau and p‐tau‐181 concentrations (Fig 3). Associations with GM volumes were widespread, but strongest in parieto‐occipital‐temporal regions.

Conclusion

WMH increases with AD pathology and the emergence of clinical symptoms in DS, a population with lower vascular risk factors. It also relates to neurodegeneration in typical AD regions at both asymptomatic and symptomatic stages. Altogether, this suggests that WMH might be intrinsically related to AD pathophysiological processes.
Non‐amnestic initial cognitive symptoms have faster trajectories of clinical progression than amnestic symptoms in Alzheimer’s, Lewy body and mixed dementia neuropathologies
Authors: Pillai Jagan A. , Bena James , Leverenz James B.
Published: December 2022

Background

Diagnostic guidelines currently exist for typical and atypical Alzheimer’s disease (AD). Significant heterogeneity exists among initial predominant clinical symptoms among Lewy body‐related pathology (LRP) in addition to primary AD pathology (ADP) and. However, the clinical relevance of initial amnestic or non‐amnestic cognitive symptoms among them are unclear. Our objective was to determine if initial cognitive symptoms had similar rates of functional decline across ADP, LRP and mixed ADP‐LRP neuropathologies.

Method

A retrospective longitudinal cohort study was conducted among 2422 participants with autopsy confirmed ADP, LRP, or mixed ADP‐LRP in the National Alzheimer Coordinating Center database from June 20, 2005, to September 4, 2019. All participants had a Clinical Dementia Rating‐Global (CDR‐G) scale ≤1 at initial clinical visit. The primary outcome of interest was Clinical Dementia Rating‐sum of boxes (CDR‐SB). Linear mixed models adjusted for baseline CDR‐SB, age, sex, education and APOEε4 status were used to evaluate longitudinal outcomes. Multiple imputations using fully conditional specification was performed to account for missing data in the multivariable models

Result

2422 Participants (1187 with ADP, 904 with ADP‐LRP and 331 with LRP) had a mean (SD) interval of 5.5 (2.8) years from initial visit to autopsy. Language symptoms had a consistently faster rate of decline per year than amnestic symptoms across all three pathologies (ADP, β 0.29, [95%CI, 0.16 to 0.41], p<0.001; LRP, β 0.69 [95%CI, 0.44 to 0.94], p<0.001;ADP‐LRP, β 0.40, [95%CI, 0.22 to 0.57], p<0.001). Executive symptoms had a faster rate of decline than amnestic symptoms in ADP, β 0.36, [95%CI, 0.21 to 0.51], p<0.001 and ADP‐LRP, β 0.25 [95%CI, 0.07 to 0.42], p = 0.008. Visuospatial symptoms had a faster rate of decline than amnestic symptoms in ADP‐LRP, β 0.38 [95%CI, 0.12 to 0.65], p = 0.013.

Conclusion

Non‐amnestic phenotypes have faster trajectories of clinical progression than amnestic across three pathology subgroups. Language phenotypes have the fastest progression.
Higher arterial stiffness and systolic blood pressure are differentially associated with lower perfusion in subcortical and cortical gray matter regions
Authors: Lipford Megan E. , Lockhart Samuel N. , Coffin Claudia Ashlyn , Suerken Cynthia , Bateman James R. , Barcus Richard A. , Whitlow Christopher T. , Craft Suzanne , Hughes Tim M.
Published: December 2022

Background

Higher arterial stiffness is associated with lower regional cerebral blood flow (CBF) in older adults. Cortical CBF also correlates with higher systolic blood pressure (SBP). We examined relationships of lobar and deep gray matter CBF with both SBP and arterial stiffness.

Method

Participants of the Clinical Core of the Wake Forest Alzheimer’s Disease Research Center completed baseline clinical examination including measures of: arterial stiffness, blood pressure, medication review, APOE genotyping, 3T MRI, detailed cognitive testing, and cognitive adjudication. T1 structural and pseudocontinuous arterial spin labeling (pcASL) MRI were used to quantify gray matter (GM) CBF in AAL atlas regions. GM CBF was quantified into lobar (frontal, temporal, parietal, occipital), subcortical (caudate, putamen, pallidum, and thalamus), Cingulate/Insula, and posterior (cerebellum and vermis) regions. Arterial stiffness was measured twice in the supine position and averaged to quantify carotid‐femoral pulse wave velocity (cfPWV). Associations for cfPWV and systolic blood pressure (SBP) with GM CBF ROIs was examined by multivariable linear regression models adjusted for age, race, gender, education, hypertension medications, and APOE‐e4 carrier status.

Result:

Among 404 participants (70±8 years; 39 dementia, 139 MCI, 226 normal cognition), higher cfPWV and SBP were differentially associated with regional GM CBF (Fig 1 & 2). Higher cfPWV was associated with lower subcortical GM CBF (p=0.04) (Table 1). Higher SBP was associated with lower GM CBF in frontal (p=0.03), temporal (p=0.02) and occipital lobes (p=0.01) (Table 1).

Conclusion

Deep subcortical brain structures may be at greater risk of damage from high arterial stiffness because they are perfused by arteries which branch relatively upstream of other branching arteries, as evidenced by lower GM CBF. High SBP may predict vascular damage in cortical regions manifested as lower GM CBF. These differential relationships with deep and cortical perfusion support and extend prior observations in this group relating vascular risk factors to abnormalities in white matter micro‐ and macro‐ structure, lower total CBF, and lower cognitive performance.
Higher arterial stiffness and systolic blood pressure are differentially associated with lower perfusion in subcortical and cortical gray matter regions
Authors: Lipford Megan E. , Lockhart Samuel N. , Coffin Claudia Ashlyn , Suerken Cynthia , Bateman James R. , Barcus Richard A. , Whitlow Christopher T. , Craft Suzanne , Hughes Tim M.
Published: December 2022

Background

Higher arterial stiffness is associated with lower regional cerebral blood flow (CBF) in older adults. Cortical CBF also correlates with higher systolic blood pressure (SBP). We examined relationships of lobar and deep gray matter CBF with both SBP and arterial stiffness.

Method

Participants of the Clinical Core of the Wake Forest Alzheimer’s Disease Research Center completed baseline clinical examination including measures of: arterial stiffness, blood pressure, medication review, APOE genotyping, 3T MRI, detailed cognitive testing, and cognitive adjudication. T1 structural and pseudocontinuous arterial spin labeling (pcASL) MRI were used to quantify gray matter (GM) CBF in AAL atlas regions. GM CBF was quantified into lobar (frontal, temporal, parietal, occipital), subcortical (caudate, putamen, pallidum, and thalamus), Cingulate/Insula, and posterior (cerebellum and vermis) regions. Arterial stiffness was measured twice in the supine position and averaged to quantify carotid‐femoral pulse wave velocity (cfPWV). Associations for cfPWV and systolic blood pressure (SBP) with GM CBF ROIs was examined by multivariable linear regression models adjusted for age, race, gender, education, hypertension medications, and APOE‐e4 carrier status.

Result

Among 404 participants (70±8 years; 39 dementia, 139 MCI, 226 normal cognition), higher cfPWV and SBP were differentially associated with regional GM CBF (Fig 1 & 2). Higher cfPWV was associated with lower subcortical GM CBF (p=0.04) (Table 1). Higher SBP was associated with lower GM CBF in frontal (p=0.03), temporal (p=0.02) and occipital lobes (p=0.01) (Table 1).

Conclusion

Deep subcortical brain structures may be at greater risk of damage from high arterial stiffness because they are perfused by arteries which branch relatively upstream of other branching arteries, as evidenced by lower GM CBF. High SBP may predict vascular damage in cortical regions manifested as lower GM CBF. These differential relationships with deep and cortical perfusion support and extend prior observations in this group relating vascular risk factors to abnormalities in white matter micro‐ and macro‐ structure, lower total CBF, and lower cognitive performance.
A Genome‐Wide Search for Pleiotropy in Cognitive Domain Scores
Authors: Kang Moonil , Mez Jesse B. , Ang Ting Fang Alvin , Devine Sherral A. , Mukherjee Shubhabrata , Trittschuh Emily H. , Saykin Andrew J. , Crane Paul K. , Au Rhoda , Lunetta Kathryn L. , Farrer Lindsay A.
Published: December 2022

Background

Genome‐wide association studies (GWASs) have identified loci for Alzheimer’s disease (AD)‐related cognitive traits, and genetic correlations among these traits suggest that a single gene may affect them jointly, i.e., pleiotropy.

Method

We conducted GWASs for scores previously generated by factor analyses for cognitive domains—executive function, language, and memory—using longitudinal data from 7,503 Framingham Heart Study (FHS) and 6,758 National Alzheimer’s Coordinating Center (NACC) subjects who had an average of five and three exams, respectively. We averaged domain scores for each participant by weighting down scores at the visit without normal cognition and used the sum of weights to account for heterogeneous residual variances. The association of each domain score with 8.9 million genetic variants (MAF>0.01), imputed using the TOPMed reference panel (GRCh38), was tested separately in each dataset using linear models including age, sex, education level, and five principal components of ancestry as covariates. Results from FHS and NACC datasets were combined by meta‐analyses using the inverse‐variance method. Pleiotropy for each pair of cognitive domains was evaluated using PLACO (pleiotropic analysis under the composite null hypothesis).

Result

Scores for paired cognitive domains were moderately genetically correlated—executive function and language (ρP
=0.46, ρG
=0.69), executive function and memory (ρP
=0.39, ρG
=0.43), language and memory (ρP
=0.44, ρG
=0.46). Pleiotropy analyses revealed genome‐wide significant associations for all paired domain scores with many variants in the APOE region (p<3.91×10‐9 for each). For pleiotropy of executive function and language, we identified genome‐wide significant associations with DOK5 (rs28663252, p=4.51×10‐8) and suggestive associations with SOX14 (rs55829884, p=8.03×10‐8), IL20RB (rs11925531, p=9.26×10‐8), and RIMS2 (rs140291972, p=8.76×10‐7). We also found suggestive associations for pleiotropy of language and memory with LHFPL4 (rs2936482, p=5.08×10‐8) and for pleiotropy of executive function and memory with MC4R (rs1943220, p=7.54×10‐8) and CDH20 (rs78756286, p=1.50×10‐7).

Conclusion

We identified significant evidence of pleiotropy for multiple cognitive domains, and these findings may improve the interpretation of the genetic basis of cognition and AD‐related traits. These results highlight the benefits of factor scores derived from groups of subjects assessed with various cognitive tests and pleiotropy analysis as a tool for identifying genes that contribute to performance in multiple cognitive domains.
Dementia neuropsychiatric prevalence, severity, and correlates in community‐dwelling Thai older adults
Authors: Hinton Ladson , Wang Kaipeng , Levkoff Sue E , Chuengsatiansup Komatra , Sihapark Siranee , Gallagher‐Thompson Dolores , Chen Hongtu
Published: December 2022

Background

Thailand is experiencing a rapid increase in the number of older persons with dementia, yet little is known about the nature and consequences of dementia neuropsychiatric symptoms (NPS), particularly outside of clinical settings. We examined the prevalence, severity, and correlates of NPS, including correlation with family caregiver burden and distress, among community‐dwelling Thai older adults with probable dementia.

Methods

This study is based on analysis of baseline data from a hybrid type III cluster randomized design comparing two different implementation approaches of an evidence‐based exercise intervention for persons with dementia. A three‐step recruitment process was used for recruiting participants from the local healthcare system and included clinical case confirmation of probable degenerative dementia. To be eligible, participants needed to be age 60 and above, have probable dementia, have 1 or more NPS, be ambulatory, and have an adult (age 18+) family caregiver. 353 participants enrolled in the study and completed based assessments, including NPS assessment, caregiver stress associated with NPS, as well as other care recipient and caregiver characteristics. We examined NPS severity with caregiver distress and used ordinary least squares (OLS) regression to examine associations between PWD and caregiver characteristics and NPS severity.

Results

NPS prevalence varied from 18% for appetite/eating changes to 42% for delusions. NPS severity was significantly (P < .05) associated with caregiver stress for all individual NPS. Among PWD characteristics, higher ADL score (less functional impairment) was inversely associated with NPS total severity (b = ‐0.16, p < 0.05). More physical role limitation was significantly associated with higher NPS total severity (b = 0.77, p < 0.001). Among caregivers’ characteristics, higher burden was significantly associated with higher NPS total severity (b = 0.19, p < 0.001).

Conclusions

Our study found that NPS are common among community dwelling PWD in Thailand and are associated with adverse impacts on both PWD and family caregivers. These findings highlight the clinical importance of NPS symptoms among Thai older adults. The high prevalence of psychotic symptoms in this community sample is noteworthy and deserves further attention. Results of the parent intervention study will be reported in 2023.