bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential gray matter connectivity correlates of CSF biomarkers: Results from the EPAD Cohort
Authors: Lorenzini Luigi , Ingala Silvia , Wottschel Viktor , Wink Alle Meije , Mutsaerts Henk‐Jan , Haller Sven , Blennow Kaj , Frisoni Giovanni B. , Chetelat Gaël , Payoux Pierre , Martinez‐Lage Pablo , Waldman Adam , Wardlaw Joanna M. , Ritchie Craig W. , Gispert Juan Domingo , Visser Pieter Jelle , Scheltens Philip , Tijms Betty M. , Barkhof Frederik 
Published: February 2022

AbstractBackgroundGray matter network (GMN) disruptions correlate with amyloid burden in the earliest stages of Alzheimer’s Disease (AD) pathology in cognitively unimpaired individuals. However, it remains unknown if and how hyperphosphorylated tau (p‐tau) influences GMNs. Here, we investigated the relation between GMNs and cerebrospinal fluid (CSF) p‐tau181 levels in non‐demented individuals from the European Prevention of Alzheimer Dementia (EPAD) cohort and evaluated whether this relationship is mediated by amyloid and Clinical Dementia Rating (CDR) status.MethodWe included 1198 participants from the EPAD v1500.0 release, who had both CSF biomarkers and structural MRI available. The cut‐off for amyloid‐β positivity (A+) was defined at <1000 pg/mL. Single‐subject network properties were extracted from 3D‐T1w MRI (Figure 1). Regional values were computed for 117 AAL atlas regions. Linear models were used to investigate main effects and interactions between amyloid status and p‐tau181 levels on global GMN measures. A three‐way interaction with CDR was modeled. Age, sex, site, total intracranial volume, and network size were included as covariates. Analyses were repeated for local network properties across AAL regions and FDR‐adjusted.ResultSample characteristics are provided in Table 1. A+ individuals had lower degree, clustering, gamma, and small world coefficients, and higher betweenness centrality (Figure 2). Higher p‐tau181 levels were associated with lower values of degree, betweenness centrality, lambda, and path length (Figure 3). Lambda, path length, and clustering showed an interaction effect of amyloid status and CDR on their relationship with p‐tau181 levels: A‐ individuals with CDR 0 had lower path length and lambda in association with tau, while A+ CDR 0.5 individuals with lower clustering coefficient values showed higher p‐tau181 (Figure 4). No associations were found for other GMN measures. Regional analysis showed a relationship of p‐tau181 with local path length in the precuneus (Figure 5).ConclusionGMN alterations show distinct associations with p‐tau181 levels, partially affected by amyloid and CDR status. Non‐amyloid related alterations of path length might be linked to axonal tau‐related changes. Clustering alterations seem instead to be linked to amyloid deposition and resulting local synaptic disconnectivity.
Clinical evaluation of SPARE‐TauAD, an AV‐1451‐derived tau index
Authors: Toledo Jon B. , Liu Hangfan , Rashid Tanweer , Habes Mohamad 
Published: February 2022

AbstractBackgroundThe deposition of abnormal proteins defines neurodegenerative diseases. Among these proteins, tau deposits define frontotemporal lobar degeneration (FTLD) tau, and together with Aβ, it defines the more prevalent Alzheimer’s disease (AD). PET scans with ligands binding AD tau neurofibrillary tangles (NFT) topographically quantify the amount of pathology. However, for clinical purposes, this information needs to be summarized into easily applicable and meaningful indices. Here we develop a machine learning‐derived tau PET index, the Spatial Pattern of Abnormality for Recognition of Tau in AD (SPARE‐TauAD).Method603 subjects were included in the study. Their clinical diagnoses were: 366 cognitively normal (CN), 177 mild cognitive impairment (MCI), and 60 dementia subjects. These subjects were classified as Aβ positive and negative based on CSF Aβ1‐42 levels or florbetapir PET summary composite. SPARE‐TauAD was derived using a support vector machine classifier comparing AV‐1451 PET scans in 141 Aβ negative CN subjects against 108 Aβ positive MCI and dementia subjects. We then evaluated its association with CSF t‐tau, global cognition (measured using ADAS‐Cog 13), clinical diagnosis, and clinical progression.ResultSPARE‐TauAD and CSF t‐tau showed a moderate correlation (rho=0.51, p<0.0001). SPARE‐TauAD explained a larger variance of ADAS‐Cog13 scores (R2=0.60) compared to CSF t‐tau (R2=0.21) and the florbetapir PET summary composite (R2=0.23). Using 5‐fold cross‐validation in an independent sample of Aβ negative CN subjects (n=77) against Aβ positive MCI and dementia subjects (n=35 for CSF), SPARE‐TauAD showed higher balanced accuracy (79.6%) compared to CSF t‐tau (61.6%). SPARE‐TauAD was also associated with faster progression from CN to MCI/dementia (H.R.=6.83, p‐value<0.0001) and MCI to dementia (H.R.=3.43, p‐value<0.0001). Whereas CSF t‐tau was no associated with clinical progression.ConclusionSPARE‐TauAD showed, as expected, a moderate association with CSF t‐tau. However, it offered better cross‐sectional classification accuracy and correlation with cognitive scores. It also outperformed CSF t‐tau to predict longitudinal progression in this small with limited longitudinal follow‐up. One limitation is that the SPARE‐TauAD index has been developed in an AD MCI and dementia cohort. The used tau ligand, AV‐1451, has a greater affinity for NFT present in AD than tau pathology present in FTLD‐tau.
Microglial activation and atrophy in frontal cortex predict executive dysfunction in frontotemporal dementia
Authors: Malpetti Maura , Jones P. Simon , Hezemans Frank H. , Mak Elijah , Street Duncan , Passamonti Luca , Rittman Timothy , Cope Thomas E. , Bevan‐Jones W. Richard , Patterson Karalyn , Fryer Tim D. , Hong Young T. , Aigbirho Franklin I. , O'Brien John T. , Rowe James B. 
Published: February 2022

AbstractBackgroundFrontotemporal dementia is clinically and neuropathologically heterogeneous, but atrophy, neuroinflammation, and executive dysfunction occur in each of the principal variants. Across the clinical spectrum of frontotemporal dementia, we assessed the predictive value of in vivo neuroimaging measures of grey‐matter volume (from structural MRI) and microglial activation (from [11C]PK11195 PET) on the rate of future executive decline. We hypothesised a detrimental effect of inflammation and atrophy severity on executive dysfunction progression.MethodThirty patients with frontotemporal dementia underwent a baseline multi‐modal imaging assessment, including [11C]PK11195 PET to index microglial activation and structural MRI for atrophy, as part of the Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study. Cognitive impairments were assessed at baseline and serially for up to 5 years with the revised Addenbrooke's Cognitive Examination (ACE‐R). Regional grey‐matter volumes and [11C]PK11195 binding potentials were averaged in four regions of interest: left and right frontal and temporal lobes. Linear mixed models were applied to the longitudinal ACE‐R attention/executive sub‐score. Regional CSF‐corrected PET values and TIV‐corrected grey‐matter volumes were included in linear mixed models as predictors, with age and education as covariates. Specifically, negative associations of atrophy and inflammation with annual rate of executive decline were tested.ResultPatients showed a mean 3.3‐point loss per year on the ACE‐R attention/executive sub‐score (p<0.001, Figure 1). Faster decline in ACE‐R was associated with reduced baseline grey‐matter volume of the left frontal lobe (beta=1.000, SE=0.285, p=0.000789, p‐FDR= 0.00316; Figure 2) and increased inflammation in frontal regions bilaterally (Left: beta=‐0.722, SE=0.251, p=0.00528, p‐FDR=0.0105, Figure 2; Right: Estimate=‐0.623, SE=0.256, p=0.0175, p‐FDR=0.0233). These associations remain significant when including both left frontal grey‐matter volume and [11C]PK11195 binding as predictors in the same model, and after controlling for baseline attention/executive scores. In these regions, grey‐matter volumes and inflammation levels were negatively correlated (left: r=‐0.414, p<0.001; right: r=‐0.374, p<0.001).ConclusionImaging markers for atrophy and microglial activation provide useful and independent information to evaluate and stratify patients with frontotemporal dementia. This may improve cohort selection in clinical trials and highlights the potential for immunomodulatory treatment strategies in frontotemporal dementia.
[18F]RO948 tau PET in bvFTD due to C9orf72 and GRN mutations
Authors: Leuzy Antoine , Santillo Alexander , Smith Ruben , Groot Colin , Ossenkoppele Rik , Hansson Oskar 
Published: February 2022

AbstractBackgroundThe behavioral variant of frontotemporal dementia (bvFTD) is characterized by marked changes in personality and behaviour. Approximately 30% of cases are genetic in nature and most commonly due to autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN) genes resulting in TAR DNA‐binding protein 43 (TDP‐43) pathology. Several tau positron emission tomography (PET) studies using [18F]flortaucipir have shown conflicting results regarding tracer retention in bvFTD due to C9orf72 (bvFTD‐C9orf72) and GRN (bvFTD‐GRN) mutations. To date, no studies in bvFTD due to either mutation have been conducted using the novel tau tracer [18F]RO948.MethodEight patients meeting criteria for definite bvFTD were included from the Swedish BioFINDER‐2 study, including seven C9orf72 expansion carriers and one with a GRN mutation. Standardized uptake value ratio (SUVR) images of [18F]RO948 PET were created using 70‐90 post‐injection data and the inferior cerebellar cortex as reference region. Age and sex matched CU individuals (n=9) and patients with Alzheimer’s disease (AD) dementia (n=9) were included for comparison. [18F]RO948 retention in bvFTD mutation carriers was also assessed relative to a larger Aβ‐negative CU group (n=50) using age‐adjusted voxelwise t‐tests.ResultBvFTD‐C9orf72 patients were on average 63 years of age (range 53‐72) and 57% were female. The bvFTD‐GRN patient was a 69‐year‐old male. Comparison of SUVR images showed that [18F]RO948 retention levels in bvFTD mutation carriers were similar to those seen in Aβ‐negative CU individuals (Figure 1). Voxelwise t‐tests showed no significant differences in comparison to the Aβ‐negative CU group. Similar findings were seen using a composite frontal region of interest (ROI) and when using the brainstem as reference instead of the inferior cerebellar cortex.ConclusionThese preliminary findings suggest that [18F]RO948 signal is specific for AD‐type tau and does not capture TDP‐43 type pathology.
White matter hyperintensities and regional tau‐PET signal independently contribute to cognitive deficits in symptomatic patients on the Alzheimer’s disease continuum
Authors: Edwards Lauren , Iaccarino Leonardo , Tanner Jeremy A , Cobigo Yann , Pham Julie Q. , Rosen Howard J. , Soleimani‐Meigooni David N. , Strom Amelia , Wolf Amy , Kramer Joel H , Miller Bruce L. , Rabinovici Gil D. , La Joie Renaud 
Published: February 2022

AbstractBackgroundWe examined the associations of white matter hyperintensities (WMH), amyloid‐PET, and tau‐PET with multi‐domain cognitive performance in symptomatic patients on the Alzheimer’s disease (AD) continuum.Method119 amyloid‐PET‐positive patients diagnosed with MCI or AD dementia underwent 3‐Tesla structural MRI, 18F‐flortaucipir (tau)‐PET,11C‐PIB (amyloid)‐PET, and neuropsychological assessment. Standardized uptake value ratio (SUVR) flortaucipir‐ and PIB‐PET images were created using tracer‐specific reference regions and warped to template space. Patients were split based on availability of FLAIR‐MRI (Figure 1). The exploratory sample (n=50; no FLAIR) was used to run voxelwise models to identify regions where flortaucipir‐ and PIB‐PET were associated with episodic memory, executive, language, semantic memory, and visuospatial composite scores. In the validation sample (n=69), WMH were segmented from FLAIR and T1‐MRIs using a two‐step supervised algorithm. Linear regression models assessed the independent contributions of global WMH volume (corrected for intracranial volume and log‐transformed) and cognitive domain‐specific regional PET‐SUVR (derived in the exploratory sample) to each cognitive domain.ResultThe two samples had comparable demographics and clinical characteristics, with relatively young age (mean ∼65.5) and moderate impairment (mean MMSE ∼ 22, Table 1). In the exploratory sample, cognitive scores were associated with regional flortaucipir‐SUVR patterns (Figure 2); PIB‐SUVR was not robustly associated with cognition. In the validation sample, global WMH volume was inversely correlated with global PIB‐SUVR (r=‐.25, p=.04) but not global cortical flortaucipir‐SUVR (r=‐.18, p=.15). Older age predicted lower cortical flortaucipir‐SUVR (r=‐.70, p<.001) and greater WMH volume (r=.46, p<.001). Female sex was specifically associated with greater cortical flortaucipir‐SUVR (d=0.64, p=.01; psdsps
ConclusionIn patients at the early clinical stages of AD, tau‐PET and global WMH volume were not associated with each other, but independently contributed to cognitive impairment. These findings emphasize the clinical relevance of cerebrovascular injury in the context of AD pathology, even in younger patients.
Retinal biomarkers predict future cognitive performance in progranulin‐haploinsufficient frontotemporal dementia
Authors: Oertel Frederike Cosima , Younes Kyan , Cobigo Yann , Keihani Azeen , Fonseca Corrina , Bennett Daniel J , Abdelhak Ahmed , Saias Alexandra , Montes Shivany Condor , Chen Robert Y , Cordano Christian , Green Ari J , Elahi Fanny M 
Published: February 2022

AbstractBackgroundProgranulin (GRN) haploinsufficiency caused by heterozygous mutations in the GRN gene is a common cause of early‐onset familial frontotemporal dementia (FTD). Our group previously described neuronal ceroid lipofuscinosis‐like features in the retinae of asymptomatic and mildly symptomatic heterozygous GRN mutation carriers (GRN‐carriers). However, additional intraretinal changes, their clinical relevance and utility as biomarkers remain unexplored. We aimed to describe the distinct retinal disease pattern in GRN‐carriers and to investigate the association of retinal change with subsequent brain atrophy and cognitive decline.MethodWe applied optical coherence tomography (OCT) and scanning laser ophthalmoscopy at baseline in 23 GRN‐carriers (age [years, mean+SD]: 62±11, gender [male, N(%)]: 11(48), mean Clinical Dementia Rating (CDR) = 0.5; CDR = 0.0 for 9 subjects) and 85 healthy controls (HCs) (age: 69±15, gender: 42(49)), investigating qualitative and quantitative retinal changes. Linear mixed‐effect models (LME) were used to study the relationships at a group‐level between OCT findings and longitudinal assessments (follow‐up time [months, median(min‐max)]: 28(12‐73)) of cognitive performance including lexical fluency (LF), semantic fluency (SF) and emotion naming (EN). MRI analyses are pending.ResultEight eyes (17%) of five GRN‐carriers (22%) had drusen‐like depositions detectable on OCT. Quantifying macular layers, GRN‐carriers had a thicker outer plexiform layer (OPL: 0.33±0.05mm3, p<0.001), thinner outer nuclear layer (ONL: 0.66±0.07mm3, p = 0.019) and thinner retinal pigment epithelium (RPE: 0.15±0.02mm3, p = 0.039) compared with HC (OPL: 0.30±0.03mm3, ONL: 0.69±0.07mm3, RPE: 0.16±0.01mm3), but no differences in inner retinal layers (confirmed excluding eyes with drusen). The OPL/ONL‐ratio was higher in GRN‐carriers (0.51±0.13) than HC (OPL/ONL‐ratio: 0.44+0.08, B = 0.079, p<0.001). GRN‐carriers with OPL/ONL‐ratio>median at baseline had a faster annualized decline of LF (‐2.60±5.62, B = 0.273, p = 0.002), SF (‐5.70±9.76, B = 0.213, p = 0.035) and EN (0.44±1.24, B = 0.066, p = 0.040) during follow‐up compared to subjects with OPL/ONL‐ratio<median (LF: 4.25±3.50; SF: 0.00±4.32, EN: 2.00±1.83).ConclusionGRN‐haploinsufficiency is associated with retinal phenotypes, including drusen and outer retinal layer thinning, suggestive of photoreceptor degeneration. OPL/ONL‐ratio predicted FTD associated cognitive worsening ‐ and thereby might have potential as biomarker of disease progression in clinical trials.
White matter tract integrity, but not amyloid burden, is related to cognition in cognitively normal older adults
Authors: Pettigrew Corinne , Soldan Anja , Alm Kylie H. , Bakker Arnold , Zhu Yuxin , Wang Mei‐Cheng , Kutten Kwame , Bilgel Murat , Miller Michael I. , Faria Andreia , Mori Susumu , Albert Marilyn S. 
Published: February 2022

AbstractBackgroundThe increased focus on preclinical Alzheimer’s disease (AD) necessitates an understanding of how general biomarkers of neuronal injury and AD‐specific biomarkers differentially contribute to the cognitive performance in cognitively normal individuals. It has been suggested that alterations in limbic white matter (WM) tracts may precede both gray matter atrophy and clinical impairment (Teipel et al., 2016). However, few studies have evaluated whether limbic tract alterations are associated with cognitive performance in individuals with normal cognition. To address this gap, this cross‐sectional, multi‐modal imaging study examined whether measures of WM tract integrity, using diffusion tensor imaging (DTI) (including fornix, hippocampal cingulum, and uncinate fasciculus), were related to cognitive performance, independent of cortical amyloid burden in cognitively normal individuals.MethodAnalyses included 130 cognitively normal participants from the BIOCARD Study (Table 1) who completed cognitive assessments, diffusion‐weighted MR and 11C‐PiB PET imaging during their annual visit. Cognitive performance was captured by cognitive composite scores reflecting verbal episodic memory, executive function, and visuospatial processing. WM tract integrity was measured by fractional anisotropy (FA) and radial diffusivity (RD) in the 3 above‐mentioned ROIs. PiB PET amyloid positivity was derived from cortical distribution volume ratios (cDVR) using cerebellar gray matter as the reference.Linear regressions (covarying age, sex, and education) were used to test 4 a priori cognition‐WM associations. The following relationships were examined: episodic memory and fornix and hippocampal cingulum integrity; executive function and uncinate fasciculus integrity; visuospatial processing and hippocampal cingulum integrity.ResultIn the linear regression models (Table 2), lower hippocampal cingulum FA and greater hippocampal cingulum RD were each associated with better episodic memory performance. Additionally, lower uncinate fasciculus RD (but not FA) was associated with better executive function performance. In contrast, amyloid positivity (i.e., cDVR > 1.06) was unrelated to any of the cognitive composite scores (all ps > .35).ConclusionMeasures of WM tract integrity account for variability in cognitive performance among cognitively normal individuals, and this association is independent of amyloid burden. Additional analyses are needed to determine whether these microstructural measures reflect general, age‐related markers of neuronal injury vs. alterations related to preclinical AD.
Subcortical brain trajectories in later life between sexes and APOE genotypes: A UK Biobank study of individuals of self‐identified Indian ancestry
Authors: Muir Alexandra M , Ching Christopher , Santhalingam Vigneshwaran , Abaryan Zvart , Zhu Alyssa H , John John P , Venkatasubramanian Ganesan , Thomopoulos Sophia I , Jahanshad Neda , Thompson Paul M 
Published: February 2022

AbstractBackgroundIn the UK, individuals with Indian ancestry show lower rates of dementia compared to other ethnicities. Most dementia studies mainly examine individuals of European ancestry and/or higher socioeconomic status, making it unclear if effects generalize to other populations. Here we map age trends in subcortical brain morphometry in later life and investigate the modulating effects of sex and APOE genotype in people of self‐identified (SI) Indian ancestry.MethodT1‐weighted MRI scans from mostly healthy individuals with SI‐Indian ancestry from the UK Biobank (; N = 297; born in India = 43.1%) were processed using FreeSurfer v7.1 to derive bilaterally averaged hippocampus, thalamus, putamen, pallidum, amygdala, caudate, nucleus accumbens, and ventricle volumes. SI‐ancestry groups were confirmed with the first three genetic principal components ()4. Sex‐stratified normative centile reference curves (nomograms) of standardized residuals corrected for intracranial volume (ICV) and scanner were plotted for each structure. Linear mixed models were used to investigate a sex‐by‐age interaction adjusted for scanner and ICV. APOE ε4 carriers and non‐carriers were compared. All results were corrected for multiple comparisons.ResultNomograms () show a similar pattern for SI‐Indian and SI‐European ancestry groups (N= 35,608). All subcortical volumes generally declined significantly with increasing age, except for the ventricles which increased as expected (; Cohen’s d: 0.12 ‐ 0.93). No subcortical region showed a significant age by sex interaction (). Subcortical volumes did not differ between carriers and non‐carriers ().ConclusionNomograms and statistical analysis of subcortical brain volume trajectories showed similar patterns between SI‐Indian and SI‐European groups. In the current sample, we detected no sex by age interaction for any subcortical volume nor detrimental effect of APOE ε4 allele, likely due to lack of power. Larger samples of SI‐Indian ancestry individuals along with analyses accounting for life expectancy, short survival with dementia, and risk/protective factors compared with populations of higher prevalence will be valuable to assess whether differential subcortical trajectories may account for lower rates of AD in India compared to other countries.