bluuebunny/crossref_metadata_2025_split huggingface dataset:
Automated semantic speech analysis in AD and lvPPA
Authors: Nevler Naomi , Ash Sharon , Cho Sunghye , Shellikeri Sanjana , Parjane Natalia , Irwin David J , Liberman Mark Y , Grossman Murray 
Published: December 2020

AbstractBackgroundSpeech is a complex behavior where restricted cognitive impairment in one domain may affect patients’ performance, thus providing opportunities to identify disease markers. A limited number of studies have examined natural connected speech in typical and atypical Alzheimer’s disease (AD). Here we implement automated language processing to characterize some semantic properties of speech in speakers with typical AD and its linguistic variant, logopenic variant primary progressive aphasia (lvPPA).MethodWe analyzed transcripts of natural speech elicited by a picture description task from AD, lvPPA and matched control speakers (Table1). We automatically parsed and tagged each word and then automatically scored for word length (in phonemes and morphemes), frequency, familiarity, semantic diversity and concreteness based on published norms. We compared these features across groups, covarying for age, sex, education and Mini Mental Status Examination (MMSE) score. We correlated each acoustic measure with MMSE scores collected within 6 months of the speech samples.ResultAD and lvPPA speakers differed from controls in all semantic scores except for word familiarity and semantic diversity: they used higher frequency words (p<0.001) that were also shorter (phoneme count, p<0.001; morpheme count, p<0.001), more ambiguous (p=0.028) and abstract (p=0.005) and acquired at a younger age compared with control speakers. lvPPA speakers did not differ from AD speakers in their words’ length in terms of the number of phonemes. However, the number of morphemes was less in lvPPA (mean 1.104±0.037) compared with AD (mean 1.129±0.038) , p=0.002). They also showed a trend towards using higher frequency words (p=0.057), acquired at a younger age (p=0.05) compared with AD speakers. lvPPAs differed from control speakers in their semantic diversity (p=0.02). All scores reflecting impaired performance correlated with MMSE scores in patient speakers.ConclusionIn natural speech AD and lvPPA speakers select words that are shorter, more frequent, semantically ambiguous and less concrete. lvPPA speakers show a specific predilection to words with fewer morphemes and higher frequency, acquired at an earlier age. These deficits correlate with the degree of cognitive impairment and may negatively impact communicational efficacy in these patients as they deteriorate.
Trajectories of depression symptoms over time differ by APOE4 carriership in older adults with type 2 diabetes
Authors: Lavie Inbar , Schnaider Beeri Michal , Berman Yuval , Schwartz Jonathan M. , Soleimani Laili , Heymann Anthony , Ravona‐Springer Ramit 
Published: December 2020

AbstractBackgroundAPOE‐ε4 is a strong and consistent risk gene for Alzheimer’s disease (AD). Depression and depressive symptoms have been shown to precede AD and are highly prevalent in older adults with type 2 diabetes (T2D). However, the relationship of APOE‐ε4 with depression has rarely been investigated T2D. We examined whether trajectories of depression symptoms over time differ by APOE‐ε4 carriership in older adults with T2D.MethodParticipants (n=754 (99 APOE‐ε4 carriers; 13.1%) were initially cognitively normal individuals from the Israel Diabetes and Cognitive Decline (IDCD) study who underwent evaluations of depression approximately every 18 months using the 15‐item version of the Geriatric Depression Scale (GDS) and the depression subscale of the Neuropsychiatric Inventory (NPI). We used Hierarchical Linear Mixed Models (HLMM) that modeled the effects of APOE status on repeated GDS and NPI depression scores adjusting for demographic (Model 1), and adding cardiovascular risk factors (Model 2) and global cognition (Model 3).ResultParticipants’ mean age was 73 (SD=4.7); 38% female. In comparison to non‐carriers, APOE‐ε4 carriers had a lower mean GDS scores (β=‐0.46, p=0.018; Plot 1) and lower NPI‐depression scores (β=‐0.170, p=0.038; Plot 2) throughout all study follow period, but the groups did not differ in the slope of change over time in GDS (β=‐0.005 for interaction of APOE with time, p=0.252) or NPI‐depression (β=‐0.001, p=0.994) scores. Additional adjustment for cardiovascular risk factors and global cognition did not alter these results.ConclusionIn older adults with T2D, APOE‐ε4 carriers have consistently lower depression scores in successive measurements. The lack of difference between the groups' slopes over time suggests that APOE‐ε4 (or lack of) does not have a progressive effect on depression or its underlying pathology. APOE‐ε4 carriers may be less susceptible to depression.
A longitudinal study of automated analysis of acoustic speech markers in FTD and PPA
Authors: Nevler Naomi , Ash Sharon , Cho Sunghye , Shellikeri Sanjana , Parjane Natalia , Irwin David J , Liberman Mark Y , Grossman Murray 
Published: December 2020

AbstractBackgroundSpeech is a complex activity requiring proper function and connectivity of multiple brain networks and as such is sensitive to focal neurodegeneration. We have previously reported on acoustic markers of dysprosody in speech samples of speakers with frontotemporal dementia (FTD) phenotypes. In the current study we explore the longitudinal changes in acoustic‐prosodic markers in FTD.MethodWe analyzed 102 speech samples of picture descriptions from 46 participants with FTD (Table 1): 8 with non‐fluent/agrammatic primary progressive aphasia (naPPA), 14 with semantic variant PPA (svPPA), 10 with logopenic aphasia (lvPPA) and 14 with behavioral FTD (bvFTD). We automatically segmented the acoustic signal into segments of continuous speech or silence, measured their durations, and derived other measures. We used linear mixed effects (lme) models to test changes over time for each acoustic measure, controlling for sex, education, and random intercepts. We also examined any interaction between phenotypes and disease duration.ResultbvFTD speakers increased their pause duration by 0.27 seconds per year and their pause rate by 3.9 pauses per minute (ppm) each year. Their speech segment duration shortened by 0.1 seconds per year (p=0.041), decreasing their total speech time by 6.6 seconds (p=0.003) per year. Thus, bvFTD patients reduced the proportion of speech in their samples by 5.16 percent per year (p=0.008). svPPA speakers increased their pause rate similarly, but in contrast, their pause duration decreased by 0.097 seconds per year and they increased their speech segment frequency by 8.32 per minute each year (p=0.054). naPPA and lvPPA speakers increased their pause rate over time and spent less total time (speech + pause) describing the picture (by 5.6 seconds per year; p=0.018). They did not differ from bvFTD and svPPA in these two acoustic measures.ConclusionIn our study all FTD speakers became more dysfluent and produced shorter descriptions with time, however, only bvFTD speakers actually exhibited reduced speech production. In contrast, svPPA speech had more frequent pauses and speech segments over time, rendering it “fragmented” and inefficient. These findings support the role of automated acoustic analysis in characterizing speech longitudinally in neurodegeneration.
The Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS): Study design and objectives
Authors: Alber Jessica , Arthur Edmund , Thompson Louisa I , Goldfarb Danielle , Fernandez Brian M , Salloway Stephen P , Sinoff Stuart , Snyder Peter J 
Published: December 2020

AbstractBackgroundThe development of widely accessible, minimally invasive, cost‐effective Alzheimer’s disease (AD) biomarkers is a global public health imperative. There is a definite need for a multi‐stage neurodiagnostic screening system that is sensitive and specific to identify high risk individuals prior to cognitive decline. There is rapidly growing evidence that retinal biomarkers have the potential to serve as diagnostic or prognostic AD biomarkers. However, some results have been discordant due to variations in methodology, equipment, and study populations. Moreover, longitudinal data is sparse, and there is lack of insight as to which retinal biomarkers are relevant for each disease stage. Finally, the field needs to understand how structural, functional/metabolic, and angiographic retinal biomarkers interact in the AD process, and whether or not these interactions reflect cerebral pathophysiology. We propose a multi‐site longitudinal, prospective, observational study evaluating the natural history of retinal imaging biomarkers associated with AD disease risk, disease burden, and disease progression. The study objective is to create a ‘gold standard’ reference database of structural anatomic and functional imaging of the retina, in order to enable the identification and development of both sensitive and reliable markers of disease risk and/or disease progression.MethodParticipants (N=330 aged 55‐80; 50 CN– low AD risk, 200 CN – high AD risk, 50 MCI, and 30 mild AD) will be examined 4 times over 5 years. Exams will include neuropsychological testing, blood draw, APOE E4 genotyping, medical/functional assessment, gait assessment, and sleep analysis for 14 days post‐visit. Retinal OCT and OCT‐A will be completed on the Heidelberg SPECTRALIS II. Pupillometry and contrast sensitivity measures will be collected at each visit.ResultWe aim to use these data to develop a multivariate screening tool with sufficient sensitivity and specificity for identifying and tracking AD severity, including the preclinical stage of the disease.ConclusionLongitudinal study of structural, functional, metabolic, and angiographic retinal AD biomarkers in a large cohort could provide the foundation for the development of early stage screening biomarkers that can be applied by point‐of‐care clinicians. Our reference database will be open access, so that researchers worldwide can use these data to develop retinal AD biomarkers.
Relationships between cerebrovascular health and tau PET uptake are associated with global cognition
Authors: Albrecht Daniel , Isenberg Lisette , Stradford Joy , Monreal Teresa , Sagare Abhay P , Pachicano Maricarmen , Toga Arthur W. , Zlokovic Berislav V , Chui Helena C , Joe Elizabeth B , Schneider Lon , Conti Peter , Jann Kay , Pa Judy 
Published: December 2020

AbstractBackgroundBrain accumulation of tau and cerebrovascular dysfunction are both important contributors to AD pathogenesis, but associations between vascular health and tau levels, and their effects on clinical outcome, are poorly understood. We investigated these associations in a cross‐sectional study, by performing comparisons between cerebral blood flow (CBF), measured with ASL perfusion MRI, and tau PET uptake, measured with [18F]flortaucipir (FTP). In a subgroup, we assessed relationships between tau uptake and a CSF marker of vascular health known to be associated with impaired cognition, soluble platelet‐derived growth factor beta (sPDGFR‐β).MethodWe conducted discovery and replication analyses using data from USC (n=68) and ADNI (n=136), respectively. Voxelwise analyses assessed relationships between CBF and FTP standardized uptake value ratio (SUVR), the results of which were used to mask the replication analysis. Secondary analyses were performed on the replication dataset with a gray matter mask. Analyses were corrected for age, sex, gray matter volume, and diagnosis (when appropriate), with voxelwise and cluster‐level thresholds of p<0.001 and p<0.05, respectively. General linear models were used to determine if CBF‐FTP relationships differed between diagnostic groups, as well as between high and low performance on the Montreal Cognitive Assessment (MoCA), a measure of global cognition. Mediation models assessed the relationship between tau, sPDGFR‐β, and cognition.ResultIn the discovery cohort, we observed negative CBF‐FTP correlations mainly in lateral and inferior temporal regions, that were largely replicated in the ADNI cohort. Secondary analyses demonstrated that early negative CBF‐FTP correlations increased in spatial extent and strength of correlation with increased disease severity. Stronger negative CBF‐FTP correlations were observed in participants with more advanced diagnoses and in those with poorer global cognitive performance. sPDGFR‐β was a significant mediator of the relationship between inferior temporal tau uptake and MoCA.ConclusionOur results provide evidence that associations between the cerebrovascular system and tau binding may affect cognition across the AD spectrum. Importantly, the sPDGFR‐β analysis suggests that vascular dysfunction may contribute to cognitive impairment via elevations in tau, potentially caused by reduced tau clearance. Future, longitudinal studies are needed to explore the complex temporal relationship between tau deposition and vascular health.
Safety and pharmacokinetics of the muscarinic positive allosteric modulator VU319: A phase 1 single dose study
Authors: Newhouse Paul A. , Conley Alexander C. , Key Alexandra P. , Blackford Jennifer U. , Rook Jerri M. , Conn Jeffrey , Lindsley Craig W. , Jones Carrie K. 
Published: December 2020

AbstractBackgroundThe investigational new drug VU319 has recently completed first‐in‐human testing in a Phase 1 Single Ascending Dose (SAD) study, which included a Food Effect substudy. The main objectives of the SAD study were to assess the safety and tolerability of VU319 in healthy adults. The Food Effect substudy examined whether the metabolism and absorption of VU319 changed when administered in a fed compared to a fasted state. Both studies also attempted to identify early markers of functional engagement which would offer information on how VU319 may enhance cognition in patient sample in future studies.MethodA double‐blind Phase 1 human SAD study consisted of five cohorts of eight participants, in which six participants received oral VU319 and two participants received placebo. The Food Effect substudy consisted of 12 participants, in which ten received oral VU319 and two received placebo. The five doses for the SAD study were 60, 120, 240, 400 and 600mg. Participants in the Food Effect substudy received VU319 at a single dose of 120mg after a meal. All six cohorts combined typical safety and PK assessment with behavioral and brain‐based measures that targeted cognitive processes and was sensitive to cholinergic drug effects both at pre‐dose and again at 5‐7 hours post‐dose.ResultResults of the SAD and Food Effect studies have shown tolerability with no observed dose limiting side effects and no observed significant adverse events suggesting non‐M1 mAChR stimulation throughout the full dose range of the first five cohorts. PK evaluation showed good oral absorption and bioavailability with a half‐life consistent with once daily dosing. Absorption of VU319 was increased in a fed compared to a fasted state. Cognitive and electrophysiological results suggested functional target engagement of the task at higher fasting doses of VU319.ConclusionSingle dose VU319 across five ascending cohorts appeared to have a favorable safety profile and a PK profile consistent with once daily dosing. Administration of VU319 with food increased absorption and was associated with improvements in performance measures. These results provide a strong foundation for the planned multiple ascending dose study and a Phase 2a POC study in MCI.
Transcriptomic profiling of APOE4/Trem2*R47H mouse models for late‐onset Alzheimer’s disease
Authors: Pandey Ravi S. , Kotredes Kevin P. , Preuss Christoph , Oblak Adrian L. , Lamb Bruce T. , Howell Gareth , Sasner Michael , Carter Gregory W. ,   MODEL‐AD Center
Published: December 2020

AbstractBackgroundLate‐onset Alzheimer’s disease (LOAD) is the leading cause of dementia in the elderly. However, most transgenic animal models are based on rare, early‐onset AD genes which have not been great preclinical models as they may not sufficiently capture the full transcriptomic signatures and complete neuropathology of disease. Animal models based on LOAD‐associated genes are necessary to connect common genetic variation with LOAD transcriptomes.MethodWe performed transcriptomic analysis at 4, 8, 12 and 24 months of age on whole brain samples from APOE4KI mouse, carrying a humanized version of the prominent APOE4genetic risk factor for LOAD, and the Trem2*R47Hmouse, carrying a rare deleterious variant R47H allele of Trem2. In addition, a mouse model expressing both human APOE4and the Trem2*R47Hmutation was used to compare the transcriptional effects in mice carrying both variants to mice carrying only a single risk allele and B6 controls.We compared mouse modules with human postmortem brain modules from the Accelerating Medicine’s Partnership for AD (AMP‐AD) to determine the AD relevance of risk genesResultDifferentially expressed genes in these mice were significantly enriched in multiple AD‐related pathways, including immune response, osteoclast differentiation, metabolism, and mRNA/protein processing. We also observed age related changes, specifically in Trem2*R47H mice, such as more differentially expressed genes and significant differential splicing events compare to the APOE4mouse models.Further, these mouse models overlapped with immune, myelination, neuronal, and DNA repair related AMP‐AD modules.ConclusionWe have characterized three novel mouse models of LOAD at young and advanced ages and observed sex as well as age‐specific transcriptional changes. These mouse models exhibited similar transcriptional changes as seen in clinical samples. Hence, this double mutant mouse model will be used as a sensitized genetic background for further addition of human AD risk variants to model late‐onset Alzheimer’s disease in mice.
Medial temporal lobe (MTL) ‐ default‐mode network (DMN) functional connectivity disruption in the progression of Alzheimer’s disease
Authors: Grajski Kamil A ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundA multi‐modal analysis of resting‐state functional connectivity disruption (fMRI) and morphometric changes characteristic of neurodegeneration (T1 structural MRI) in Alzheimer's disease (AD) was performed to develop biomarkers for the transition from cognitively normal (CN) to significant memory concern (SMC) to early and late mild cognitive impairment (EMCI, LMCI).MethodsFalse Detection Rate (FDR) corrected (q=0.005) parallel group‐level one‐way four‐factor (CN, SMC, EMCI, LMCI) ANOVA and post hoc pairwise t tests of ROI pairs [1]; same‐session functional connectivity (AFNI) and morphometry (FreeSurfer); ADNI‐3 sub‐population with baseline diagnosis CN (N=33), SMC (N=35), EMCI (N=13), and LMCI (N=14) matched for age (p=0.33), education (p=0.63), and gender (p=0.127).ResultsA 3‐mm grid of ROI seeds (r=6mm) in left MTL yielded 435 ROI “anchors”. 3D (Fisher Z‐transformed) correlation maps were computed for each subject for each anchor ROI and input to a group‐level one‐way four‐factor 3D ANOVA. Cluster analysis (N
vox 20; p=0.02; P=3.45) of the 3D F Statistic maps yielded 4,185 target ROIs. An r=6mm ROI was placed at the center of mass of each target cluster. ROI anchor‐target pair correlations were input to a group‐level one‐way four‐factor ANOVA and FDR corrected (q=0.005; p*=0.003) (estimated by permutation, N=1000) which identified 2,420 significant tests (ROI pairs). Post hoc pairwise t tests only on the significant ANOVA tests were FDR‐corrected (q=0.005) and yielded 31 significant SMC‐CN tests (p*=6.3x10‐5); 54 EMCI‐CN tests (p*=1.1x10‐4); and 209 LMCI‐CN tests (p*=4.2x10‐4). The spatial distribution of target ROIs included (bilaterally) MTL and DMN‐associated regions. Of the significant SMC‐CN tests, 39% were positive (increased connectivity). In the significant EMCI‐CN tests, 100% were positive. However, in the significant LMCI‐CN comparisons, the pattern reversed and only 5% were positive. An independent analysis of right hemisphere yielded similar results.ConclusionsAn hybrid a priori data‐driven approach identified a population of MTL‐anchored ROI pairs whose spatial distribution of target ROIs included regions associated with DMN and MTL, and whose functional connectivity revealed a striking pattern of change with clinical progression when compared to CN: SMC, a mixture of hyper‐ and hypo‐connectivity; EMCI, widespread hyper‐connectivity; and LMCI, widespread hypo‐connectivity. Reference: (1) Grajski, K. A., Bressler, S., and ADNI. (2019). Neuroimage Clin. 2019;23:101860.
Discordant results in CSF/PET Aβ biomarkers are dependent on APOE genotype and related to inter‐individual differences in CSF Aβ42, Aβ40 and Aβ38 isoforms
Authors: Sala Arianna , Nordberg Agneta K , Rodriguez‐Vieitez Elena ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundRecently, we provided evidence that discordance in CSF vs. PET Aβ‐biomarkers represents a natural phase in the progression of Aβ‐pathology, with either CSF or PET becoming abnormal first (Figure 1). The reasons why CSF‐Aβ42 becomes abnormal first in some subjects, while Aβ‐PET does in others, are unknown. Here, we aimed to investigate biomarker and genetic factors characterizing these alternative “CSF+ first” vs. “PET+ first” pathways of Aβ accumulation.MethodWe retrospectively selected N=867 cases from ADNI, ranging from cognitively normal to overtly demented, with [18F]Florbetapir‐PET and CSF‐Aβ42 measurements obtained within three months; a subset (N=289) also had two‐year longitudinal CSF/PET data. Each participant was classified as belonging to the “CSF+ first” or “PET+ first” pathway based on modelling of the continuous distribution of CSF‐Aβ42 and Aβ‐PET measures to a hyperbolic function, followed by residuals analysis, and avoiding the use of CSF or PET cut‐off values. This method allowed to assign each subject to a “CSF+ first” vs. “PET+ first” pathway and yielded highly stable results at two‐year follow‐up (Figure 2).ResultSignificant differences between participants belonging to the “CSF+ first” vs. “PET+ first” pathways were found in biomarkers for Aβ‐pathology (Figure 3) but not for tau or neurodegeneration, with CSF‐Aβ42 driving most of the difference (partial η2=0.67 [CSFAβ42]; partial η2=0.29 [Aβ‐PET]). Participants belonging to the “CSF+ first” pathway showed significantly lower levels of CSF‐Aβ42, Aβ40 and Aβ38 compared to their “PET+ first” counterparts, consistently across all concordant and discordant CSF/PET stages (Figure 4). At the genetic level, a significantly higher prevalence of homozygous carriers of APOE‐ε4 was found in the “CSF+ first” vs. “PET+ first” pathway (18.9% vs. 1.6%; Figure 5). No differences in modifiable risk/protective factors for Alzheimer’s disease were found.ConclusionThis evidence argues against the claim that discordant Aβ CSF vs. PET findings systematically represent false positive/negative results. Instead, our findings suggest that CSF vs. PET discordance carries relevant information reflecting differences in Aβ clearance mechanisms, with genetic determinants partly leading each subject towards a CSF+ first or a PET+ first trajectory. Combination of CSF/PET Aβ biomarkers might help identifying subjects most likely to benefit from treatments targeting Aβ clearance.