bluuebunny/crossref_metadata_2025 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

Background

Speech 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).

Method

We 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.

Result

AD 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.

Conclusion

In 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

Background

APOE‐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.

Method

Participants (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).

Result

Participants’ 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.

Conclusion

In 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

Background

Speech 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.

Method

We 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.

Result

bvFTD 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.

Conclusion

In 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

Background

The 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.

Method

Participants (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.

Result

We 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.

Conclusion

Longitudinal 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

Background

Brain 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).

Method

We 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.

Result

In 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.

Conclusion

Our 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

Background

The 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.

Method

A 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.

Result

Results 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.

Conclusion

Single 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

Background

Late‐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.

Method

We 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 genes

Result

Differentially 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.

Conclusion

We 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

Background

A 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).

Methods

False 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).

Results

A 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.

Conclusions

An 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

Background

Recently, 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.

Method

We 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).

Result

Significant 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.

Conclusion

This 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.
Cholesterol content in peripheral blood cells of patients with Alzheimer's disease
Authors: Montes Angel Martin , Recuero Maria , Sastre Isabel , Sanchez‐Caro Juan Maria , Frank‐García Ana , Bullido María J.
Published: December 2020

Background

Alzheimer's disease (AD) is the most frequent degenerative dementia, with a prevalence expected to increase in coming years. Deposits of amyloid and hyperphosphorylated TAU protein constitute the characteristic pathological findings of the disease, although its etiology in sporadic cases is still unknown. Cholesterol metabolism has been related to AD through multiple evidences. Filipin is a macrolide that binds to cholesterol and allows its quantification. We consider assessing whether there are differences in cholesterol content determined by Filipin’s fluorescence (FF) in peripheral blood mononuclear cells (PBMCs) of patients with AD and healthy controls.

Method

Cross‐sectional study.Patients diagnosed with AD at different stages with support of biomarkers in cerebrospinal fluid (CSF) and cognitively healthy controls were included. PBMCs obtained from whole blood were co stained with Filipin and antibodies specific for several leucocyte subpopulations (CD8, CD4, CD11b, CD19, CD14 and CD16).FF was measured by flow cytometry in PBMCs and in different subpopulations.

Results

N=61 (51 AD,10 controls);When the whole PBMCs were compared, no significant differences in filipin fluorescence among diagnostic groups were observed (AD 1280, controls 1218.9; p=0.65). However, subpopulation analysis revealed significant decrease in cholesterol content in CD14+ cells of patients with AD (AD 2623.9, controls 4433.2; p = 0.007). Differences in cholesterol content in this CD14+ subpopulation were also significant in ApoE4 carriers (2427.1 in carriers, 3130.43 non‐carriers, p=0.017)

Conclusions

Cholesterol content of CD14+ peripheral blood mononuclear cells could be a neurodegeneration biomarker and it could be related with AD,which supports the involvement of cellular cholesterol homeostasis in the pathophysiology of the disease.
Initial exploration of a brain age score based on validated computerized cognitive assessments in Japanese individuals
Authors: Edgar Chris J. , Schembri Adrian , Maruff Paul T. , Gee Michelle , Iwatsubo Takeshi , Aisen Paul S. , Sperling Reisa A. , Irizarry Michael C.
Published: December 2020

Background

Differences between chronological age and biological age can be used to communicate health related information to the general population. For the brain, cognitive performance can be used to define biological age. We utilized data from performance on tests from the Cogstate Brief Battery (CBB) to develop a ‘Brain Age’ score for characterizing the presence of any cognitive impairment in Japanese older adults at risk of dementia.

Methods

To compute an Brain Age, data from the One Card Learning and One Back tests from the CBB was compared to age stratified normative data. Brain Age was computed as the difference in standardized score from age matched normative data. For every point better or worse than the normative mean (0), 0.5 years was added or subtracted from chronological age, to a maximum of 10 years (20 points, or 2 SD). For the current analysis, Brain Age scores were derived for 106 Japanese cognitively normal (CN) individuals from clinical trial screening data for the A4 study and 611 Japanese adults classified with a memory impairment during their screening for the elenbecestat MissionAD program (memory impaired). Differences between these groups were used to determine known groups validity.

Results

Mean chronological age was equivalent in the CN (mean = 71.7, SD = 4.6) and memory impaired (mean =72.6, SD= 7.4) samples. Brain Age score was equivalent to chronological age in the CN sample (mean Brain Age = 72.4, SD = 7.45). However in the memory impaired group Brain Age was 6.3 years greater than chronological age (mean Brain Age = 78.9, SD = 8.2). Accordingly, Brain Age was significantly greater in the memory impaired than cognitively normal groups (p < 0.01; d = 0.81).

Conclusion

Brain Age score is a valid construct for defining biological age impairment in Japanese individuals at risk for dementia. The current data suggest the presence of a difference between chronological and biological age of approximately six years is a criterion that would warrant more detailed investigations. The Brain Age score may be a useful means for communicating brain health information, including the need to adopt a healthier lifestyle.
Fractional anisotropy in white matter hyperintensities is linked to associative memory performance
Authors: Haddad Seyyed Mohammad Hassan , Scott Christopher J.M. , Ozzoude Miracle , Holmes Melissa F. , Arnott Stephen R. , Nanayakkara Nuwan D. , Kwan Donna , Tan Brian , Casaubon Leanne , Mandzia Jennifer , Sahlas Demetrios J. , Saposnik Gustavo , Hassan Ayman , Black Sandra E. , Dowlatshahi Dar , Strother Stephen C. , Swartz Richard H. , Symons Sean , Montero‐Odasso Manuel , Bartha Robert
Published: December 2020

Background

Alzheimer’s disease pathology commonly coexists with cerebrovascular anomalies, suggesting a strong association between cerebrovascular lesions and cognitive performance. While different types and locations of cerebrovascular lesions such as strokes and white matter hyperintensities (WMHs) may interfere with various cognitive domains, these associations are not thoroughly understood. The most common approach to characterize and evaluate cerebral lesions is with structural neuroimaging. However, diffusion tensor imaging (DTI) can assess the microstructural integrity of cerebral tissue lesions, which may directly impact neuronal communication and consequently cognitive function. This study examines the variation in DTI metrics within different cerebrovascular lesions and their association with cognition in people with cerebrovascular disease (CVD).

Method

The variation of DTI metrics in 10 different cerebral tissues and lesions was examined in 152 subjects (aged 55‐85 years, 32% female) with CVD, (evidenced by an ischemic stroke event documented by MRI or CT, with a modified Rankin score 0‐3) available from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). Fractional anisotropy (FA) and mean diffusivity (MD) were measured using an established DTI processing pipeline from 3 Tesla DTI images (32 directions, b=1000 s/mm2). Cerebral tissue lesion masks were obtained by semi‐automated segmentation of the structural T1‐weighted images to calculate average DTI metrics in each region of interest (ROI). In addition, FA in normal appearing WM (NAWM) and WMHs were correlated with MoCA score (measure of gross cognition), Rey Auditory Verbal Learning Test Long‐Delayed Recall score (measure of episodic memory), Trail Making Test‐Part B in seconds (measure of executive function), and Face‐Name Associative Memory Test score (measure of associative memory).

Result

Figure 1 shows a T1‐weighted anatomical image, corresponding tissue mask identifying vascular lesions, and corresponding MD and FA maps. Fig. 2 provides the average FA and MD in different cerebral tissues/lesions. FA within WMHs was found to be significantly correlated with Face Name Associative Memory Test score (p‐value<0.01, r=0.23, Fig. 3) after Bonferroni correction. No other significant associations were identified.

Conclusion

Considerable heterogeneity in DTI metrics was observed between cerebral tissues and lesions. Importantly, the structural integrity within WMHs also associated with higher associative memory performance.
Circadian rhythms and misalignment in older adults and those ‘at risk’ for dementia: A study examining correlates of dim‐light melatonin onset
Authors: Schrire Zoe M. , Naismith Sharon L. , Pye Jonathon , Duffy Shantel L. , Gordon Christopher J. , Lewis Simon J.G. , Hoyos Camilla M
Published: December 2020

Background

Circadian rhythms are altered with ageing, mild cognitive impairment and dementia and may be aetiologically linked to neurodegeneration. The gold standard measure of the circadian system is melatonin. This can be measured using Dim‐Light Melatonin Onset (DLMO), which measures the initial rise of melatonin signalling preceding sleep. However, DLMO collection is resource intensive, expensive and not feasible within the clinical environment. In older adults and those ‘at risk’ for dementia, the current study aims to determine 1) the best clinical and actigraphic associations of DLMO and 2) misalignment between melatonin onset and habitual sleep onset (phase angle of entrainment).

Method

Individuals who were healthy or ‘at risk’ (diagnosed with depression and/or mild cognitive impairment) had 14‐days of actigraphy followed by in‐lab measurement of salivary melatonin, from which DLMO and phase angle were computed. Standard nonparametric analyses were computed from actigraphy.

Result

21 healthy (age=66±9.6, MMSE =29.25±0.79) and 44 individuals ‘at risk’ (age=66±10.3, MMSE=28.34±1.73) completed the study. Across all participants, multiple linear regression showed BMI(β=0.20), age(β=‐0.02), sex(β=‐0.26) and sleep onset time(β=0.35) predicted DLMO(F(4,59) =4.70, p=0.002, R2=0.238), driven by the strong correlation between DLMO and sleep onset (r=0.41, p=0.001). An additional exploratory analysis revealed M10 onset, the start of the 10 hours with greatest activity, was significantly correlated with phase angle in individuals ‘at risk’ (r=0.36, p=0.02) and not controls (r=‐0.31, p=0.19), Fisher’s r‐to‐z p=0.02. No other variables differed between groups.

Conclusion

The current study demonstrates that earlier habitual sleep onset is associated with advanced circadian rhythms in older adults, and that aside from demographic factors, BMI is a factor affecting circadian timing. Of significance, this study also shows that ‘at risk’ individuals who begin activity later in the day exhibit greater misalignment between their biological clock and external cues. This work highlights the potential use of actigraphy‐derived sleep onset as a circadian marker in ageing. Moreover, for those at risk for dementia, the timing of daytime activity may play a vital role in circadian misalignment. With growing evidence that circadian misalignment is involved in the pathogenesis of neurodegeneration, BMI and actigraphy markers could yield viable targets focusing on chronotherapeutic interventions.
Analysis of cell‐type specific exosomes isolated from cryopreserved human brain
Authors: Bilousova Tina , Melnik Mikhail , Cohn Whitaker , Huang Calvin , Teter Bruce , John Varghese , Gylys Karen H.
Published: December 2020

Background

Exosomes are small extracellular vesicles (EVs) originated from multivesicular endosomes which carry biochemical information about their cell‐of‐origin and signals for surrounding cells. EVs may also play a role in spread of proteopathic tau and amyloid beta seeds in Alzheimer’s disease (AD). Thus, brain exosomes may be a valuable therapeutic target for AD treatment. Ability of brain exosomes to cross the blood brain barrier make them a potential diagnostic and monitoring tool. Despite recent progress in development of EV isolation methods, our knowledge of human brain exosomal subpopulations and their roles in disease progression is very limited.

Method

Cryopreserved parietal cortex from 5 late stage AD (Braak V‐VI) and 3 control (NL) cases were used for the experiment. Brain exosomes/EVs were purified by sucrose density gradient ultracentrifugation after gentle enzymatic and mechanical dissociation of the brain tissue. Microglia‐derived EVs were isolated from the brain EV fraction by immunoprecipitation with anti‐CD11b antibodies. We performed analysis of miRNA transcriptome and proteome using NanoString and quantitative proteomics respectively.

Result

We identified 105 miRNAs which are present in more than 80% of analyzed human cases. The pathways controlled by five significantly upregulated miRNAs can be converged to control microglia activation (TGFβ, TLRs, and chemokine signaling pathways) and neuronal survival and function (LTD and LTP, NGF and neurotrophin signaling pathways). One of the upregulated exosomal miRNAs (miR‐188‐5p) is known to be downregulated in human AD brain and it can restore synaptic and cognitive deficits in 5xFAD mice. MiR‐381‐3p can promote recovery of spinal cord injury in rats. On the protein level we found a moderate increase (around 50%) in exosomal markers CD9 and CD81 and decrease in CHMP4B (ESCRT‐III) protein in the AD group. Levels of mitochondrial proteins and annexins were around 2 times higher in AD group compared to NL controls. ApoE protein was also significantly upregulated in AD microglial EVs.

Conclusion

Our data revealed the presence of anti‐inflammatory and neuroprotective miRNA signature in CD11b‐positive microglia‐derived exosomes. Proteomics data suggests upregulation of ESCRT‐independent pathway of exosome biogenesis in AD microglia. Increased association of microglial EVs with ApoE maybe related to amyloid packaging and release by exosome‐mediated mechanism.
Higher diastolic blood pressure aged 40‐44 is associated with declining cognition and increasing white matter lesions over 8‐12 year follow up.
Authors: Peters Ruth , Xu Ying , Cherbuin Nicolas , Sachdev Perminder S. , Anstey Kaarin J
Published: December 2020

Background

Background: High midlife blood pressure (BP) is an accepted risk factor for later life cognitive decline and dementia. However, the changing patterns of systolic and diastolic (DBP) blood pressure from our 40s to our 60s highlight the need for a more sophisticated understanding of the relationships between BP during the midlife period and cognition as well as brain measures, including white matter lesion (WHL) volume as a marker of small vessel disease.

Method

The Personality and total health (PATH) study is an Australian longitudinal population based cohort with four waves of follow‐up at approximately 4‐year intervals (W1‐4). Data was used from two PATH cohorts, one aged 40‐44 at W1 (40s) and the other aged 60‐64 at W1 (60s) and included the subset of participants with BP (W1), neuropsychological testing (W1, W4), imaging (MRI)(40s W2, W4, 60s W1, W4). Linear regression models with relevant adjustment, including antihypertensive use, were used to examine the relationship between baseline BP and change in imaging and cognition over time. P≤0.01 was taken as significant.

Result

Data were available for 492 participants,’40s’: 218 (53% female) ‘60s’: 274 (42%). Key findings were that higher DBP at ages 40‐44 was associated with a significant decline in performance over the subsequent 12 years on the symbol digit modalities test (slope‐0.7 (95% CI ‐1.2, ‐0.3) p=0.002) and to a lesser extent, trail making A (0.9 (0.2, 1.6)p=0.01) per 10mmHg increment. There were no associations for recall, digit span or dexterity tests. There were no associations for the 60s. Higher DBP aged 60‐64 was associated with a 31% (95% CI 13%, 51%) increase in WML over 12 years (p<0.001) per 10mmHg and a similar but less strong relationship (13% (3%, 24%) in the 40s over 8 years (p=0.008). There were no relationships between change in hippocampal or total brain volume. There were no significant relationships for SBP.

Conclusion

Higher DBP was associated with decline in processing speed in the 40s and growth of WML overall. The next step is to examine the relationship between change in BP and change in cognition and imaging measures.
The protective effect of physical activity on the alpha power is influenced by age and APOE genotype
Authors: de Frutos Jaisalmer , Cuesta Pablo , Toraño Federico Ramirez , Cuadrado‐Soto Esther , Peral‐Suarez Africa , Nebreda Alberto , Fernández Ricardo Bruña , Sanz David López , Marcos Silvia , Losada María Luisa Delgado , Sobaler Ana Maria Lopez , Rojo Inmaculada Concepción Rodríguez , Barabash Ana , Rodriguez Juan Manuel Serrano , Laws Simon M , Dolado Alberto Marcos , Higes Ramón López , Brown Belinda M , Maestú Fernando
Published: December 2020

Background

Physical activity (PA) has been identified as one of the most relevant modifiable lifestyle factors against Alzheimer's disease (AD). Magnetoencephalography has proven to be a useful tool to predict future risk of AD. In particular, decreased power in the alpha band has been associated with pathological aging. We had already reported how PA was significantly associated with higher alpha peak frequencies in older adults, especially among those at standard genetic risk for AD (APOE ε4 non‐carriers). Recent literature suggest that age could play an important role in the emergence of these relationships, a role that has not been explored yet.

Method

We used a sample of 112 cognitively normal individuals aging <50 who had worn an accelerometer for one week, divided into four carefully matched groups: younger adults at increased risk (age <60;APOE ε3ε4;n=20), older adults at increased risk (age >60;APOE ε3ε4;n=15), younger adults at standard risk (age <60;APOE ε3ε3;n=44) and older adults at standard risk (age>60;APOE ε3ε3;n=33). Each subject underwent four minutes of closed eyes resting state MEG recording. The aim was to detect any robust correlation between power values derived from clusters of nodes localized in certain brain regions and TPA, using network‐based statistics. Clusters consisted of several adjacent nodes, which systematically showed a significant partial correlation (with age as covariate) in at least 3 consecutive frequency steps between their corresponding power values and TPA (spearman correlation p‐value<0.01).

Result

A significant cluster was found in the frequency interval 10.75–13Hz involving mainly posterior brain regions (rho=0.360;p=0.0001;see Figure 1/Table 1). This correlation remained significant for both ε3ε3 carriers (rho=0.326;p=0.004;n=77;) and ε3ε4 carriers (rho=0.442;p=0.007;n=35;see Figure 2). It also remained significant for younger adults (rho=0.456;p>0.001) but not for older adults (Figure 3). Interestingly, when looking at the four groups individually, only younger ε4 non‐carriers (rho=0.487;p>0.001) and older ε4 carriers (rho=0.603;p=0.013) show this association.

Conclusion

Greater PA seems to be associated with increased alpha power in posterior brain regions, a robust biomarker of brain health which is negatively affected in AD. However, the time window when this association can be observed seems to differ between ε4 carriers and non‐carriers.
Neuropsychiatric symptoms and cognition: An observational study in a Filipino memory clinic setting
Authors: Cano Jemellee , Uy Judy Grace Laurilla , Cruz Precy S. , Lorca Maria Leni Lat , Martinez Ma. Socorro , Dominguez Jacqueline C.
Published: December 2020

Background

A growing body of evidence has described neuropsychiatric symptoms (NPS) as early markers of cognitive decline and may precede onset of measurable neurocognitive changes.1,2 NPS have been associated with accelerated cognitive decline and higher dementia conversion rates.3 The repeated observation that individuals with NPS are at increased risk of further cognitive decline delineates this group as high risk and suitable for early interventions to prevent cognitive and functional loss.4 The objectives are to determine the prevalence and compare the demographic and cognitive profiles of non‐demented individuals with NPS in a Filipino cohort.

Method

A total of 435 patients with no cognitive impairment (NCI) and Mild Cognitive Impairment (MCI) from St. Luke’s Medical Center Memory Clinic were included. NPS were assessed by administration of the Neuropsychiatric Inventory Questionnaire (NPI‐Q) to a reliable caregiver. Participants were administered the Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS‐Cog).

Result

Compared to patients without NPS, patients with NPS have more impaired cognition with lower MMSE (25 + 4 vs 27 + 3, p=0.001); MoCA (21 + 5 vs 23 + 5, p=0.002) and higher ADAS‐Cog scores (12.4.6 + 6 vs 10.6 + 6, p=0.01). A fully adjusted model showed NPS to be significantly associated with MMSE (‐0.8, 95% CI ‐1.6 to ‐0.02, p=0.04) and MoCA scores (‐1.2, 95% CI ‐2.3 to ‐0.2, p=0.02).

Conclusion

This study shows that non‐demented individuals with NPS have more cognitive impairment suggesting the importance of NPS as a potential marker for early cognitive decline and a need for further trials that targets treatment for NPS even at an early stage to prevent cognitive impairment.
Integrative metabolomics‐genomics approach reveals that pathways related to the metabolism of acylcarnitines and amines are new potential targets of Alzheimer’s disease
Authors: Horgusluoglu‐Moloch Emrin , Wang Minghui , Arnold Matthias , Krumsiek Jan , Galindo‐Prieto Beatriz , Kastenmüller Gabi , Han Xianlin , Baillie Rebecca , Nho Kwangsik , Saykin Andrew J. , Kaddurah‐Daouk Rima F. , Zhang Bin
Published: December 2020

Background

The metabolic basis of Alzheimer’s Disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis remain elusive. In this study, we systematically interrogated metabolomics, genetics, proteomics, and clinical data from the matched subjects in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to identify key drivers and metabolic pathways associated with changes in metabolites with disease severity.

Method

140 Metabolites in fasting serum samples from the ADNI (362 controls, 94 significant memory concerns, 764 mild cognitive impairment, and 298 AD) were analyzed using the AbsoluteIDQ‐p180 kit. Values adjusted for age, gender, body mass index (BMI), education, cohort, and medication. A metabolite co‐expression network was constructed using Multiscale Embedded Gene co‐Expression Network Analysis (MEGENA). Co‐expressed metabolite modules were then prioritized for the strength of association with clinical/cognitive and pathology biomarker variables. Correlation analysis of the co‐metabolite modules and the matched gene/protein expression data was performed. The ROS/MAP cohort was used as a replication study of the co‐expression network. Six brain transcriptomic datasets from the Mount Sinai Brain Bank, ROS/MAP, and MAYO clinic cohorts were utilized to build up gene‐centered correlation networks to elucidate functions of upstream regulators of candidate metabolites.

Result

Modules comprised of short‐chain acylcarnitines/amino acids (M8, M3), and medium/long‐chain acylcarnitines (M6) were most associated with worse AD clinical outcomes, including episodic memory scores and disease severity (CDR‐SB) (Figure 1A‐C). CPT1A gene expression was highly correlated with an increased level of the medium/long‐chain acylcarnitines (corrected p‐value = 1.87 × 10‐6). Increased ABCA1 gene expression and adiponectin protein (a regulator of ABCA1) levels corresponded to decreased short‐chain acylcarnitines and amines in AD (corrected p‐value < 0.02) (Figure 2A‐C). In addition, CPT1A and ABCA1 were differently expressed in the brains of AD patients compared to controls (Table 1), and their subnetworks were enriched for AD, aging, and neuronal system‐related gene signatures/pathways (Figure 3A‐D). Eight out of eleven modules were highly preserved between the ADNI and ROS/MAP cohorts (Z summary preservation score > 5; corrected p‐value < 0.05).

Conclusion

Identification of acylcarnitines enriched modules and their potential upstream genetic and transcriptional regulators paves the way for developing novel biomarkers and targets for AD.