bluuebunny/crossref_metadata_2025 huggingface dataset:
Alterations in olfaction‐related brain regions in the ageing population: A structural MRI study
Authors: AlOtaibi Majed , De Marco Matteo , Venneri Annalena
Published: December 2021

Background

Ageing plays a major role in neurodegenerative disorders such as Alzheimer’s disease. Olfactory dysfunction can be an early alteration heralding the presence of a neurodegenerative disorder in ageing. Studying alterations in olfaction‐related brain regions might help detection of neurodegenerative diseases at an earlier stage. Objectives: To assess the volume of olfactory cortex and areas associated with odour processing in different age groups in the cognitively healthy population using high resolution 3D structural MRI scans. To test whether normal ageing determines any volumetric alterations of olfactory cortex, hippocampus and other associated areas and whether there are any differential predictive values of these alterations for neurodegenerative disorders. To determine if atrophy of the olfactory cortex occurs prior to atrophy of the hippocampus and other areas involved in some aspects of odour processing in the healthy population.

Method

Neurologically healthy participants were divided based on their age into three age groups: young (20–35 year; n=53), middle‐aged (36‐65 year; n=66) and elderly (66‐85 year; n=95). T1‐ weighted MRI scans acquired at 1.5T were processed using SPM12. Smoothed images were used to extract the volume of olfaction‐related regions including primary olfactory cortex, hippocampus, parahippocampus and amygdala.

Result

One‐way ANOVA analyses showed significant decreases in volume between age groups in all olfaction‐related brain regions (p≤0.0001). Post‐hoc multiple comparisons tests showed that significant differences were found between age groups except in the young vs the middle‐aged where no significant differences were found for hippocampal and amygdala volumes. Pairwise comparisons of groups following ANCOVA showed no significant difference in all olfaction‐related brain regions when controlling for age. Adjusting for education showed significant age‐group differences in olfactory cortex and parahippocampus volumes except for hippocampus in all groups, and for the amygdala for young versus middle‐aged groups

Conclusion

These preliminary data showed significant reduction in the volume of olfaction‐related brain regions with ageing, but hippocampus and amygdala appeared to have a more limited volume reduction than primary olfactory cortex and parahippocampus. The results suggest that monitoring of volume of olfaction‐related brain regions in the ageing population may be valuable to detect risk of neurodegenerative diseases.
The relationship between beta‐amyloid accumulation and P3 event‐related potential in older adults: A pilot study
Authors: Devos Hannes , Gustafson Kathleen , Liao Ke , Ahmadnezhad Pedram , Brooks William , Mahnken Jonathan D , Burns Jeffrey M.
Published: December 2021

Background

Emerging evidence from animal and human studies shows that beta‐amyloid (Aβ) may induce neuronal hyperexcitability in the early stage of Alzheimer’s disease (AD). Electroencephalography (EEG) offers unparalleled temporal resolution in tracing distinct neurophysiological processes even in preclinical AD. The aim of this pilot study was to determine the relationship of Aβ accumulation and event‐related potential (ERP) in cognitively normal older adults.

Method

Aβ accumulation was characterized with [18F] Florbetapir positron emission tomography (PET) scans. Global Aβ burden was assessed by taking the mean standard uptake value ratios (SUVR) of 6 predefined regions: anterior cingulate, posterior cingulate, precuneus, inferior medial frontal, lateral temporal, and superior parietal cortex. All participants completed a working memory task with three levels of difficulty (0‐,1‐,2‐back). ERP P3 peak amplitude and latency were extracted from the task effect (non‐target minus target). We used Pearson r to calculate associations between mean SUVR and P3 ERP at the midline channels Fz and Cz. Since the working memory task induced frontal cortical activity, we also explored the relationship between SUVR in the inferior medial frontal cortex and the frontal channels Fz, F3, and F4.

Result

Twenty‐seven (age: 73.9 ± 5.5; MOCA: 27.37 ± 2.0) completed both PET and EEG scans. Mean SUVR ranged from 0.95 to 1.60 and correlated negatively with P3 latency of the 2‐back at Cz (r = ‐0.40; p = 0.04) and Fz (r = ‐0.58; p = 0.002). SUVR in the inferior medial frontal cortex correlated negatively with P3 peak latency of 1‐back at Fz (r = ‐0.42; p = 0.03) and F3 (r = ‐0.49; p = 0.009), and of 2‐back at Fz (‐0.54; p = 0.004) and F3 (r = ‐0.40; p = 0.045). No correlations were found between global Aβ burden and P3 peak amplitude.

Conclusion

The negative relationship between Aβ accumulation and P3 latency provides preliminary support for the neuronal hyperexcitability hypothesis in preclinical AD. However, these findings need to be confirmed in a longitudinal cohort study with larger sample size.
The relationship between hippocampal volume and P3 event‐related potential in cognitively normal older adults without and with elevated amyloid: A pilot study
Authors: Devos Hannes , Brooks William , Gustafson Kathleen , Liao Ke , Ahmadnezhad Pedram , Mahnken Jonathan D , Burns Jeffrey M.
Published: December 2021

Background

The P3 event‐related potential (ERP) is typically reduced and delayed in patients with Alzheimer’s disease (AD). The hippocampus is a core regulator of the P3 ERP. The aim of this study was to investigate the relationship between hippocampal volume and P3 peak amplitude and latency in cognitively normal older adults with (Aβ+) and without elevated amyloid (Aβ‐).

Method

Aβ was assessed using a Florbetapir F‐18A positron emission tomography scan. No participants showed cognitive impairments based on performance on neuropsychological tests. Hippocampal volume was measured from T1‐weighted magnetic resonance imaging using Freesurfer. 256‐channel high‐definition electroencephalography (EEG) was used to record brain activity while completing a working memory (1‐back) test. The 1‐back test consisted of 120 non‐targets and 60 targets and lasted about 7 minutes. P3 amplitude and latency of the task effect (non‐target – target) was extracted using EEGlab software. Midline (Fz, Cz, Pz) and frontal (F3, F4) were identified a priori as channels of interest.

Result

We assessed 12 Aβ‐ participants (age 75.0 ± 6.4; MOCA 27.8 ±1.4; 6 (50%) women) and 11 Aβ+ participants (age 71.8 ± 5.6; MOCA 27.7 ± 2.0; 8 (72% women). Pearson r correlations for the total group (n = 23) demonstrated significant and positive correlations between both left and right hippocampal volume (L/R HV) and peak P3 amplitude at Fz (L HV, r = 0.55, p = 0.006); R HV, r = 0.52, p = 0.01), Cz (L HV, r = 0.55, p = 0.006; R HV, r = 0.53, p = 0.01), F3 (L HV, r = 0.50, p = 0.01; R HV, r = 0.44, p = 0.03), F4 (L HV, r = 0.57, p = 0.004; R HV, r = 0.55, p = 0.007), but not with Pz (L HV, r = 0.24, p = 0.26; R HV, r = 0.33, p = 0.12). Hippocampal volume did not correlate with any P3 peak latencies.

Conclusion

Our preliminary findings suggest a relationship between hippocampal volume and P3 peak amplitude in the frontocentral channels in cognitively normal older adults. Further research will reveal the putative mechanisms of neurophysiological changes in preclinical AD.
Association of peripheral blood DNA methylation levels with Alzheimer’s disease progression
Authors: Li Qingqin S. , Vasanthakumar Aparna , Davis Justin W. , Idler Kenneth , Nho Kwangsik , Waring Jeffrey , Saykin Andrew J.
Published: December 2021

Background

Identifying biomarkers associated with Alzheimer’s disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome‐wide association studies (EWAS) have revealed correlations between DNA methylation level at cytosine‐phosphate‐guanine (CpG) sites and AD pathology in the brain or diagnosis in peripheral blood.

Method

We performed cross‐sectional analysis of DNA methylation in peripheral blood as a predictor of AD progression in participants in the Alzheimer’s Disease Neuroimaging Initiative cohort.

Result

The rate of cognitive decline in participants from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACCdigit and mPACCtrailsB) and Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. Two differentially methylated positions were identified (P < 5.79 × 10−8 [Bonferroni correction threshold]): cg00386386 was associated with the slope of mPACCdigit in CN participants, and cg09422696 annotated to RP11‐661A12.5 was associated with the slope of CDR‐SB in MCI participants. No CpG sites significantly associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 70, 76, and 102 differentially methylated regions (DMRs) with Sidak‐corrected P < 0.05 were identified as associated with the slopes of mPACCtrailsB, mPACCdigit in CN participants, and CDR‐SB in MCI participants, respectively; these included DMRs annotated to HOXA4, HOXB6, and HOXB9. Overall, 75 and 123 DMRs were associated with conversion status in participants with CN and with MCI, respectively. The most significant DMR was annotated to an AD‐associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak‐corrected P = 7.74 × 10−24), which was associated with both the slope of CDR‐SB and the MCI conversion status. The identified DMRs were enriched in CpG islands, promoter, and exons, including 5’ untranslated region and protein coding, whereas intergenic region, short and long interspersed nuclear element repeats, and introns were depleted.

Conclusion

Candidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in CN and MCI participants, respectively, in the longitudinal ADNI cohort.
Stability of plasma amyloid‐β 1‐40, amyloid‐β 1‐42 and total Tau protein over repeated freeze/thaw cycles
Authors: Yang Shieh‐Yueh , Liu H.C. , Lin Chin‐Hsien , Chiu Ming‐Jang
Published: December 2021

Background

Blood biomarkers of Alzheimer’s disease (AD) attract much attention of researchers recently. In clinical studies, repeated freeze/thaw cycles often occur and may influence the stability of biomarkers. This study is to investigate the stability of amyloid‐β 1‐40 (Aβ1‐40), amyloid‐β 1‐42 (Aβ1‐42) and total Tau protein (T‐Tau) in plasma over freeze/thaw cycles.

Method

Plasma samples from healthy control (HC, n = 3), AD patients (AD, n = 3) and Parkinson’s disease (PD, n = 3) were collected by standardized procedure, immediately frozen at ‐80 °C. Samples underwent 5 freeze/thaw (‐80°C/room temperature) cycles. The concentrations of Aβ1‐40, Aβ1‐42 and T‐Tau were monitored during the freeze/thaw tests by using immunomagnetic reduction (IMR) assay. The relative percentage (%) of concentrations after every freeze/thaw cycle was calculated for each biomarker.

Result

A tendency of decrease in the averaged relative percentages over samples through the freeze and thaw cycles for Aβ1‐40 (100 to 97.37%), Aβ1‐42 (100 to 95.56%) and T‐Tau (100 to 96.42%) was found. However, the decreases are less than 5%. For all three biomarkers, no statistical significance was found between the levels of fresh plasma and that of the plasma experiencing five freeze/thaw cycles (p > 0.1).

Conclusion

Plasma Aβ1‐40, Aβ1‐42 and T‐Tau are stable through five freeze/thaw cycles measured with IMR.
Identification and validation of plasma proteome signatures associated with MRI measurements in healthy individuals
Authors: Shi Liu , Hillary Robert Francis , Marioni Riccardo E. , Campbell Archie , Hayward Caroline , Stolicyn Aleks , Whalley Heather C. , Buckley Noel , Nevado‐Holgado Alejo J
Published: December 2021

Background

Peripheral biomarkers reflecting early neurodegeneration change are critical to the development of treatments for Alzheimer’s disease (AD). The most widely used indicator of AD neurodegeneration in life at present is neuroimaging evidence of brain atrophy. We therefore performed a proteomic analysis of plasma to derive biomarkers associated with neuroimaging in prodromal disease stage.

Method

To identify blood‐based proteins relating to neurodegeneration (“N”) in preclinical or prodromal disease stage, we used SOMAscan assay to measure 5033 proteins in two groups of healthy individuals (discovery group = 564, validation group = 497) selected from Generation Scotland cohort. We firstly performed both linear regression and protein co‐expression network to identify differentially expressed proteins and co‐expressed protein modules associated with “N” in the discovery group. We then validated such associations in the validation group.

Result

Using linear regression, we identified different proteins that were significantly associated with whole brain volume, cortical volume and hippocampus volume after multiple correction, indicating that the associations between proteins and “N” were dependent on brain regions. From protein co‐expression network analysis, we identified seven modules (from 20 to 2088 proteins) in the discovery group, all of which were significantly preserved in the validation group. Furthermore, several modules were significantly associated with “N” and such associations were affected by sex and APOE genotype. Moreover, we replicated the associations between differentially expressed proteins and modules with “N” in the validation group.

Conclusion

Our study is the largest we are aware of to report a plasma biomarker indicative of neurodegeneration in prodromal disease stage both in terms of the number of proteins assayed and in sample size. We identified and validated a groups of proteins in two large independent groups of healthy individuals. These proteins provide tractable targets for further mechanistic studies of neurodegeneration pathology, particularly in preclinical stages of Alzheimer’s.
The association of KIBRA rs17070145 polymorphism with dementia and cognitive function among older adults in China: A population‐based cross‐sectional study
Authors: Wang Chaoqun , Han Xiaolei , Wang Yongxiang , Qiu Chengxuan , Du Yifeng
Published: December 2021

Background

KIBRA, as a ligand protein, is mainly expressed in kidney and brain. A genome‐wide association study in 2006 revealed that KIBRA rs17070145 was associated with impairment in episodic memory. Since then, several studies that investigate the association of this SNP and cognitive function have yielded mixed results. This study aims to explore the association of KIBRA rs17070145 with dementia and cognitive function among rural‐dwelling older adults in China.

Method

This population‐based cross‐sectional study included 4700 participants from the Multidomain Interventions to Delay Dementia and Disability in Rural China (MIND‐CHINA), who were aged ≥65 years (mean 71.7 years; 57.2% women). Data on demographic features and cognitive function were collected through face‐to‐face interviews, clinical examinations, and laboratory tests. SNPs were detected by multiplex PCR assay. Global cognitive function was assessed with the Mini‐Mental State Examination (MMSE). Diagnoses of dementia Alzheimer’s disease (AD), and vascular dementia (VaD) were reached according to the DSM‐IV, NIA‐AA, and NINDS‐AIREN criteria, respectively. Data were analyzed using multiple logistic regression and general linear regression models.

Result

Of all participants, 2689(57.2%) carried the KIBRA rs17070145 TT polymorphism in intron 9, 1719(36.6%) carried CT polymorphism, and 292(6.2%) were homozygous CC carriers. The multi‐adjusted odds ratio (95% CI) of dementia associated with C allele and genotype CC was 1.27 (1.02‐1.58) and 1.78 (1.07‐2.97), respectively. The association of KIBRA genotype CC with VaD was significantly, but not with AD. However, the association of genotype CC with VaD was reduced and became non‐significant when further adjusting for cerebrovascular diseases.

Conclusion

KIBRA rs17070145 genotype CC is associated with an increased likelihood of dementia among rural‐dwelling Chinese older adults, driven largely by the association with VaD. Cerebrovascular disease may partly explain the association of genotype CC with VaD.
Impairment of hippocampal synaptic plasticity induced by pathological microglial activation
Authors: Piccioni Gaia , Mango Dalila , Nisticò Robert
Published: December 2021

Background

Neuroinflammation has demonstrated a key role in the pathogenesis of Alzheimer disease (AD). Among the innate immune cells, microglia are the primary players in neuroinflammation. When microglia is activated under pathological inflammatory conditions, it can lead to synaptic alterations thereby influencing the progression of AD. Among other mechanisms, an increased activation of microglial colony stimulating factor 1 receptor (CSF1R) can lead to pathological microglia activation in experimental models of AD (Olmos‐Alonso et al., 2016). In this work, using electrophysiological techniques, we investigated hippocampal synaptic transmission and plasticity in experimental models of neuroinflammation. We then tested whether the pharmacological manipulation of microglia activation was able to restore the neuroplasticity alterations associated with these models.

Method

The experiments were conducted using C57BL6/J mice of both sexes aged between 30‐ and 40‐days. Using electrophysiological approach (field and whole cell patch clamp), we performed recordings in area CA1 in response to stimulation of the Schaffer collaterals. We evaluated Long‐Term Potentiation (LTP) induced by theta‐burst stimulation. Responses were recorded for 1 hour after tetanization and measured as field Excitatory Post‐Synaptic Potential (fEPSP). Two in vitro inflammatory models were obtained applying Lipopolysaccharide (LPS) (10 μg/ml) or Aβ 1‐42 oligomers (200 nM). As a control, we tested the effect of Aβ 1‐42 with a scrambled sequence applied in the same condition of Aβ 1‐42. To inhibit the activation of microglia we used Pexidartinib (PLX‐3397) (10 μM), a specific inhibitor of activated microglia, and Minocycline (500 nM) a no‐specific blocker.

Result

Slices treated with Aβ 1‐42 and LPS showed impairment of LTP. Indeed, LTP was fully suppressed after exposition to oligomeric Aβ while no change of fEPSP was observed after incubation of slices with Aβ scrambled. Similarly, a selective inhibition of LTP was observed in the presence of LPS. Minocycline application reversed synaptic dysfunction in slices treated with Aβ 1‐42 and LPS. Preliminary data also indicate that PLX‐3397 rescues LTP impairment mediated by oligomeric Aβ.

Conclusion

Our data show a functional role of activated microglia in the synaptic plasticity alteration induced by neuroinflammation and suggest CSF1R as an emerging target in the treatment of AD.
Evidence for the role of semantic cueing and executive functioning tools in early and differential diagnosis of neurocognitive disorder (NCD): A neuropsychological approach
Authors: Abbatantuono Chiara , Taurisano Paolo , Pepe Ilaria , Clemente Livio , Alfeo Federica , Ricciardi Elisabetta , Calia Clara , Lancioni Giulio , De Caro Maria Fara
Published: December 2021

Background

Recent advances in the diagnosis of Mild Cognitive Impairment (MCI) and Neurocognitive Disorders (NCDs) build on neuropsychological models (Dodich et al., 2018; Possin et al., 2018). Despite the lack of harmonized protocols (Costa et al., 2017), tools such as the Free and Cued Selective Reminding Test (FCSRT) yield specific scores (e.g., ISC for cue sensitivity) for the early detection of hippocampal syndromes involved in Alzheimer’s Disease (AD), and for the prediction of MCI‐to‐AD conversion (Brugnolo et al., 2021). Accordingly, the study aims to investigate the correlation between neuropsychological profiles and cognitive patterns through an extensive assessment procedure accounting for the heterogeneity of MCI and NCDs.

Methods

N=150 outpatients (mean age=72.29±5.42 SD) were administered a battery meeting both MCI (Petersen et al., 2014) and NCD criteria (APA, 2013) including: two screening tools; ten domain‐specific cognitive tests; psychodiagnostic‐functional assessment. Analyses through paired‐sample tests and multivariate models focused on: (1) episodic memory and executive deficits; (2) predictive indices for MCI/NCD diagnosis.

Results

70.7% of the clinical sample obtained scores consistent with MCI or mildNCD profiles, and 75% showed episodic memory impairment on cut‐off basis (FCSRT‐ISC<0.9). Wilcoxon signed‐rank test revealed poorer performance in FCSRT‐ISC compared to Babcock Story‐IR (p‐value<0,001<α=0,05), notably in MCI/mildNCDs but not in majorNCDs. The full sample and MCI/mildNCD subset also obtained lower scores in Digit Span Backward (DS‐B) than in the Clock Drawing Test (CDT), whereas majorNCD performed worse in CDT. Logistic regression showed three predictive indices for majorNCD: the lower the scores on FCSRT‐IFR, DS‐B and CDT, the greater the chances of fitting majorNCD profile.

Conclusion

Driven by the need for early and differential diagnosis of NCDs, our findings showed episodic memory impairment within the total sample and the MCI/mildNCD subsets, indicating: (1) a high prevalence of AD‐type MCI/mildNCDs; (2) the possible key role of FCSRT‐ISC in detecting early or mild conditions of impairment; (3) the good predictive values (86%) of some memory (i.e. FCSRT‐IFR) and executive tasks (i.e. DS‐B and CDT) contributing to a major NCD diagnosis, potentially enhancing NCD nosography and differential diagnosis.
Tau and synaptic biomarkers but not amyloid‐β are associated with cerebral perfusion in the Alzheimer’s disease spectrum
Authors: Ahmadi Khazar , Pereira Joana B. , Berron David , Vogel Jacob W. , Ingala Silvia , Strandberg Olof , Janelidze Shorena , Barkhof Frederik , Knutsson Linda , van Westen Danielle , Mutsaerts Henri J.M.M. , Palmqvist Sebastian , Hansson Oskar
Published: December 2021

Background

A large body of evidence has shown decreased cerebral blood flow (CBF) in Alzheimer’s disease (AD). However, the link between CBF and the primary AD pathologies as well as synaptic integrity remains unclear.

Method

Baseline CBF was measured using arterial spin labeling (ASL) in a 3T MRI scanner in 137 cognitively unimpaired individuals with and without amyloid‐beta (Aβ) pathology, in addition to 119 cognitively impaired participants with mild cognitive impairment or AD dementia who all had Aβ pathology from the Swedish BioFINDER‐2 study. Aβ and tau pathology were measured using cerebrospinal fluid (CSF) levels of Aβ42/40 and amyloid‐PET, as well as CSF P‐tau217 levels and tau‐PET, respectively. Synaptic integrity was estimated using CSF neuronal pentraxin 2 (NPTX2)/total‐tau (T‐tau) ratio. Voxel‐wise and linear regression analyses in a set of a priori defined regions of interest (ROIs) were used to assess between‐group differences in CBF, and the relationship between CBF and the PET and CSF measures.

Result

CBF was decreased in the lateral temporal, lateral and medial parietal and superior lateral occipital cortex in the cognitively impaired compared to cognitively unimpaired individuals, independent of Aβ pathology. In contrast, no differences were found in CBF between the cognitively unimpaired groups with and without Aβ pathology. Further, in cognitively unimpaired individuals, CBF was not associated with any of the biomarkers of Aβ, tau or synaptic integrity. However, in individuals on the AD spectrum i.e., those with Aβ pathology regardless of their cognitive status, an inverse association was observed between CBF and tau pathology (tau‐PET and CSF P‐tau217), but not Aβ pathology (CSF Aβ42/40 and amyloid‐PET), predominantly in the occipito‐temporo‐parietal regions. Moreover, lower NPTX2/T‐tau was associated with hypoperfusion in similar regions.

Conclusion

These findings suggest that tau‐tangle pathology and synaptic degeneration are more closely associated with overt changes in CBF than Aβ pathology. This supports the notion that blood flow changes, at least those measured by ASL, are not an early event associated with the build‐up of Aβ pathology during the preclinical phases of AD.
Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer's disease (THC‐AD)
Authors: Rosenberg Paul B. , Outen John D. , Amjad Halima , Burhanullah Haroon , Vandrey Ryan , Agronin Marc , Castaneda Ricardo , Isesalaya Maria , Walsh Patricia , Ash Eleanor T. , Cohen Leah , Wilkins James M , Harper David G. , Forester Brent P.
Published: December 2021

Background

Although agitation in Alzheimer’s Disease (Agit‐AD) is a common and troubling neuropsychiatric syndrome, behavioral interventions lack consistent efficacy and there are no FDA‐approved medications. Neurobiological mechanisms that contribute to Agit‐AD include brain atrophy, degradation of neurotransmission, neuroinflammation, disrupted circadian rhythms, comorbidities and frailty. Agit‐AD is a major source of disease progression, patient disability, financial burden, and caregiver stress. Dronabinol is synthetic tetrahydrocannabinol (THC, one of the predominant biochemical constituents of cannabis). Cannabinoids may improve Agit‐AD by providing protection against neuroinflammation and excitotoxicity, regulating neurotransmitters, improving comorbidities, stabilizing circadian rhythms, and increasing cerebral blood flow.

Method

THC‐AD is a three‐week placebo‐controlled, double‐blind, RCT of dronabinol (10 mg QD) in 80 patients with severe Agit‐AD. Twice daily administration maximizes daytime coverage for agitation and minimizes sundowning. Inclusionary criteria include a diagnosis of AD, severe agitation, and being 60‐95 years old, while exclusionary criteria include serious or unstable medical illness, seizure disorder, delirium, current use of lithium, and inability to swallow a pill. Primary outcomes include a change in the Pittsburgh Agitation Scale and NPI‐C Agitation/Aggression subscales.

Result

We have enrolled 37 out of 80 participants (Table 1: mean age 78.2 years, 78.4% female, 83.8% Caucasian, mean education 13.2 years, 48.6% family history). Study participants are significantly cognitively impaired (Table 2: mean baseline MMSE of 7.1), agitated (mean NPI‐C Agitation 14.8, mean NPI‐C Aggression 6.4) and in reasonable overall health (Figure 1: General Medical Health Rating, 10.8% “excellent,” 48.6% "good" and 40.5% "fair”). Recorded AEs have been tolerable (Figure 2). Due to the COVID‐19 pandemic, we expanded our inpatient trial to include outpatient enrollments and implemented hybrid visits with telemedicine to limit in‐person interactions. To bolster our recruitment, we are collaborating with additional clinical sites, increasing dementia bed capacity, and deploying recruitment strategies for outpatients, including referrals from providers and other research trials, social media ads, and virtual community outreach. Updated results will be presented at AAIC (estimated 6‐10 additional participants).

Conclusion

Safe and effective interventions for severe agitation are greatly needed. This pilot trial will help to examine the safety and efficacy of dronabinol for Agit‐AD.
Identifying veterans at risk for dementia using claims‐based electronic health record data and machine learning
Authors: Castellanos Alejandro , Ysea‐Hill Otoniel , Lin Chaohao , Hasan Shafiul , Bai Ou , Ruiz Jorge G
Published: December 2021

Background

Early identification of individuals at risk for dementia represents an important challenge for the design and implementation of prevention strategies. Machine learning (ML) algorithms might help to identify dementia risk from claims‐based electronic health records (EHR). The study aim was to develop and validate a new method based on ML to identify Veterans at risk for dementia using EHR claims‐based data.

Method

We propose a ML–based probabilistic method to evaluate dementia risk within 10 years, based on information from claims‐based EHR data as part of a retrospective cohort study. We identified veterans without baseline dementia from January 2000 to December 2009 and followed them until December 2019 for dementia onset (ICD codes). A ML model was established using veteran’s EHR data to predict dementia occurrence during follow‐up. The features for the modeling included 72 EHR associated with dementia in previous studies including socio‐demographic, medical and mental morbidities, vital signs, medications, hospitalizations and laboratory data. ML algorithms including Linear Discrimination, Random Forest Classifier, Ensemble Bootstrapping, and Multilayer Perception (MLP) neural network. MLP provided more robust prediction outcomes and was employed for the final dementia modeling and prediction.

Result

Data comes from 7202 veterans, mean age 54.89 (SD=6.64, range 40‐65) years, 90.3% male, 49.3% Caucasian, and 72.1% Non‐Hispanic. Over a median follow up of 9.82 (IQR=3.44) years, 786 (10.9%) of these veterans developed dementia. The training and testing sets at a ratio of 9:1 were pseudo‐randomly extracted from the original EHR database. The performance was determined on the testing dataset using the neural network model learned from the training dataset. The results from three experiments of modeling and testing are (Overall Accuracy/Sensitivity/Specificity): (1) 84.2%/12.8%/92.9%, (2) 85.7%/13.9%/94.5%, and (3) 87.5%/17.7%/96.1%. The modeling and prediction were implemented by missing data for some variables. The experimental results are: (1) 82.4%/9.84%/89.1%, (2) 82.9%/12.2%/91.1%, (3) 83.1%/16.5%/92.0%.

Conclusion

Though the model prediction specificity is acceptable (above 90%), the sensitivity of the prediction is low (less than 20%). Exploring better modeling algorithms and treatment methods for unbalanced samples may improve prediction. Future research could benefit from ML techniques that evaluate the optimal combination of variables that best predict dementia.
Can MR imaging biomarkers readily available in rural and underserved areas aid in the accurate clinical diagnosis of Alzheimer’s disease?
Authors: Gustavsen Tanner , He Yao , Duff Kevin M. , Anzai Yoshimi , Hoffman John M.
Published: December 2021

Background

Hippocampal volume (HV) measured with brain magnetic resonance imaging (MRI), a NIA‐AA biomarker of Alzheimer’s disease (AD), could be widely available in rural and underserved areas in the United States. Amyloid positron imaging tomography (aPET) identifies the presence of amyloid AD pathology but is available only to cognitive specialty centers in predominantly large metropolitan areas. We wished to determine whether rural primary care providers could benefit from commercially available automated measurements of HV to improve the accuracy of their diagnosis of early AD

Method

We used NeuroQuant ®□ (NQ) to derive operator‐independent volumetric measurements of HV relative to total intracranial volume (rHV) in 70 patients (27 men, 43 women; mean age 73 ± 8, range 45‐89) found to have cognitive impairment during a clinical evaluation. We compared the frequency of abnormal rHV using a recommended 5th percentile cutoff value from NQ’s extensive normative database in patients with visually interpreted positive (n=57) or negative (n=13) aPET with flutemetamol. We assessed the validity of rHV to measure underlying AD pathology with a 2x2 factorial analysis to calculate sensitivity, specificity, positive and negative predictive value (PPV, NPV). We measured the rHV in MCI (n=39) versus dementia (n=31). We contrasted the age and severity at time of referral of rural (n=16) and non‐rural (n=54) patients.

Result

12/14 (86%) patients with an abnormal rHV had a positive aPET, however most patients with a positive aPET did not have an abnormal rHV (45/57). The ability of small rHV to predict underlying AD pathology had a specificity=0.84, PPV=0.85, sensitivity=0.21, and NPV=0.19. rHV was smaller in dementia than MCI (0.37,0.42; p=.003). Rural patients were younger (68 ± 11 vs. 75 ± 7; p=.02) and more likely to have dementia when referred (56% vs. 40%; p=.03).

Conclusion

An abnormal rHV is highly predictive of cortical amyloid AD pathology in the right setting, but is insensitive at the time of initial cognitive evaluation. Commercially available automated rHV decreases as the severity of cognitive impairment increases. Imaging biomarkers could aid rural primary care providers to validate the clinical significance of a memory complaint and justify earlier evaluation, referral, and treatment.
Sleep apnea is associated with entorhinal cortex and hippocampal subfield atrophy in asymptomatic amyloid‐positive older adults
Authors: André Claire , de Flores Robin , Kuhn Elizabeth , Rehel Stéphane , Landeau Brigitte , Mézenge Florence , De la Sayette Vincent , Chetelat Gaël , Rauchs Géraldine ,   Medit‐Ageing Research Group
Published: December 2021

Background

Sleep‐disordered breathing (SDB) has been associated to greater amyloid deposition and dementia risk. However, the pattern of SDB‐associated structural brain changes is unclear, especially within the medial temporal lobe (MTL). We investigated the associations between SDB severity and the volume of MTL subregions, and hypothesized that SDB would be associated with atrophy in regions early affected by Alzheimer’s disease (AD) pathology and/or sensitive to hypoxia (i.e., the perirhinal and entorhinal cortices, and CA1 hippocampal subfield), particularly in amyloid‐positive participants.

Method

We included 120 cognitively unimpaired older participants from the Age‐Well randomized controlled trial (mean age=69 ± 3,8 years; 25 Aβ+ and 95 Aβ‐ participants). They underwent a structural MRI, including a high‐resolution T2‐weighted sequence of the MTL (0.4x0.4x2.5mm3), a Florbetapir‐PET scan to measure amyloid deposition, as well as a polysomnography. The ASHS (Automatic Segmentation of Hippocampal Subfields) software was used to segment the entorhinal, perirhinal, and parahippocampal cortices, as well as hippocampal subfields (i.e., the subiculum, CA1, CA2‐3, the dentate gyrus, their sum representing total hippocampal volume) on high‐resolution MRI sequences. Bilateral volumes normalized to the total intracranial volume were used in statistical analyses. We performed linear regressions with the volume of each MTL subregion as dependent variables, the apnea‐hypopnea index (AHI, reflecting SDB severity) and amyloid status as independent variables, and age, sex, education and the ApoE4 status as covariates.

Result

We found significant interactions between the AHI and amyloid status on the volumes of the entorhinal cortex (p<0.001), whole hippocampus (p<0.001), subiculum (p<0.001), CA1 (p=0.003) and dentate gyrus (p=0.007), such that the AHI significantly predicted the volume of these MTL subregions only in amyloid‐positive participants (Figure 1).

Conclusion

Untreated SDB has been previously associated with increased amyloid deposition, even in the absence of cognitive or sleep symptoms. Our data complement these findings by showing that once amyloid deposition reaches positivity, greater SDB severity is related to neurodegeneration in several MTL subregions, including the entorhinal cortex and hippocampus. Thus, the presence of SDB in cognitively unimpaired older adults who are engaged in the Alzheimer’s continuum may increase the risk of developing memory impairment over time.
Stability of blood‐based biomarkers of cognitive impairment
Authors: Thyagarajan Bharat , Crimmins Eileen M. , Barcelo Helene , Langa Kenneth M. , Weir David , Faul Jessica D.
Published: December 2021

Background

Widespread investigation of these biomarkers in large population studies has been hampered as several blood biomarkers of cognitive impairment need the blood to be processed immediately into plasma/serum. We evaluated the stability of these biomarkers to delayed blood processing using an ultra‐sensitive assay.

Method

We processed blood collected from 20 volunteers immediately (0 hours), and after a delay of 24 hours and 48 hours to obtain serum. In addition, we also processed blood from five volunteers immediately (0 hours) and after a delay of 24 hours, 48 hours and 72 hours to obtain plasma. All serum and plasma samples were analyzed in duplicate for Aβ42, Aβ40, tau and neurofilament light (NfL) on the Quanterix platform using commercially available assays.

Result

The decrease in plasma Aβ42 and Aβ40 values were relatively modest in blood processed after a delay of 24 hours (6% and 11% respectively), 48 hours (20% and 21% respectively) and 72 hours (30% and 32% respectively) as compared to samples processed immediately. Furthermore, the plasma Aβ42/ Aβ40 ratio showed only a 9% decrease in plasma processed after a delay of 72 hours. Plasma tau levels decreased by 20% at 48 hours as compared to a 9% decrease in serum. Plasma levels of Aβ42, Aβ40 and tau were substantially higher than serum levels. However, even at 48 hours, plasma tau levels were higher as compared to serum levels. NfL levels were comparable in serum and plasma and NfL levels decreased 10% and 6% in plasma and serum at 48 hours.

Conclusion

Despite a decrease in plasma levels of Aβ42 and Aβ40 was substantial after 48 hours the Aβ42/ Aβ40 was stable in plasma processed up to 72 hours after blood collection. Plasma and serum levels of NfL appear to be stable even when blood was processed for up to 48 hours after blood collection while plasma tau levels showed only modest reduction in values over 48 hours. These results suggest that blood‐based biomarkers of cognitive impairment can be reliably measured in plasma samples that were processed even after a delay of up to 48 hours after blood collection.
CSF biomarkers and blood pressure trajectories in normotensive individuals and subjects with controlled and uncontrolled hypertension
Authors: Glodzik Lidia , Butler Tracy , Li Yi , Tanzi Emily , Harvey Patrick , Blennow Kaj , Zetterberg Henrik , de Leon Mony J.
Published: December 2021

Background

Hypertension is a risk factor for Alzheimer’s disease, however relationships between this disease and CSF amyloidβ42, total tau and phosphorylated tau (p‐181) are inconclusive. Even less is known about associations between trajectories of blood pressure and AD biomarkers.

Method

Longitudinal CSF examinations were performed in 132 normotensive subjects (BP<140/90, and no antihypertensive treatment), 35 subject with controlled hypertension ((BP<140/90, and antihypertensive treatment), and 32 subjects with uncontrolled hypertension (BP≥140/90, irrespective of treatment), mean age 64.3 ± 9.3 years, 61% women.

Biomarker changes over time, and relationship between changes in biomarkers and changes in systolic and diastolic blood pressure were tested using repeated measures mixed model.

Result

Normotensive group was younger than 2 other groups, percentage of women did not differ. Baseline biomarkers levels were not different between groups.

After a mean follow‐up time of 3.7±2.7 years total tau and p‐tau181 increased in the normotensive and uncontrolled groups, but did not change in the controlled group (group*time: F=3.2, p=.04 and F=3.2, p=.04 for total tau and p‐tau181, respectively). Amyloidβ42 remained unchanged in the normotensive and controlled groups, but decreased in the uncontrolled group (group*time: F=3.1, p=.04).

Change in systolic blood pressure was inversely related to change in total tau only in the uncontrolled group (group*time: F=5.0, p=.007). Change in diastolic blood pressure was inversely related to change in ptau‐181 tau only in the uncontrolled group (group*time: F=4.2, p=.02). No other relationship between blood pressure and biomarkers was detected.

Conclusion

Subjects with baseline uncontrolled hypertension experienced longitudinal changes in amyloid and tau markers most consistent with progression toward Alzheimer’s disease. Interestingly, in this group increases in tau and p‐tau181 coincided with reduction in blood pressure. This may indicate relationship with relative hypoperfusion in subjects with vasculature compromised by years of high blood pressure.
Correlations between cognitive assessment and RNFL changes in OCT in healthy aging subjects
Authors: Shen Ting , Sheriff Samran , Schulz Angela , You Yuyi , Graham Stuart , Gupta Vivek K
Published: December 2021

Background

The retinal nerve fibre layer (RNFL) comprises retinal ganglion cell axons and link the outer neuroretina to the higher visual cortex. The retina is the only part of the central nervous system that can be visualised directly and non‐invasively by optical coherence tomography (OCT). The study aimed to examine whether changes in the visual pathway are correlated with various domains of cognitive function assessment. We evaluated correlation between retinal structural (OCT) and neuropsychological (trail making test, TMT; Boston naming test, BNT) measures in healthy aging subjects.

Method

In the present cross‐sectional clinical study, 74 healthy aging subjects were recruited from the Optic Nerve Decline and Cognitive Changes (ONDCC) study. All participants underwent OCT peripapillary ring scan protocol for RNFL analysis, TMT testing for attention and executive function and BNT neuropsychological examination for the detection of word‐retrieval or naming difficulties. Averaged RNFL thickness measures were used to analyse the relationship with TMT and BNT. Correlations between TMT, BNT and OCT parameters were analysed using partial correlation and controlled for age and gender (P < 0.05).

Result

The mean (SD) age of the current cohort is 67.5 (± 9.0 years). At baseline, significant correlation was observed between TMT‐test A and nasal RNFL thickness (r = ‐0.33, P = 0.009). The BNT also demonstrated mild but significant positive correlations with global (r = 0.32, P = 0.01), nasal (r = 0.27, P = 0.03) and nasal inferior (r = 0.33, P = 0.01) sectoral RNFL thicknesses respectively.

Conclusion

The results indicated a significant correlation between RNFL thickness and executive function domain of cognitive assessment. Sectoral RNFL was also significantly correlated with naming ability (BNT) across the cohort of healthy elderly. These findings suggest that the RNFL measures may parallel cognitive decline in the aging population. Further studies are planned in confirmed cognitively impaired subjects.
Language learning for people living with dementia and their carers: A feasibility study
Authors: Mendoza Mariana Vega , Blankinship Brittany , Norval Robbie , Bak Thomas H
Published: December 2021

Background

Converging evidence from across the world suggests positive effects of bilingualism on cognitive ageing and dementia, including a ca. 4‐6 years delay in the onset of dementia and’or Mild Cognitive Impairment. However, it is less clear whether language learning can also have a positive effect after the onset of dementia. A positive influence would include psychological and social variables, such as patients’ well‐being and their relationship with relatives and carers.

Method

We examined the feasibility and tolerability of language learning for people in early stages of dementia and their family carers in two Scottish Dementia Day Care Centres. A total of 12 people with dementia and 7 family carers participated in the study. All participants had only limited experience of language learning and none were bi‐/multilingual. The 2‐week courses of beginners Italian were delivered by specially trained tutors from Lingo Flamingo, a social enterprise specialising in language teaching for older learners and learners with Dementia. Before and after the course, we conducted focus group sessions with learners and their carers as well as interviews with teachers and Day Centre care workers.

Results

Qualitative analyses revealed a positive perception of the courses by patients, carers, and centre managers, impacting both the individual (e.g., boosting self‐esteem) and group (e.g., socialising) levels. No adverse effects (e.g., confusion) were reported. The family carers perceived the courses as empowering, as they allowed them to take an active part. The courses led also to a higher attendance in other activities conducted in the Day Care Centre.

Conclusions

Despite initial fears from professional carers that being confronted with the task of learning a new language might be stressful and lead to frustration and confusion, all participants reported a highly positive experience of the course, including a higher self‐esteem and self‐confidence as well as establishment of new social contacts and a more positive attitude to other activities of the day care centre. Further studies will be required to determine the optimal frequency, intensity and duration of language courses for people with dementia as well as the best practice of their delivery.
Racial differences in Alzheimer biomarkers among early‐stage symptomatic and cognitively normal Alzheimer Disease Research Center (ADRC) participants
Authors: Morris John C. , Ances Beau M. , Meeker Karin L. , Schindler Suzanne E. , Xiong Chengjie ,   Knight Alzheimer Disease Research Center, Washington University, St. Louis, Missouri USA
Published: December 2021

Background

There are few assessments of possible racial differences in Alzheimer disease (AD) biomarkers because research cohorts typically are not diverse. Should differences exist, they may inform the understanding of AD pathogenesis as well as the role of social determinants of health (SDOH).

Method

We assessed a non‐clinic‐based cohort of 1255 community living persons, age 45 and older, who were enrolled in studies of aging and dementia at the Knight ADRC (St Louis, Missouri, USA). Participants completed at least one brain magnetic resonance imaging (MRI) study, and/or at least one amyloid positron emission tomography (PET) scan, and/or at least one lumbar puncture to obtain cerebrospinal fluid (CSF) for biomarker assays. The cohort included 1082 white participants and 173 participants who self‐identified as Black or African American (AA); 33% of participants in each group had early‐stage symptomatic AD and 67% in each group were cognitively normal.

Result

Both racial groups demonstrated expected biomarker changes as a function of clinical status (eg, lower hippocampal volumes in persons with symptomatic AD). Higher body mass index and HgA1c levels were noted in AAs, but there was no racial difference in the frequency of MRI‐confirmed cerebral infarcts. There also were no differences in the mean cortical standardized uptake value ratios for Pittsburgh Compound B or in amyloid‐beta42 concentrations in CSF. However, mean CSF concentrations of tau and phosphorylated tau181 were lower in AA participants, a finding that was evident primarily in carriers of the ε4 allele of APOE. The CSF concentrations of soluble TREM2, a mediator of the inflammatory response to AD pathology, also were lower in AAs. Finally, decreased volumes in brain regions comprising the AD cortical signature were lower in AAs but this difference was mediated, at least in part, by SDOH.

Conclusion

There are racial differences in AD biomarkers between white and AA research participants, including for the AD cortical signature, a putative marker of neurodegeneration in the AT(N) framework. SDOH contribute to these differences, either independently or through interactions with biological factors.