bluuebunny/crossref_metadata_2025 huggingface dataset:
Practising brain health through traditional teachings and arts: A project funded by the Centre for Aging and Brain Health Innovation
Authors: Legare Marlin
Published: February 2022

Background

The loss of Indigenous culture in Canada through colonial interventions such as Residential Schools and the 60’s Scoop have left Indigenous Peoples and communities with deep‐rooted trauma. This type of trauma, in addition to the social isolation of living in remote communities, places Indigenous populations at risk for developing dementia. There is a need to increase opportunities for aging Indigenous populations to engage in social interaction that is culturally‐relevant and based in Traditional ways and culture.

Method

Morning Star Lodge, an Indigenous Health Research lab, has developed workshops for aging Indigenous adults who are at risk for developing dementia and their caregiver(s) to engage in traditional activities such as: games, arts and crafts, prayer (smudging). Research circles were conducted with Indigenous community members aging in place along with their caregiver(s) to discuss their perceived impacts on social functioning and cognitive health.

Result

The community members engaged in social interaction through Indigenous languages and story‐sharing. Traditional Knowledges and teachings were also weaved into the project design as many aging individuals expressed a feeling of isolation from cultural events and ceremonies due to immobility or lack of assistance with transportation, other needs, and the COVID‐19 pandemic. Through the data collected via an Indigenous, community‐led qualitative data analysis method the research team was able to identify central themes regarding practising Traditional arts and the cognitive health benefits that caregivers would like integrated in their communities.

Conclusion

Further research is needed to evaluate the long‐term benefits of health outcomes for Indigenous Peoples living with dementia and the effects on caregiver stress. Indigenous caregivers have expressed a desire for Traditional arts and teachings in their communities to alleviate stressors caused by dementia.
Neuroanatomical signatures of genetic risk for Alzheimer's disease in healthy adults
Authors: Waters Sheena , Watson Cameron , Jacobs Benjamin M. , Foote Isabelle F. , Dey Sumit , Noyce Alastair J. , Marshall Charles R.
Published: February 2022

Background

Early detection of Alzheimer’s disease (AD) is critical for the development of interventions that delay or prevent neurodegeneration. Previous studies suggest that genetic liability to AD may be associated with structural brain changes that start 20‐30 years before symptoms manifest.

Method

We derived an optimised AD polygenic risk score (AD‐PRS) using imputed genotype data from 488,377 participants in UK Biobank. We examined the structural brain correlates of AD‐PRS in 27,496 healthy UK Biobank participants using voxel‐based morphometry (VBM) with multiple regression and additionally performed regression analyses using image‐derived phenotypes (IDPs) from T1‐weighted and diffusion‐weighted magnetic resonance images.

Result

VBM revealed that high AD‐PRS was associated with reduced grey matter volume (GMV) in bilateral hippocampus and putamen (family wise error correction, p<0.05). IDP analysis further revealed GMV deficits in a bihemispheric limbic network incorporating hippocampus, parahippocampal gyrus, ventral striatum, orbitofrontal cortex, and thalamus, as well as reduced white matter integrity in the major white matter tracts of this network (fornix, cingulum hippocampus, and thalamic radiation).

Conclusion

Genetic liability to AD is associated with preclinical neurodegeneration in grey and white matter components of the limbic system. Integrity of this network could serve as a marker of preclinical AD and an outcome measure in prevention trials.
Multi‐center study of regulation of cerebral perfusion using spontaneous time‐series data shows impairment of CO2 vasoreactivity in MCI & AD patients
Authors: Marmarelis Vasilis , Billinger Sandra A. , Chui Helena C. , Joe Elizabeth B. , Shin Dae , Cardim Danilo , Hashem Suhaib , Kaufman Carolyn S. , Cullum Munro , Kelley Brendan , Zhang Rong
Published: February 2022

Background

Three AD Centers have joined together to study the regulation of cerebral perfusion at resting conditions using spontaneous time‐series data with a modeling methodology that previously yielded indications of reduced dynamic vasomotor CO2 reactivity in amnestic MCI patients [Marmarelis et al., J. Alzh. Dis. 56:89–105, 2017] and significant correlation of this reduction with functional impairment of the chemoreflex in these MCI patients [Marmarelis et al., J. Alzh. Dis. 75:1‐16, 2020]. The goal of this multi‐center study is to confirm these preliminary findings with larger cohorts of MCI patients, AD patients and age‐matched cognitively normal controls (NC), and to examine the time‐course of these impairments with longitudinal data over 5 years.

Method

Quantitative results were obtained through dynamic modeling of the effects of spontaneous changes in arterial blood pressure (ABP) and end‐tidal CO2 (etCO2) upon cerebral blood flow velocity (CBFV) in the middle cerebral arteries measured via transcranial Doppler. The obtained subject‐specific input‐output predictive models were used to compute indices (physio‐markers) that quantify the Dynamic Vasomotor Reactivity (DVR) in each subject/patient and to compare differences between NC, and MCI/AD patients.

Result

The obtained DVR indices were significantly different for patients (9 MCI and 4 AD taken together due to small numbers) vs. 32 controls (p=0.026). Notably, the delineation between patients and controls improved (p=0.009) after a session of slow paced‐breathing (8 breaths/minute) that led to larger average DVR for controls and to reduction of inter‐subject variability of DVR indices. This is illustrated in Figure 1, where the average model‐predicted responses (representing the CBFV response to a unit‐step change of etCO2) are shown for 13 MCI/AD patients (red line) and 32 controls (blue line) before and after the paced‐breathing session. Further improvement in delineating patients from controls is achieved (p=9x10‐5) when the DVR indices from the two sessions were averaged for each subject/patient.

Conclusion

Significantly lower DVR index under resting spontaneous conditions was observed in 13 MCI/AD patients relative to 32 NC before (p= 0.026) and after (p=0.009) slow paced‐breathing session. Averaging of the DVR indices obtained from data before and after paced‐breathing improved substantially this delineation (p=9x10‐5).
Technology use and attitudes among individuals with mild cognitive impairment and their care partners
Authors: Vickers Kayci L , Saurman Jessica L , Goldstein Felicia C
Published: February 2022

Background

During the COVID‐19 pandemic, the shift toward telehealth has drastically increased providers’ need to quickly gauge patient comfort with various technologies, especially for older individuals exhibiting cognitive impairments. Existing measures require significant training for administration and scoring, and do not include many technologies in use by older adults (e.g., social media or common smart phone applications). The present study aimed to adapt the Everyday Technology Use Questionnaire (ETUQ) to be self‐administered by individuals with MCI and their Care Partners.

Method

Twelve older adults with MCI (Mean Age= 74.1, SD= 8.4) and 10 Care Partners (Mean Age= 69.0, SD= 8.2) completed the 28‐item ETUQ and a Technology Attitudes Questionnaire (TAQ). The adapted ETUQ lists different technologies (e.g., television, smart phone, ride share apps). Participants were asked to rate their comfort using these technologies on a scale from 1 to 6, with higher ratings indicating greater comfort.

Result

Total scores in the MCI group ranged from 72 to 168 (Mean= 129.3, SD= 31.2) and in the Care Partners ranged from 137 to 162 (Mean= 149.2, SD=9.9). Independent samples t‐tests revealed a trend in ETUQ scores, wherein individuals with MCI reported lower overall comfort with technologies than care partners, t(13.6)= ‐2.09, p = .056. This represented a large effect size, d= 0.83. Items rated lower by individuals with MCI included: ride share apps (Lyft or Uber), Fitbit or activity trackers, social media (e.g., Facebook), Skype or video call, and WIFI routers. Analyses revealed no significant differences in age, attitudes toward technology or dependence on technology between groups.

Conclusion

These results support the use of an adapted ETUQ for individuals with MCI and their care partners. Interestingly, these ratings suggest individuals with MCI feel less comfortable with complex technology than their care partners, possibly reflecting cognitive difficulties. Future directions include validation of the adapted ETUQ and correlation to real‐world behaviors through in‐home monitoring.
Data‐driven staging and subtyping of genetic frontotemporal dementia using multi‐modal MRI
Authors: McCarthy Jillian , Medina Yasser Iturria , Ducharme Simon ,   for the GENetic Frontotemporal dementia Initiative (GENFI)
Published: February 2022

Background

Frontotemporal dementia is a highly heterogeneous disorder and neurodegeneration begins years prior to symptom onset, complicating disease understanding and treatment. Here we used an unsupervised machine learning algorithm to identify disease sub‐trajectories in genetic frontotemporal dementia.

Method

The contrastive trajectory inference (cTI, available at neuropm‐lab.com/neuropm‐box.html) is a method to analyze temporal patterns in multi‐dimensional populational datasets, consisting of unsupervised feature selection, contrastive prinicipal component analysis and subject ordering to obtain individual disease severity scores and distinct subtypes. We applied the cTI to cross‐sectional MRI data (gray matter density, T1/T2 ratio, fALFF, gray matter fractional ansiotrophy and mean diffusivity) from 383 gene carriers (269 presymptomatic and 115 symptomatic) from the GENFI study (148 with C9orf72 expansions, 169 with GRN mutations, and 67 with MAPT mutations) and a control group of 253 non‐carriers. The cTI was applied to all modalities in combination and individually. We compared the obtained disease severity scores to the estimated years to onset (EYO; age ‐ mean age of onset in relatives), clinical, and neuropsychological test scores. cTI subtypes were compared to genetic variants, as gene variants have specific pathology and group‐level differences in neuroimaging.

Result

The cTI identified disease severity scores were significantly correlated with all clinical and neuropsychiatric tests (measuring behavioural symptoms, attention, memory, language, and executive function) for all modalities, in combination and individually, and for the EYO for all modalities except mean diffusivity. The combination of all modalities provided the best overall results (CBI: r = 0.581, p < 0.001; EYO: r = 0.321, p < 0.001) (figure 1). Among individual modalities, gray matter density performed best (CBI: r = 0.475, p < 0.001; EYO: r = 0.286, p < 0.001). The cTI did not recover the three genetic variants, instead assigning most gene carriers (> 80%) to subtype 1 (figure 2). The cTI distinguished non‐carriers from carriers (87% of non‐carriers are in subtype 2).

Conclusion

The cTI can identify disease severity in a heterogeneous sample of genetic FTD using only neuroimaging metrics. It is unable to uncover genetic variants, suggesting that genetic variants may have similar neuroimaging features at early presymptomatic stages.
Baseline biomarker (tau PET) characteristics from TANGO: A phase 2 trial of gosuranemab (BIIB092) in early Alzheimer's disease
Authors: Racine Annie M. , Rajagovindan Raj , Collins Jessica A. , Kong Jessica , Li Yumeng , O'Gorman John , Jones Stephanie , Graham Danielle , Ratti Elena , Shulman Melanie
Published: February 2022

Background

Gosuranemab is a humanized monoclonal antibody that is hypothesized to neutralize extracellular tau and prevent the trans‐neuronal propagation of tau pathology across the brain. The TANGO study is an ongoing randomized, placebo‐controlled, global Phase 2 study evaluating safety and clinical efficacy of gosuranemab in individuals diagnosed with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or mild AD dementia. The TANGO study included two biomarker sub‐studies: cerebrospinal fluid (CSF) sub‐study and Tau positron emission tomography (PET) sub‐study; the baseline characteristics of the Tau PET sub‐study are described below.

Method

TANGO enrolled 654 individuals aged 50‐80 years, diagnosed with MCI or mild AD, who were amyloid positive as assessed by amyloid PET or CSF testing. Approximately 350 patients enrolled in the longitudinal 18F‐MK‐6240 Tau PET sub‐study. Randomization was stratified by biomarker sub‐study participation among other factors. Baseline standardized uptake value ratio (SUVR) was measured in composite brain regions of interest (ROIs) corresponding to Braak I‐II, Braak III‐IV, and Braak V‐VI regions using superior‐eroded cerebellum as the reference region. Tau extent (percentage of supra‐threshold voxels within an ROI relative to reference region), an exploratory measure of the spatial extent of 18F‐MK‐6240 binding, was also investigated.

Result

The baseline demographics of the Tau PET sub‐study population were consistent with the overall TANGO study population including clinical stage (MCI vs. mild AD), age, gender, APOE4, and clinical scores. At baseline, average SUVR (±SD) was 1.92±0.6 in Braak I‐II, 1.90±0.7 in Braak III‐IV and 1.75±0.8 in Braak V‐VI composite ROIs. The Braak composite SUVRs were positively associated with disease stage (i.e. higher SUVR with increasing disease severity). Exploratory analyses of extent were supportive of the SUVR results.

Conclusion

At study baseline, tau SUVR was highest in Braak I‐II, followed by Braak III‐IV, then Braak V‐VI. Cross‐sectionally, higher tau PET SUVR was associated with increasing disease severity and worse clinical scores, as expected. The TANGO Tau PET sub‐study will aid our understanding of gosuranemab’s effect on tau pathology and further inform on the value of tau PET in clinical trials.
Neuroanatomical predictors of progression to dementia in primary progressive aphasia
Authors: Quimby Megan , Hochberg Daisy , Katsumi Yuta , Carvalho Nicole , Brickhouse Michael , Flaherty Ryn , Dickerson Brad C. , Touroutoglou Alexandra
Published: February 2022

Background

Patients with Primary Progressive Aphasia (PPA) have a prominent, isolated language deficit during the initial phase of the illness, with other cognitive and affective functions being affected later on (Gorno‐Tempini et al. 2011; Mesulam, 2001). Based on evidence that executive, memory and socioaffective functions are associated with functional independence (De Paula et al. 2015), we hypothesized that greater atrophy in cognitive or affective brain networks outside language networks is predictive of dementia in PPA. The development of quantitative neuroanatomical prognostic biomarkers for loss of independent functioning would be valuable in research and clinically (e.g. treatment recommendations, family education).

Method

50 PPA patients (17 agrammatic, 14 semantic, and 19 logopenic variant), who underwent a clinical and MRI evaluation at baseline and had at least 6 months of follow‐up, were selected. For each patient we measured the time between the first visit and the progression to dementia or last observation. We estimated individual network atrophy using surface‐based analyses described in our previous studies and using large‐scale cortical cognitive and affective networks derived from the Yeo et al. 2011 parcellation. We performed Cox regression models to test the hypothesis that greater baseline atrophy in cortical networks subserving non‐language cognitive or affective functions predicts time to dementia, but that greater atrophy in the visual association network (serving as a control) does not.

Result

Univariate Cox regression analysis showed that patients with greater atrophy outside the language network, in left hemisphere heteromodal association and paralimbic areas, including the default mode, frontoparietal, salience and ventral frontotemporal networks, had the highest risk of progression to dementia within a shorter time period of time (HR: 2.26, 95% CI: 1.45‐ 3.51). Atrophy in the language network was also a predictor, although slightly weaker (HR: 2.05, 95% CI: 1.41‐ 2.98). Atrophy in the visual association network did not predict time of conversion to dementia (left hemisphere: HR: 1.19, 95% CI: 0.86‐ 1.64; right hemisphere: HR: 1.21, 95% CI: 0.86‐ 1.68).

Conclusion

In PPA patients, baseline cortical atrophy outside language networks is an important predictor of more rapid progression to dementia. This measure should be included in precision medicine models of prognosis in PPA.
Normative morphometrics from MRI are associated with episodic memory test performance in amnestic MCI
Authors: Kraal A. Zarina , Benitez Andreana
Published: February 2022

Background

Proprietary software that generate normative scores for brain regions using MRI (e.g. NeuroQuant, Neuroreader) have identified greater atrophy in MCI patients than controls, particularly in the hippocampus, and have associated these measurements with episodic memory performance (Tanpitukpongse et al., 2017; Umfleet et al., 2020). While useful in clinical settings, these may be cost‐prohibitive for research purposes. Our goal was to conduct a validation study using free, non‐proprietary morphometric software (Potvin et al., 2016; 2017) with data from a cross‐sectional study of amnestic MCI (aMCI) and normal controls (NC).

Method

102 older adults ages 60 to 86 (nNC=75; naMCI=27) underwent 3T brain MRI and neuropsychological testing (Weintraub et al., 2018). T1‐weighted images were segmented using FreeSurfer v5.3, and from these outputs normed z‐scores were generated, adjusting for age, sex, total intracranial volume, and MRI field strength (Potvin et al., 2016a; 2016b; 2017). We hypothesized that volumes of AD‐relevant regions (hippocampus, amygdala, entorhinal cortex, parahippocampus) would be smaller in aMCI than NC with no differences in non‐AD “control regions” (cuneus, lingual gyrus, pericalcarine; Fig. 1.A), and that AD‐relevant volumes would correlate with episodic memory composites (i.e. average of normed scores (percentiles) on immediate, delay, and recognition trials from list‐learning (Rey‐Auditory Verbal Learning Test) and story‐learning (Wechsler‐Logical Memory) tests).

Result

Bonferroni‐corrected t‐tests showed significantly lower volumes of all AD‐relevant regions in the aMCI versus NC, with large effect sizes (Hedge’s g=0.9 to 1.2), and no group differences in control regions (ps<0.05, Hedge’s g<0.3). Bivariate correlations showed moderate (rs=0.38 to 0.55) associations between memory composites and most AD‐relevant regions in the aMCI but not the NC group (Fig. 1.B.1), and no associations between memory composites and control regions except for a positive association between story‐learning and cuneus volume in aMCI (Fig. 1.B.2).

Conclusion

Similar to results using proprietary software, this study validates the potential clinical utility of a non‐proprietary normative morphometric software when distinguishing aMCI from NC, with AD‐relevant volumes associated with episodic memory in aMCI. Future studies are needed to characterize associations between other AD‐relevant brain regions and cognitive domains.
The relationship between APOE genotype and subcortical volume: A UK Biobank study (N=36,920)
Authors: Muir Alexandra M , Ching Christopher , Santhalingam Vigneshwaran , Abaryan Zvart , Zhu Alyssa H , Thomopoulos Sophia I , Jahanshad Neda , Thompson Paul M
Published: February 2022

Background

Two copies of the apolipoprotein (APOE) ε4 allele is associated with approximately 10 to 20 times greater risk for late‐onset Alzheimer’s disease (AD)1,2,3, depending on genetic ancestry. Although reduced hippocampus and amygdala volumes are seen in ε4 carriers with mild cognitive impairment (MCI) and AD4,5, the relationship between genetic risk and brain structure in healthy older adults is unresolved. Here we mapped normative subcortical volume trajectories in a large sample of healthy adults and tested for the effects of APOE genotype.

Method

T1‐weighted images from 36,920 UK Biobank7,8 participants () were processed using FreeSurfer 7.1. Averaged thalamus, pallidum, hippocampus, amygdala, caudate, nucleus accumbens, and lateral ventricle volumes were calculated. APOE genotypes included ε2ε2, ε2ε3, ε3ε3, ε3ε4, and ε4ε4. ε2ε4 carriers and individuals with neurological/psychological disorders were not included. Nomograms of subcortical volumes were plotted. The statistical relationship between subcortical volume and APOE genotype was assessed using linear mixed models, adjusting for age, sex, intracranial volume, population structure, and scan site. Additionally, an age‐by‐APOE interaction was assessed, with all p‐values corrected using the standard false discovery rate9.

Result

Nomograms separated by APOE genotype () show a general trend of smaller volumes, but larger ventricles, with increasing age. Statistically, hippocampal and amygdala volumes were smaller in ε4ε4 compared to carriers of the ε3 allele (; d: ‐0.12 to ‐0.05). Carriers of at least one ε4 allele had smaller nucleus accumbens and thalamic volumes compared to carriers of the ε3 allele (d: ‐0.08 to ‐0.03). Lower thalamic volumes were associated with ε2ε2 compared to ε2ε3 and ε3ε3 (d: ‐0.14 to ‐0.03). No ROI showed a significant age‐by‐APOE genotype interaction.

Conclusion

These results suggest a pattern of subtle and structure‐specific effects of AD genetic risk on subcortical volume across adulthood. Future studies aim to bolster the ε2ε2 sample size to confirm lower thalamic volume in these carriers. Additionally, we will investigate other genetic and environmental risk factors that affect brain structure, modulate healthy brain aging, and predict conversion to MCI or AD.
Sensory stimulation for nursing home residents: Systematic review and meta‐analysis of its effects on sleep quality and rest‐activity rhythm in dementia
Authors: Prins Angela J , Scherder Erik JA , van Straten Annemieke , Zwaagstra Yvonne , Milders Maarten V
Published: February 2022

Background

Despite the evidence that disrupted sleep‐wake cycles are associated with an exacerbation of behavioural disturbances and an acceleration of the disease progression in dementia, the effect of sensory stimulation for improving sleep quality and rest‐activity rhythm is unclear. The aim of the current meta‐analysis is to give an overview of the effectiveness of sensory stimulation interventions on reduction and prevention of sleep disturbances in nursing homes residents with dementia.

Method

A systematic literature search and meta‐analysis were performed on December 3, 2019. Twenty‐seven studies examining the effects of a sensory stimulation intervention on rest‐activity rhythm and/or nocturnal restlessness in nursing home residents with dementia were included. Outcomes were measured with Actiwatches and/or standardized observation scales. Extensive subgroup meta‐analyses were performed to adjust for varying characteristics of included studies.

Result

Uni‐sensory stimulation including tactile and visual stimulation (i.e. light therapy, massage, acupuncture, animal‐assisted interventions) seemed effective for improving sleep quality and strengthen the rest‐activity rhythm (Hedges g=.47, p ≤ .01, Figure 1). More specifically, visual and tactile stimulation with a minimum of 30 minutes/day for two weeks have effectively reduced the duration of nocturnal awakenings (g=‐.29, p≤.05), sleep onset latency (g=‐.25, p≤.05), and nocturnal behaviour disturbances (g=‐.57, p≤.01), and have improved nocturnal sleep duration (g = .38, p ≤ .01), and sleep efficiency (g=.48, p≤.01). The heterogeneity within the majority of outcomes varied between medium and large. The majority of studies were of poor quality (59%, Figure 2). Dementia type and severity, gender, treatment duration and intensity (light levels in lux values) were not related to the effectiveness of sensory stimulation in all outcomes.

Conclusion

Although the methodological quality of the studies was limited, we found indications that sleep quality and nocturnal restlessness in nursing home residents with dementia may benefit from sensory stimulation. Recommended is to use a sensory stimulating environment in nursing homes which may prevent or improve sleep disturbances, and therefore can contribute to higher quality of life of their patients. Future research should conduct RCTs, while using comparable interventions, measuring instruments and procure, so the quality of dementia can be further improved.
Association of deep‐learning–derived brain computed tomography measures with cognition and blood‐based biomarkers of neurodegenerative diseases
Authors: Srikrishna Meera , Ashton Nicholas J. , Pereira Joana B. , Heckemann Rolf A. , Westen Danielle , Volpe Giovanni , Simrén Joel , Zettergren Anna , Kern Silke , Wahlund Lars‐Olof , Gyanwali Bibek , Hilal Saima , Chong Joyce R. , Zetterberg Henrik , Blennow Kaj , Westman Eric , Chen Christopher , Skoog Ingmar , Schöll Michael
Published: February 2022

Background

Existing imaging biomarkers for neurodegenerative diseases such as magnetic resonance imaging (MRI) and positron emission tomography are costly or have limited accessibility. Computed tomography (CT) and novel blood tests have greater potential as screening modalities for suspected neurodegenerative diseases and to potentially exclude other treatable causes of neurodegeneration.

Objective

To evaluate the association of volumetric brain measures, derived using a novel CT‐based deep‐learning algorithm with cognition and blood levels of neurodegeneration markers.

Method

We previously developed deep‐learning‐based models using 734 datasets (722 cognitively normals (CN)) from Gothenburg H70 Birth Cohort to segment head CTs by learning from MRI‐derived labels. We used these models to segment, without further training, 204 novel CT datasets (73 Alzheimer's disease (AD), 49 mild cognitive impairment (MCI), 20 vascular dementia (VAD), 40 vascular cognitive impairment (VCI), 22 CN) recruited from the Singaporean Memory Clinic cohort (mean age= 74.0±8.2 years, 50.5% female), without MRI intervention. We tested associations between six CT‐derived volumetric measures (grey matter (GM), white matter (WM), GM/CSF, GM/ventricular CSF (VCSF), brain volume (BV)/CSF, BV/VCSF) with diagnosis, plasma biomarkers, and cognition. The plasma biomarkers were measured using a Simoa platform (Quanterix, Bilerica, MA,USA).

Result

The novel CT segmentations correlated significantly with their corresponding MRI‐segmentations. Lower CT‐derived tissue volumes correlated with higher plasma neurofilament (NFL) concentrations in the H70 cohort. In the MCC NUH cohort, lower CT‐derived volumes correlated with lower MMSE scores and higher plasma NFL. CT‐derived volumes yielded high diagnostic accuracy for AD vs CN (AUC ROC 0.87). Mean CT‐based volumetric measures were lower in AD and VAD compared with CN. Kruskal‐Wallis tests showed a statistically significant difference in CT‐based volumetric measures predominantly for GM/CSF and BV/CSF across all diagnostic groups, notably between AD vs CN and CN vs early stages of dementia.

Conclusion

Deep‐learning‐derived CT‐based volumetric measures correlate with relevant other imaging, cognitive and biochemical markers of neurodegenerative diseases. This supports the potential application of CT‐derived volumetric measures in aiding diagnostics and early detection of dementia. Further explorations of the association between CT‐based measures with visual assessments and other clinical and imaging biomarkers will be undertaken.
Influence of amyloid deposition on the interaction between tau and glucose metabolism
Authors: Nowell Joseph , Raza Sanara , Livingston Nicholas R. , Crook Harry , Young Megan , Edison Paul
Published: February 2022

Background

Pathological hallmarks of Alzheimer’s disease include the formation of extracellular Aβ plaques and intracellular neurofibrillary tau tangles, which with recent PET imaging advances can be assessed in vivo. Accumulation of tau has been closely linked to metabolic abnormalities in PET imaging studies, with inverse associations between tau deposition and glucose metabolism. This study aimed to assess whether the association between [18F]FDG and [18F]AV1451 in cognitively impaired patients is dependent on the presence of significant amyloid pathology.

Method

240 patients with mild cognitive impairment or Alzheimer’s disease (Mean age = 74.5 years, SD = 8.03) were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (adni.loni.usc.edu). All participants completed a T1‐weighted MPRAGE MRI, amyloid ([18F]AV45 or [18F]florbetaben), [18F]AV1451 and [18F]FDG scans. Standard uptake ratio values were calculated in SPM12 to identify the glucose metabolic rate and tau deposition within cortical regions. Amyloid status (Aβ‐positive/Aβ‐negative) was determined from processed data using a whole brain cerebellar ratio with a cut‐off value of 1.11 ([18F]AV45) and 1.08 ([18F)florbetaben). Pearson’s correlation coefficients were calculated to assess the relationship between imaging modalities.

Result

There were significant negative associations between AV1451 and FDG tracer uptake in the medial temporal lobe (r = ‐0.389, p <0 .001), occipital lobe (r = ‐0.276, p = 0.001), parietal lobe (r = ‐0.209, p = 0.014), and posterior cingulate (r = ‐0.245, p = 0.004) in Aβ‐positive patients. Similarly, a strong negative relationship was observed between the imaging modalities in Aβ‐negative patients in the medial temporal lobe (r = ‐0.345, p < 0.001), however a significant positive association was also observed in the anterior cingulate cortex (r = 0.350, p < 0.001).

Conclusion

This study demonstrated that [18]FDG and [18F]AV1451 tracers have strong regional signal associations in patients with cognitive impairment. The results indicate that tau has a detrimental effect on glucose metabolism in the medial temporal lobe, independent of significant amyloid plaque formation. In patients determined as amyloid‐negative, we may be observing some compensatory regional increase in glucose metabolism in the early stages of tau accumulation.
Fixel‐based analysis of the effect of amyloid beta on white matter tracts in neurologically normal 70 year olds
Authors: Wagen Aaron Z. , Zarkali Angeliki , Coath William , Buchanan Sarah M. , Keuss Sarah E. , Keshavan Ashvini , Lu Kirsty , James Sarah‐Naomi , Pavisic Ivanna M. , Street Rebecca E. , Parker Thomas D. , Lane Christopher A. , Murray‐Smith Heidi , Cash David M. , Malone Ian B. , Wong Andrew , Richards Marcus , Fox Nick C. , Altmann Andre , Cole James H. , Weil Rimona S. , Schott Jonathan M.
Published: February 2022

Background

Fixel‐based analysis (FBA) of diffusion MRI allows analysis of brain white matter (WM) tracts with greater specificity than voxel‐based approaches, including measures of microstructural fibre density (FD), macrostructural fibre cross section (FC), and representations of crossing fibres. We use FBA to explore early WM changes associated with amyloid‐β (Aβ) prior to manifestations of Alzheimer’s disease. We additionally explored global WM changes associated with increased cardiovascular risk.

Method

We performed FBA on 233 participants in the Insight 46 birth cohort study, all of whom have been followed prospectively since birth in a single week in 1946, including cardiovascular risk assessment using the Framingham Risk Score (FRS). At age 69‐71 participants underwent cognitive assessment and combined 18F‐florbetapir PET‐MRI scans on a single scanner. Aβ positive status was defined using a Gaussian mixed model as a standardised uptake value ratio over 0.6103. Using Aβ positive (n=40) and negative (n=193) participants with no major brain disorders and excellent scan quality, we assessed FD and FC, as well as the combined FD and FC (FDC) metric across all white matter fixels. Subsequently we performed a tract‐of‐interest analysis of associations between Aβ and FDC in 13 selected white matter tracts, 7 defined a priori based on Alzheimer’s disease mechanisms, and 6 based on results of the global analysis.

Result

Aβ positivity was associated with changes in microstructural and macrostructural changes (FD, FC and FDC), throughout the right corticospinal tract inferior to the internal capsule, and microstructurally in the right inferior longitudinal fasciculus. Similar left sided corticospinal changes were seen in FC and FDC only. Increased FRS was associated with FD changes in the right superior longitudinal fasciculus. Tract‐of‐interest analyses showed no significant associations between FDC and Aβ after false discovery correction using the Benjamini‐Hochberg method.

Conclusion

We show Aβ associated changes in fixel‐based metrics in the corticospinal tracts, predominantly affecting the right hemisphere. These preliminary results raise the possibility of these fibres being predisposed to damage, perhaps in a length dependent manner, though longitudinal analysis based on further phases of Insight 46 may prove more powerful to detect change at this very early stage.
Longitudinal associations between amyloid and tau‐PET: Impact for prevention trials
Authors: Hanseeuw Bernard , Jacobs Heidi I.L. , Becker Alex , Buckley Rachel F. , Properzi Michael J. , Farrell Michelle E. , Schultz Aaron P. , Sanchez Justin S. , Chhatwal Jasmeer P. , Price Julie C. , Sperling Reisa A. , Johnson Keith A.
Published: February 2022

Background

In Alzheimer’s disease, cognitive decline is associated with a rapid increase in tau pathology, making tau‐PET a potentially useful outcome in prevention trials. To identify individuals most at‐risk of tau accumulation, we investigated the longitudinal associations between amyloid and tau in clinically normal (CN) and impaired (MCI/AD) participants from the Harvard Aging Brain Study.

Method

Serial Flortaucipir tau‐PET measures (2‐4 observations over a median 2.2years [0.8 to 6.0]) were obtained from 128CN and 11MCI/AD participants (Table 1). PiB (amyloid‐PET) data were expressed as Centiloid (CL) values. Flortaucipir data were expressed as PVC‐SUVr in inferior temporal neocortex scaled to subcortical white matter. We obtained tau slopes per subject from linear mixed‐effect models with random intercept and slopes. We tested in the entire sample, and in CN only, the association between Tau slope and baseline PiB and Tau‐PET. Linear, quadratic, and cubic relationships were tested. Age and sex were used as covariates. We computed power curves simulating therapeutic trials.

Result

In the entire sample (n=139), both baseline Tau (R2=0.34, Fig. 1 red‐line) and PiB (R2=0.30, Fig. 2 red‐line) were linearly associated with subsequent tau slope. In CN (n=128), these associations were lower than in MCI/AD, but significant (Tau: R2=0.16, PiB: R2=0.15, p≤0.00001). Importantly, a cubic fit best matched the PiB data (Fig. 2 blue‐line): A positive association between baseline PiB and Tau changes was only observed between PiB CL=‐2 and CL=66, with a maximal association at CL=32. In CN, the greatest tau changes were observed at CL=66. There was evidence of slowing in tau accumulation rate in the small number of CN with higher PiB CL. As a result, trials simulations demonstrated that increasing the Centiloid threshold to enroll CN participants did not increase power (Fig. 3 blue‐lines); in contrast, power was increased when excluding CN with CL>66 (Fig. 3 red‐line) or when enrolling CN with high baseline tau (Fig. 4 red‐lines). Enrolling MCI patients in therapeutic trials had a similar effect than enrolling high‐amyloid CN participants with baseline Tau SUVr>1.30 (Fig. 4 blue‐line).

Conclusion

A combination of amyloid and tau thresholds proved more effective to increase the power of Tau‐PET outcomes in prevention trials than using only amyloid.
Longitudinal FDG‐PET and FTP‐PET demonstrates the relationship between glucose metabolism and tau accumulation in Alzheimer’s disease atrophy‐associated brain regions in cognitively normal older adults
Authors: Crook Harry , Nowell Joseph , Raza Sanara , Edison Paul
Published: February 2022

Background

In certain brain regions, glucose hypometabolism, amyloid‐β and tau accumulation all increase in the pre‐clinical stages of mild cognitive impairment and Alzheimer’s disease (AD). Studies demonstrate associations between glucose metabolism, amyloid‐β, and tau protein and neurodegeneration, however, little has been done to elucidate any direct associations between tau accumulation and glucose metabolism in the pre‐clinical stage of AD. Here, we evaluate the relationship between cerebral tau accumulation and glucose metabolism longitudinally, in a cohort of cognitively normal older adults.

Method

To assess cerebral glucose metabolism and tau accumulation, the standardised uptake value (SUV) from fluorine‐18 fluorodeoxyglucose (FDG) and fluorine‐18 flortaucipir (FTP) positron emission tomography (PET) was calculated from a cohort of cognitively normal participants recruited through the Harvard Ageing Brain Study. This included 43 subjects (mean±SD age at baseline, 73.6 ±5.6 years) who had both baseline and follow‐up (mean±SD time from baseline, 3.1 ±0.19 years) FDG‐ and FTP‐PET scans. Regional glucose metabolism and tau accumulation was calculated using SUV ratios, and correlations were calculated for different AD pathology‐specific brain regions to assess any potential relationship between cerebral tau and glucose metabolism.

Result

In this cohort, tau accumulation significantly increased in the inferior temporal lobe (p=0.001) and temporal pole (p=0.024), while glucose metabolism significantly decreased in the entorhinal cortex (p=0.035) and the temporal pole (p=0.033) from baseline to follow‐up assessment. The rate of tau accumulation was significantly correlated with baseline tau levels in the inferior temporal lobe (r=0.344, p=0.024), and baseline FDG levels in the left hippocampus (r=0.527 , p<0.001).

Conclusion

Cerebral tau accumulation and glucose metabolism seem to be linked in cognitively normal older adults, especially in temporal regions of the brain. This highlights the potential requirement for Alzheimer’s disease treatments to be administered in the pre‐clinical stage of the disease, before cognitive symptoms develop.
Head‐to‐head comparison of [18F]Flortaucipir and amyloid PET visual reads for differential diagnosis: An international, multi‐center study
Authors: Soleimani‐Meigooni David N. , Smith Ruben , Provost Karine , Lesman‐Segev Orit H. , Cho Hanna , Edwards Lauren , Iaccarino Leonardo , La Joie Renaud , Ossenkoppele Rik , Strandberg Olof , Strom Amelia , Lyoo Chul Hyoung , Hansson Oskar , Rabinovici Gil D.
Published: February 2022

Background

Quantitative [18F]Flortaucipir (FTP) tau PET analysis has good discriminative accuracy for Alzheimer’s disease (AD), but visual reads are used clinically. We aimed to compare the diagnostic accuracy of FTP‐PET to amyloid PET visual reads for distinguishing AD dementia and amyloid‐positive mild cognitive impairment (MCI) from other neurodegenerative diseases and cognitively normal (CN) controls.

Method

We included 661 participants studied with FTP and amyloid PET at UCSF, Lund University, and Gangnam Severance Hospital (Table 1). Amyloid PET tracers were site‐specific (UCSF, [11C]PIB; Lund, [18F]Flutemetamol; Gangnam, [18F]Florbetaben). Three visual raters interpreted amyloid PET using tracer‐specific criteria and FTP‐PET using a recently proposed method (Figure 1; Sonni et al. Alzheimer's Dement. 2020, 12:e12133. doi: 10.1002/dad2.12133). Amyloid and FTP‐PET were read in separate, randomized batches, blinded to the reads of the other physicians. The majority interpretation of each scan as amyloid positive/negative and tau positive/negative was used in the primary analysis. Diagnostic performance of FTP and amyloid PET visual reads, including sensitivity and specificity, were calculated. Kappa statistics for intra‐ and inter‐rater reliability were calculated.

Result

Amyloid and FTP‐PET visual reads had similar sensitivity (92.6%, 95%‐confidence interval [88.7‐95.5%], 92.2% [88.2‐95.2%], respectively) and specificity (82.9% [78.9‐86.5%], 78.2% [73.9‐82.1%], respectively) for distinguishing AD and amyloid‐positive MCI from all other dementias and CN controls (Table 2). Amyloid PET and FTP‐PET visual reads had similar diagnostic performance for distinguishing AD or amyloid‐positive MCI from non‐AD neurodegenerative disorders or CN controls (Table 3). FTP‐PET intra‐rater reliability ranged from κ=0.80‐1.00 (p<0.0001), and inter‐rater reliability between reader pairs ranged from κ=0.78‐0.85 (p<0.0001). Amyloid PET intra‐rater reliability was κ=0.97 (p<0.0001) for each reader, and inter‐rater reliability between reader pairs ranged from κ=0.82‐0.88 (p<0.0001).

Conclusion

FTP and amyloid PET visual reads have similar diagnostic performance and high intra‐ and inter‐rater reliability. Further analysis will be performed to determine if patient characteristics can predict when one PET modality will outperform the other for AD diagnosis.
White matter network structure as a substrate of cognitive brain reserve in cerebral small‐vessel disease: The Maastricht Study
Authors: De Jong Nathan , Backes Walter H. , Jansen Jacobus F.A. , van Boxtel Martin P.J. , Schram Miranda T. , Stehouwer Coen D.A. , Dagnelie Pieter C. , van Greevenbroek Marleen M.J. , van der Kallen Carla J.H. , Kroon Abraham A. , Schaper Nicolaas C. , Eussen Simone J.P.M. , Koster Annemarie , Wesselius Anke , Sep Simone J.S. , Koehler Sebastian
Published: February 2022

Method

The Maastricht Study is a population‐based cohort study with extensive phenotyping, enriched for type‐2 diabetes. Cognitive test scores, structural connectivity data, and 3T MRI were available for n=4798 participants (mean age(±SD)=59.2(±8.7), 50.0% male). Images were assessed by Fazekas score (£1 or ≥2), presence of microbleeds and lacunar infarcts in terms of dichotomous measures, and combined into a cSVD score (range 0‐3). Node degree (ND), a measure of the mean interconnectedness of nodes in the structural connectome, was used as connectivity score. A composite cognition score (CS) was taken as the mean score across three cognitive domains (Memory, Information Processing Speed and Executive Function). Multivariable linear regression analyses were used to investigate the interaction effect between ND and cSVD score on CS, adjusted for age, sex, education, and diabetes status.

Result

Higher cSVD score was associated with lower CS. ND modified the association between cSVD score and CS in the adjusted model (p for interaction p<0.004). While there were clear cognitive differences across cSVD levels if ND was low, the association between cSVD and cognition was attenuated in a dose‐response fashion with increasing ND (Figure 1).

Conclusion

Structural ND provides evidence of an individual’s CR based on white matter organization in the presence of damage from cSVD. Even in participants with the highest cSVD burden, sufficiently high ND score was associated with normal CS.
Genetic association of APOE epsilon2 genotype with neurophysiological characteristics in healthy adults
Authors: Ponomareva Natalya V. , Andreeva Tatiana , Protasova Maria , Kolesnikova Ekaterina V. , Malina Daria , Fokin Vitaly , Illarioshkin Sergey , Rogaev Evgeny I
Published: February 2022

Background

The association of apolipoprotein E genotype with late‐onset AD (LOAD) is well established. APOE e4 allele is the major common risk factor for LOAD (Saunders et al., 1993), and the rare APOE e2 allele appears to confer protective effect for LOAD (Goldberg et al., 2020). The mechanisms underlying the impact of the APOE e2 allele on LOAD development remain largely unknown. The study was aimed at determining the possible APOE e2 genotype effect on EEG and cognitive event‐related potentials (ERP) in non‐demented adults.

Method

The enrolled cohort included 135 healthy volunteers, age range 20‐69 years, stratified by APOE genotype. APOE e2/e3 subgroup included 21 subjects, APOE e3/e3 subgroup ‐ 76 subjects, APOE e4/e3 subgroup ‐ 38 subjects. Informed written consent was obtained from all participants. All subjects underwent a neurological examination and cognitive screening. The significance of the differences between the EEG and cognitive ERP characteristics in different subgroups was estimated using ANOVA in the general linear model

Result

The presence of the APOE e2/e3 genotype was associated with higher individual alpha peak frequency (IAPF) relative to the presence of APOE e3/e3 and APOE e4/e3 genotypes. IAPF a stable neurophysiological 'trait' marker which has been shown to correlate with better memory scores (Grandy et al., 2013). In the carriers of APOE e2 allele P300 latency remained stable during aging, while in the carriers of APOE e3/e3 as well as APOE e4/e3 genotypes P300 latency showed positive correlation with age.

Conclusion

APOE e2 genotype is associated with higher EEG IAPF and stable P300 latency during aging that can underlie better cognitive reserve and protective effect against LOAD. The effect may be related to larger hippocampal volume and better maintenance of neuronal connections in APOE e2 healthy carriers compared to non‐carriers.
Identification of a robust cortical thickness signature of AD in the Framingham Heart Study
Authors: Satizabal Claudia L. , Beiser Alexa S. , Fletcher Evan M. , Seshadri Sudha , DeCarli Charles S.
Published: February 2022

Background

Alzheimer’s disease (AD) starts decades before the onset of clinical symptoms, posing enormous challenges for the development and administration of timely treatments. Therefore, the development of robust AD biomarkers continues to be a high priority in the field. MRI‐derived measures are suitable, non‐invasive biomarkers in populations at risk. We aimed to identify and validate a signature region of AD in the Framingham Heart Study (FHS).

Method

For the training set, we identified a group of cases with prevalent AD at the time of MRI (n=69), and controls matched on age and sex (n=133). Cortical thickness maps from 3DT1 sequences were compared between cases and controls to derive an AD signature ROI (Figure 1). For validation, we computed signature ROI cortical thickness means in a non‐overlapping stroke‐ and dementia‐free sample. We used Cox proportional hazard models to relate the cortical AD signature in those aged ≥60 years to dementia risk over 10‐years adjusting for age and sex, and linear regression models to assess the cross‐sectional association between the cortical AD signature and cognitive function adjusting for age, sex, and education. In analyses, a second model additionally adjusted for MRI markers.

Result

The validation sample included n=1,146 participants (mean age 70±7 years, 53% women), of whom 95 developed AD. Participants in the bottom quartile of the AD signature ROI had more than four times increased AD risk compared to those in the upper three quartiles (Table 1; Hazard Ratio [HR]= 4.44, 95% CI 2.84‐6.94, p<0.0001). This association remained after the inclusion of classic MRI markers of brain aging (i.e., hippocampal, total brain, and white matter hyperintensity volumes; HR=2.54, 95%CI 1.56‐4.13, p<0.0001). Our cross‐sectional sample included n=2,163 participants (mean age 63±10 years, 54% women). Greater thickness in the AD signature ROI was related to better general cognitive function (Beta=0.04±0.02, p=0.02), and logical memory (Beta=0.22±0.08, p=0.004), although adjustment for other MRI markers attenuated the association with general cognitive function (Table 2).

Conclusion

We have identified a strong neuroimaging biomarker for risk stratification of persons at increased risk of AD. Additional analyses are underway to validate this signature region in multiethnic samples.