bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of florbetaben acquisition timing on continuous and dichotomous measures of amyloid burden: implications for real‐world amyloid PET interpretation
Authors: Johns Emily , Young Christina B. , Vossler Hillary , Younes Kyan , Trelle Alexandra N , Poston Kathleen L. , Davidzon Guido , Mormino Elizabeth C.
Published: December 2023

Background

The magnitude of Standardized Uptake Value Ratios (SUVRs) and Centiloid (CL) values increase at later acquisition windows for Florbetaben (FBB). As amyloid PET is anticipated to be utilized for treatment decisions with anti‐amyloid therapeutics (van Dyck, 2022), it is important to understand acquisition factors that influence PET quantification.

Method

We analyzed 120 FBB scans from the Stanford Alzheimer’s Disease Research Center with 5‐minute frame data spanning 70‐110 minutes post‐injection (Table 1). Frame data were motion corrected, summed into 70‐90 and 90‐110‐minute files, and processed through an MRI‐Free pipeline. A global cortical target region and whole cerebellum reference region from the GAAIN atlas were used to create SUVRs and CLs (Klunk, 2014). SUVRs and CLs computed across the two acquisition windows were compared using linear regression to understand the effects of timing acquisition on magnitude. Gaussian Mixture Models (GMM) were used to convert SUVRs to a probability scale separately for 70‐90 and 90‐110 datasets. 10,000 bootstrapped mixed timing datasets were created by randomly selecting either 70‐90 or 90‐110 SUVRs for a given participant, which was then used to understand the impact of GMM‐based classification into A‐ and A+ groups when acquisition time varies within dataset.

Result

CLs were systematically lower during the earlier acquisition window (2.01 CL for the CL<10 group, ΔCL range = ‐8.83,9.16; 2.89 CL for the 10‐25 group, ΔCL range = ‐2.18,9.33; 3.62 CL for the 25‐50 group, ΔCL range = ‐0.04,11.34; and 10.94 for the >50 group, ΔCL range = 1.81,26.98) (Fig. 1). GMM classification into A‐ and A+ groups was consistent across the two acquisition windows and in the mixed timing datasets (Table 2).

Conclusion

GMM is a robust quantitative method that can be used to characterize amyloid PET scans into A‐ and A+ groups when acquisition time varies. However, given the inconsistent impact of acquisition time on CL magnitude, comparison of CL values before and after anti‐amyloid treatments will require adjustment for scan acquisition time. Future work is needed to establish methods that can measure amyloid PET change when acquisition times vary within an individual patient. This is especially important for evaluating the efficacy of currently approved anti‐amyloid therapeutic approaches.
Estimating the time between amyloid and tau‐pet positivity: implications for Alzheimer’s disease prevention trials
Authors: Moscoso Alexis , Heeman Fiona , Dunås Tora , Schöll Michael
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by a preclinical stage in which abnormal accumulation of amyloid‐ß (Aß) leads to phosphorylated tau aggregation. This sequence of events represents the transition between “AD pathologic change” (A+T‐) to the much riskier full AD neuropathology (A+T+, Jack et al. Alzheimers Dement. 2018). Thus, to understand the clinical relevance of the A+T‐ stage in the long term, it is important to understand the temporal course of Aß and tau. In this study, we used longitudinal Aß‐ and tau‐positron emission tomography (PET) to estimate the expected time gap between Aß‐ and tau‐PET positivity, and explored factors that influenced this gap.

Method

We estimated the natural history of amyloid accumulation in AD using longitudinal Aß‐PET data from 1690 AD‐continuum subjects from the ADNI. Specifically, we fitted a non‐linear mixed effects model (3‐knot spline) and modelled the subject‐specific “age of Aß positivity” as random effects (Figure 1). An interval‐censored time‐to‐event analysis using “time to amyloid positivity” as time variable was performed on 318 Aß+ ADNI participants who had available tau‐PET ([18F]flortaucipir) visual reads. Cox proportional hazards regression was used to assess whether age of onset of amyloid positivity, sex, APOE status, and cognitive impairment at follow‐up influenced the onset of tau‐PET positivity relative to Aß‐positivity.

Result

After ∼11 years from Aß positivity, 50% of the CU individuals progressed to tau‐PET positivity, while only ∼17% remained tau‐PET negative after 20 years (Figure 2). Among the studied factors, only the presence of cognitive impairment accelerated the onset of visual tau‐PET positivity (HR = 2.52, p<0.001, median tau‐free survival difference ∼6 years) (Figure 3). Both female sex (HR = 1.44, p = 0.16, median tau‐free survival difference∼2.5 years) and presence of the APOE‐e4 allele (HR = 1.44, p = 0.15, median tau‐free survival difference∼2.5 years) were trend‐level associated to faster onset of tau‐PET positivity.

Conclusion

The time gap between Aß‐ and tau‐PET positivity typically spans a decade and is highly variable across individuals. This long gap implies that a significant fraction of A+T‐ CU older individuals will never develop tau‐PET positivity and subsequent symptoms in their lifespan, which suggests that these subjects may not benefit from current disease‐modifying therapies for AD.
Interactions of synaptic and inflammatory biomarkers in Alzheimer’s Disease
Authors: Rahmouni Nesrine , Tissot Cécile , Servaes Stijn , Therriault Joseph , Macedo Arthur C. , Stevenson Jenna , Lussier Firoza Z , Machado Luiza Santos , Arias Jaime Fernandez , Wang Yi‐Ting , Stevenson Alyssa , Socualaya Kely Quispialaya , Kunach Peter , Nazneen Tahnia , Hosseini Seyyed Ali , Gauthier Serge , Karikari Thomas K , Benedet Andrea Lessa , Ashton Nicholas J. , Zetterberg Henrik , Pascoal Tharick A. , Blennow Kaj , Zimmer Eduardo R , Rosa‐Neto Pedro
Published: December 2023

Background

The sequential model predicts synaptic depletion as a downstream of amyloid, tau and neuroinflammation. However, synaptic toxicity might be consequence of toxic forms of amyloid in the absence of tau. In this study we explore the role of synaptic depletion and neuroinflammation as determinants of tau pathology. GAP‐43 and neurogranin are pre‐ and post‐synaptic biomarkers known to be detected at elevated levels in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD).

Method

We included 126 individuals from TRIAD cohort. Brain inflammation, tau tangle and amyloid‐ß (Aß) deposition were assessed via [11C]PBR28‐PET, [18F]MK6240‐PET and [18F]AZD4694‐PET, respectively. All patients had plasma GFAP quantified, and a subset of 78 individuals had CSF GFAP, CSF Neurogranin and CSF GAP‐43 quantifications available. Voxel and region of interest regression models evaluated the relationship between PET tracers and the fluid biomarkers. Models with [18F]AZD4694‐PET as the outcome were adjusted for [18F]MK6240‐PET voxel‐wise and vice‐versa. A linear regression interaction model evaluated the interaction between CSF GFAP and both synaptic biomarkers with Aß‐ and tau‐PET as the outcome.

Result

Positive associations were found between CSF neurogranin and Aß‐, tau‐ and brain inflammation‐PET in AD related regions; the strongest associations were found with tau‐pet and CSF neurogranin in the medial temporal lobe. GAP‐43 was also positively associated with tau‐ and TSPO‐PET, but no associations were found with Aß‐PET. Both plasma and CSF GFAP were associated with Aß‐, tau‐ and TSPO‐PET in AD related regions, with the strongest t‐values in the model including plasma GFAP and amyloid‐PET. A negative interaction was found between CSF GFAP and both synaptic biomarkers with amyloid‐ and tau‐PET as the outcomes. These associations were stronger with tau‐PET and were found in the temporal, occipital and parietal areas.

Conclusion

This study supports the role of synaptic dysfunction and neuroinflammation on tau load. As both synaptic biomarkers and GFAP increase as a function of tangles load, tau accumulation is linked to the relationship between synaptic abnormalities and inflammation in early stages of the disease. Our results suggest that synaptic depletion is a phenomenon that might start prior to tau tangles.
Genome‐wide association study of brain MRI and other phenotypes in the Tohoku Medical Megabank Organization
Authors: Taira Makiko , Saykin Andrew J. , Fuse Nobuo
Published: December 2023

Background

The Tohoku Medical Megabank Organization (ToMMo) is a large cohort study and biobank established in 2013 in the Miyagi Prefecture of Northern Japan following the Great East Japan Earthquake and Tsunami. ToMMo enrolled 150K individuals in a planned longitudinal study aiming to reveal numerous and diverse biological, psychological, and lifestyle characteristics associated with important diseases, and it collects and analyzes a rich set of biological data, including genomics, from participants to support innovative research on these diseases. Importantly, aging and Alzheimer’s disease are key areas of our research agenda, but little is known about common genetic variants that affect quantitative traits related to AD in Japanese people. MRI brain scans and cognitive screening on 12,164 cohort participants were collected at baseline (the TMM Brain‐MRI Study) since 2014 to 2019.

Method

The TMM Brain‐MRI study acquired multiple MRI sequences, including T1‐weighted imaging (T1WI). The ADNI Phantom was used, and each scan’s quality was checked. Following pre‐processing steps, Freesurfer (v7.2.0) was used with the Destrieux or Desikan‐Killiany atlas to parcellate multiple anatomical brain regions and derive cortical thickness data. We conducted a Genome‐Wide Association Study (GWAS) on all Brain‐MRI Study participants who were also genetically profiled with a Japanese‐oriented microarray (Japonica‐Array® v1, v2 and NEO) and WGS.

Result

Along with the other data types, the genotyping data for the TMM Brain‐MRI study participants represented etiological characteristics. The attached Figure shows the age distribution by decile for 7,630 male and female participants who were profiled with the Japonica‐Array® v2. The usable archived volumetric T1WI data demonstrated inverse correlations between brain volume and age, as well as very good agreement with correlations observed in previous clinical studies. We identified nominally genome‐wide significant loci (P < 5×10‐8) associated with imaging phenotypes in this sample consisted of Japanese adults as the discovery stage of the study.

Conclusion

The ToMMo MRI and genetic data provide insights into the genetic architecture of the brain that are relevant to understanding brain aging and AD. Our results require some replication stages and meta‐analyses using samples of Japanese individuals in other studies.
Neurodegenerative biomarkers of A‐T+ compared to A+T+ and A‐T‐ older adults
Authors: Jung Joon Hyung , Yi Dahyun , Byun Min Soo , Kong Nayeong , Chang Yoon Young , Keum Musung , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Lee Yun‐Sang , Kim Yu Kyeong , Kang Kyoung Mi , Sohn Chul‐Ho , Lee Dong Young
Published: December 2023

Background

Primary age‐related tauopathy (PART) is a neuropathological entity with neurofibrillary tangles in the absence of beta‐amyloid plaques in the brain. Recent advances in neuroimaging made it possible to identify amyloid PET‐negative (A‐) tau PET‐positive (T+) condition as a possible candidate for PART in living human brains. We tried to investigate neurodegenerative biomarkers of A‐T+ older adults compared to those of A+T+ and A‐T‐ [corresponding to Alzheimer’s disease (AD) and no AD pathology, respectively] individuals.

Method

A total of 156 older participants (64 cognitively normal, 43 mild cognitive impairment (MCI), and 49 dementia), were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE). All participants underwent comprehensive clinical evaluation and multimodal brain imaging including amyloid and tau PET, and MRI. Global PiB retention measured by 11C‐PiB‐PET and tau deposition in the regions corresponding to Braak stages measured by 18F‐AV‐1451 PET were used in this study. A+ was defined as global mean Aß deposition standardized uptake value ratio (SUVR) > 1.4 and T+ was defined as tau burden corresponding to Braak stages I/II, III/IV, or V/VI. Hippocampal volume, AD‐signature cortical thickness (AD‐CT), AD‐signature cerebral glucose metabolism (AD‐CM) and white matter hyperintensity (WMH) volume were also measured as neurodegenerative biomarkers. Multiple linear regression analysis controlling for age, gender, and APOE e4 positivity was used to investigate the group differences of neurodegenerative biomarkers.

Result

Of the 156 participants, 31 were defined as A‐T‐, 53 as A+T‐, and 72 as A+T+. A‐T+ group had higher levels of hippocampal volume (B = 683.448, p<0.001), AD‐CT (B = 0.267, p<0.001) and AD‐CM (B = 0.174, p<0.001), but not WMH volume (B = ‐1.188, p = 0.651), compared to A+T+ group. When compared to A‐T‐ group, A‐T+ group did not show significant difference in any of the neurodegenerative biomarkers.

Conclusion

Our findings suggest that, in regard of neurodegeneration, older adults with A‐T+ condition, close to pathological PART, are less severe than those with A+T+, while they appear similar to those with A‐T‐.
A Centiloid cut‐off to help predict true amyloid accumulation
Authors: Bollack Ariane , Collij Lyduine E. , García David Vállez , Shekari Mahnaz , Altomare Daniele , Payoux Pierre , Dubois Bruno , Grau‐Rivera Oriol , Rovira Mercè Boada , Nordberg Agneta K , Walker Zuzana , Scheltens Philip , Schöll Michael , Wolz Robin , Schmidt Mark E , Gismondi Rossella , Stephens Andrew W. , Buckley Christopher , Frisoni Giovanni B , Hanseeuw Bernard J , Visser Pieter Jelle , Vandenberghe Rik , Drzezga Alexander , Yaqub Maqsood , Boellaard Ronald , Markiewicz Pawel J , Cash David M , Farrar Gill , Gispert Juan Domingo , Barkhof Frederik
Published: December 2023

Background

Longitudinal amyloid‐PET‐based imaging endpoints are often included in clinical trials, where they provide critical evidence of treatment efficacy. We assessed the longitudinal variability of the Centiloid (CL) scale and its ability to predict early amyloid accumulation.

Method

Longitudinal amyloid‐PET with 18F‐flutemetamol and 18F‐florbetaben (N = 711 at follow‐up 1, time interval: 3.0±1.3years; N = 98 at follow‐up 2, 5.1±0.7years) was conducted in predominantly cognitively unimpaired participants of the AMYPAD Prognostic and Natural History Study (PNHS). Quantification of scans was performed using the MR‐based CL pipeline and visually read (VR) by local certified assessors. Longitudinal change in CL was modelled using linear mixed effects models corrected for age, sex, and education. Subjects were classified based on VR status over time (i.e., Stable VR‐, VR‐Converters or Stable VR+) and based on amyloid accumulation over time (i.e., Accumulator or Non‐accumulator; Accumulator if annualised rate of change [ARC]>95th percentile of a subset of 110 subjects for whom no amyloid accumulation was expected, selection criteria in Table‐1). Finally, a baseline CL cut‐off to identify future Accumulators was derived from a receiver operating characteristic (ROC) curve analysis.

Result

Participants had a median age of 65 years, 57% were females, 41% were APOE‐e4 carriers, and 18% had baseline VR+ scan (Table‐1). The 95th percentile of ARC in the stable 110 subjects was 2.7 CL/year. Baseline CL was higher in Accumulators compared to Non‐accumulators (24.8 versus 8.7 CL, p<.001). Based on the ROC analysis, the optimal baseline CL threshold to predict Accumulators was 12.1 CL (sensitivity = 67% and specificity = 74%, Figure B‐C‐D), in line with the baseline CL threshold that best predicts VR conversion (11.6 CL). Baseline CL values and ARC were also higher in Stable VR+ and VR‐Converters compared to Stable VR‐ (p<.001), but no significant difference in ARC was found between VR‐Converters and Stable VR+ (Table‐1, Figure A). Results were robust across tracers.

Conclusion

Increases over 2.7 CL/year can be indicative of reliable amyloid accumulation. A CL cut‐off of ∼12CL can help identify subjects more likely to accumulate amyloid in the short future. Annualised rates of change in amyloid deposition where highly comparable across tracers.
Age in Place, Move in VR: Investigating the Feasibility and Usability of a Custom‐made Virtual Reality Exergame to Promote the Well‐being of Community‐Dwelling Older Adults
Authors: Mehrabi Samira , Basharat Aysha , Mazen Sarah , Cao Shi , Boger Jennifer , Barnett‐Cowan Michael , Muñoz John , Middleton Laura E
Published: December 2023

Background

Interactive virtual reality (VR) games combined with exercise (exergames) are a plausible strategy to encourage physical activity (PA) among older adults. However, there is little systematic evaluation of the feasibility, usability, and potential benefits of deploying at‐home VR exergames among this population.

Method

Fifteen community‐dwelling older adults (M = 67.33 ± 5.3, age range 60‐77) (Table1) were recruited to play 18 sessions (each 15‐20 min) of a custom‐made VR exergame at home over six weeks. Recruitment, retention, and adherence rates were calculated to determine feasibility. The usability of the exergame was assessed through i) a game user experience questionnaire, ii) a self‐reported physical/emotional discomfort questionnaire, and iii) a perceived enjoyment scale. The exploratory outcome measures included changes in i) PA, ii) exercise self‐efficacy, iii) affect, iv) various cognitive and perceptual tasks and were assessed i) before and after acute data, and ii) before and after the intervention.

Result

Thirteen participants completed the study (13% attrition rate) without missing any exergaming session (100% adherence rate). The completion rate of cognitive assessments, perceptual tasks, and self‐reported questionnaires was = 97%. Low levels of cybersickness were reported (M = 0.9 ±1.0 out of 10). The average perceived enjoyment and perceived rate of exertion were 3.2. ±1.1 (out of 5) and 2.4±1.9 (out of 10), respectively. Most of the participants (92.3%) found the exergame’s instructions easy to follow and had an overall positive experience (84.6%). Whereas the exergame was perceived as useful for increasing PA levels (61.6%), mood enhancement was reported among less than half of participants (46.2%) and only 38% indicated that they would choose VR exergaming for at‐home PA. The likelihood of playing VR exergames in the future was also low (38.5%). The exploratory outcome measures are presented in Table 2.

Conclusion

Our study provides insights into the feasibility and usability of a custom‐made VR exergaming intervention to promote PA in community‐dwelling older adults which may potentially benefit their well‐being. Our findings inform the future adoption of VR at home. Our results can also be used to inform large‐scale trials and support the design and deployment of other remote exergames and assessments.
DETECT‐AD (Digital Evaluations and Technologies Enabling Clinical Translation for Alzheimer’s Disease): A simulated anti‐amyloid clinical trial using digital biomarkers as primary outcome measures
Authors: Kaye Jeffrey A , Marcoe Jennifer , Mar Amanda B , Hanna Elise J , Pierce Aimee , Silbert Lisa C , Shang Yanan , Schwartz Daniel , Gothard Sarah , Mattek Nora , Au‐Yeung Wan‐Tai M. , Steele Joel S. , Beattie Zachary T
Published: December 2023

Background

Early detection and precise monitoring of cognitive and functional decline in persons with Alzheimer’s Disease (AD) in clinical trials is a high priority. Unfortunately, early detection and monitoring of the subtle and slow changes of disease with conventional cognitive testing and self‐report questionnaires has been fraught with poor sensitivity and lack ecological validity. Digital biomarkers using ambient sensing technologies may afford a more effective approach to conducting trials. Remaining to be established is the ability of this approach to fundamentally improve early AD treatment response readout in a formal clinical trial setting. A simulated clinical trial (DETECT‐AD: ClinicalTrials.gov, NCT05385913) is being conducted to determine how well continuously assessed, home‐based digital biomarkers may detect clinically meaningful changes in individuals with changing amyloid (Aß) burdens in pre‐symptomatic AD.

Method

Clinically prodromal AD patients with estimable rates of AD progression based on Aß Florbetapir‐PET status are enrolled divided n = 50:n = 50 into Aß “positive” (higher amyloid burden) patients who predictably progress (as if they were receiving placebo) and Aß “negative” patients progressing more slowly (representing the treatment group). A study‐provided multivitamin mimics RCT conditions and study drug adherence behavior. Baseline standard clinical and biomarker measures are obtained along with digital biomarkers (DB) captured with passive and active sensors (actigraphy, bed mats, IR sensing, e‐pillbox, computing/phone device use, weekly online reporting/cognitive assessment). Primary outcome is the change in a composite DB composed of measures in 4 domains: mobility, cognition, sleep, and socialization. Secondary measures are the relationship of DB to fluid biomarkers (plasma ptau181/217, amyloid, NfL) and MRI/PET measures.

Result

To date (01/16/2023), 46/100 have been enrolled with mean(SD): follow‐up = 27.0(7.9) weeks (no dropout); age = 78(6.6); 63% women; MoCA = 25.5(2.3); PET SUVR = 1.09(0.20), range: 0.850‐2.07. Exemplary baseline digital biomarker metrics are presented in the Table. Preliminary data shows an inverse Aß‐SUVR correlation with mean steps/day (r = ‐.41, p = .012) and a positive correlation of MoCA with computer use (r = .61; p = .036).

Conclusion

Home‐based continuous capture of multi‐domain DBs is feasible in a clinical trial setting and may yield early meaningful indicators of clinically relevant changes in older adults with pre‐AD dementia. Further evidence will evolve as sample sizes and longitudinal follow‐up increases.
Diagnostic Performance of MRI‐based Alzheimer’s Disease Resemblance Atrophy Index and Plasma‐Based Biomarkers on Alzheimer’s Disease
Authors: Fu Siu Ting , Cai Yuan , Huang Junzhe , Liu Wanting , Shi Lin , Au Lisa Wing Chi , Ko Ho , Mok Vincent Chung Tong
Published: December 2023

Background

Although positron emission tomography (PET) or cerebrospinal fluid measurements of amyloid and tau burden are available for the detection of Alzheimer’s disease pathology, such methods are invasive and not easily accessible. Recent studies show that Alzheimer’s Disease‐resemblance atrophy index (AD‐RAI), an MRI‐based machine learning‐derived biomarker, and plasma‐based biomarkers can be used as accurate biomarkers for Alzheimer’s disease pathology. We aim to evaluate the diagnostic metrics of AD‐RAI and plasma‐based biomarkers for detecting Alzheimer’s disease.

Method

We recruited 69 subjects from the CU‐SEEDS (The Chinese University of Hong Kong‐Screening for Early AlzhEimer’s DiseaSe) study who were stroke‐free and had different degrees of cognitive impairment: 8 cognitive unimpaired [CU], 26 with subjective cognitive decline [SCD], 21 with mild cognitive impairment [MCI] and 14 with dementia. All subjects underwent 11C‐ PIB and 18F‐T807 PET to measure pathological Aß deposition (A+) and tau burden (T+). Subjects received structural MRI for deriving AD‐RAI. Plasma levels of Aß40, Aß42, total tau (t‐tau), phosphorylated tau at 181 (p‐tau181), and neurofilament light chain (NfL) were measured by Single Molecule Array (SiMoA) assays.

Result

Among 69 subjects (mean [SD] age, 67.7 [6.8] years; 28 men [40.6%]), 25 (36.23%) subjects were confirmed to be A+ and T+. AD‐RAI, plasma p‐tau 181, and plasma Aß42 were associated with A+T+ after adjusting for age, gender, and education (p<0.01). AD‐RAI individually outperformed all plasma‐based biomarkers (AUC = 0.911; Sensitivity = 0.826; Specificity = 0.905). The combination of AD‐RAI, p‐tau181 and Aß42 yielded the best diagnostic metrics for detecting A+T+ subjects (AUC = 0.957; Sensitivity = 0.870; Specificity = 0.929).

Conclusion

A panel of AD‐RAI, plasma p‐tau, and plasma Aß42 might help with screening and diagnosis of Alzheimer’s disease.
Longitudinal changes in driving behaviours among older adults with different A/T/N biomarker profiles
Authors: Long Kelly , Bayat Sayeh , Babulal Ganesh M.
Published: December 2023

Background

The pathophysiological process of Alzheimer’s disease (AD) spans approximately 10‐15 years. To define AD by its pathologic processes, the A/T/N classification framework was proposed constituting ß‐amyloid (A), tau (T), and neurodegeneration (N) biomarkers derived from cerebrospinal fluid (CSF) or imaging. With these biomarkers, individuals can be divided into four categories: normal (A‐T‐N‐), AD pathologic change (A+T‐N‐), AD (A+T+N‐, A+T‐N+, A+T+N+), and suspected non‐AD pathology (SNAP) (A‐T+N‐, A‐T‐N+, A‐T+N+). Recent evidence indicates that daily driving behaviours can identify preclinical AD, solely based on CSF ß‐amyloid (A), with high accuracy. This study aims to determine the extent to which longitudinal changes in driving behaviour vary between individuals with different A/T/N profile categories.

Method

Participants were enrolled in a longitudinal study on driving and preclinical AD biomarkers from Washington University School of Medicine. Temporospatial driving behaviours were collected with a data logger installed in participant vehicles over a period between January 2015 and March 2020. CSF collected within three years of each driving event was used to assign A/T/N categories. The cohort included 132 cognitively normal (Clinical Dementia Rating of 0) older adults (>65). Changes in driving behaviours over time were modelled for each group using linear mixed‐effects models. A Z‐test was used to determine if the slopes significantly differed between individuals with normal biomarkers and the remaining groups.

Result

Participants were classified as 59 individuals with normal biomarkers, 9 with AD pathologic change biomarkers, 45 with AD biomarkers, and 19 with SNAP biomarkers. Compared to normal aging, the AD pathology group had a statistically significantly higher increase in average occurrences of under‐speeding (p = 0.001), a significant decrease in average trip duration (p = 0.021), and a significant decrease in the average standard deviation of vehicle speed (p = 0.029). The AD group had no significant differences from the normally aging group. The SNAP group showed a significantly higher increase in the average occurrences of over‐speeding (p<0.001) than normal aging.

Conclusion

Driving behaviours and their rate of change over time vary between individuals with different A/T/N profile categories. These differences provide an opportunity to strengthen our understanding of the disease trajectory.
Long‐term results of Alzheimers’ dementia treated with transcranial pulse stimulation
Authors: Lohse‐Busch Henning
Published: December 2023

Background

The treatment of the brain with focused extracorporal shock waves (ESW) in patients with unresponsive wakefulness syndrome dates back to 2006 (1). This was followed by preliminary investigations for the treatment of Alzheimer’s dementia and Parkinson’s disease in the years up to 2014. The introduction of a shock wave generator with a navigation system in 2016 (Neurolith, Storz Medical) was a breakthrough for the precise treatment of brain structures. This method of brain treatment was then called TPS. After a 3 month study with people living with Alzheimer’s dementia in 2019 (2), we now present patients with long‐term follow‐up over 3 years during continous monthly TPS treatment as a critical undertaking for future treatments.

Method

6 persons living with mild Alzheimer’s dementia (Mini Mental Status >18) were treated initially 6 times during 2 weeks with TPS. Subsequently, they received one TPS session monthly over 3 years. The results were assessed with the CERAD Plus score and compared with the data of the expected natural development with standard medication according to the ALSOVA study of Hallikainen.

Result

While cognitive skills improved by 12% over 12 months, outcomes returned to the baseline in the second year. A two‐week booster of 6 sessions with TPS improved outcomes again by 4.5% compared to the baseline. After 3 years, the results were at the level of the expected natural development with standard medication.

Conclusion

A symptomatic improvement of Alzheimer’s symptoms with low‐energy TPS over several years seems to be possible. It was a methodological mistake not to examine the patients more frequently neuropsychologically. It is conceivable that this would achieve a better long‐term result. (1.) H. Lohse‐Busch, U. Reime and R. Falland, (2014) Symptomatic treatment of unresponsive wakefulness syndrome with transcranially focused extracorporeal shock waves. NeuroRehabilitation 35 (2014) 235‐244 (2.) Beisteiner R, Matt E, …… Lohse‐Busch H (2019) Transcranial pulse stimulation with ultrasound in Alzheimer’s disease—A new navigated focal brain therapy. Adv Sci (Weinh) 23;7(3):1902583.
Developing an occupational telerehabilitation program for caregivers of people with dementia to increase their ability to care and reduce burden
Authors: Giovanni Orientina Miriam Di , Chinaglia Cinzia Negri , Petrucci Bianca Maria , Fritzsching Daniela Matilde , Fabbo Andrea
Published: December 2023

Background People with dementia (PwD) require high levels of care, most of which is provided by either family or informal caregivers. Psychosocial interventions have been demonstrated to reduce caregiver burden and delay nursing home admission. Telemedicine could provide caregivers access to such interventions, increasing their sense of competence and resilience. Method Through a co‐design process involving geriatricians, psychologists, neurologists, nurses, occupational therapists and 25 dyads, a telerehabilitation program has been developed and tested through a 12‐months Beta Test protocol. The program comprises a multidimensional clinical assessment and a telerehabilitation plan. Whilst occupational therapists act as care manager interface towards caregivers through a telemedicine platform, a multidisciplinary team including nurses, psychologists and geriatricians, regularly oversees each plan and delivers interventions whenever required. Results Almost all caregivers were spouses or children (22 out of 25). 79% were female and 59% lived with the care recipient in the same household. The average age of caregivers was 63,72 and Zarit index 36,88. On average PwD’s age was 83,75, Barthel Index 61,27, IADL 0,97, NPI Index 24,86 with 4,8 BPSD. The program has required on average 18,8 sessions per caregiver: which comprised of 4,5 sessions for multidimensional evaluation of both PwD and caregiver, 9,1 sessions for the execution of the telerehabilitation plan and 5,2 sessions for follow up. Sessions could range from 45 minutes (clinical scales‐based assessment) to 10 minutes (follow up). 48% of telerehabilitation sessions addressed BPSD, 17% provided emotional support, 14% supported caregivers in ADL activities, 11% addressed comorbidities and 10% addressed other issues (communication and cognition). A self‐developed caregivers' reported outcome questionnaire (24 responders out of 25) reported that 88% of caregivers improved their health literacy, 87% their sense of competence and 97% felt emotionally supported. After at least 6 months, a follow up analysis on 13 PwD and 10 family caregivers, NPI Index has improved on average by 41% while Zarit Index by 16%. Average yearly cost of the program reached 2 euro per day per dyad. Conclusions The beta test showed encouraging outcomes in terms of caregivers’ satisfaction that require further investigation in terms of clinical outcomes and cost‐effectiveness.
Effect of an eHealth intervention to support care management in caregivers of people with dementia: a pre‐post pilot study
Authors: Solorzano Claudio Singh , Orini Stefania , Zanetti Orazio , Chattat Rabih , Pievani Michela , Festari Cristina
Published: December 2023

Background

Most people with dementia are cared for by family members. The workload associated with caregiving tasks is often associated with physical, mental, and social impairment. In line with the WHO’s Global Action Plan on Dementia 2017‐2025 (WHO, 2017), calling for the provision of affordable and accessible interventions for dementia caregivers, we tested an eHealth intervention to improve self‐efficacy and mental health in dementia caregivers.

Method

8‐week eHealth psycho‐educational intervention aiming at increasing the knowledge of neurocognitive disorders, their at‐home management, and the presence of national and local support services. The intervention was conducted by an experienced psychotherapist assisted by a professional expert (e.g., geriatrician, educator, social worker, lawyer and advocacy patient organisations), according to the topic of each meeting. A pre‐post study design was used and validated psychosocial self‐report questionnaires were administered before and after the intervention (e.g., State‐Trait Anxiety Inventory ‐STAI‐Y1‐2, Zarit Burden Interview ‐ZBI, Beck Depression Inventory‐II BDI‐II, Revised Scale of Caregiving Self‐Efficacy ‐RSCSE). Pre‐post differences were tested with paired t‐test, correlations between scales with Pearson correlation coefficient

Result

41 caregivers (mean age: 57; range 31‐82; female: 78%; children: 61%) completed the study. The intervention had high participation (88% attended at least seven meetings). Following the intervention, the self‐efficacy regarding the ability to respond to the patient’s disruptive behaviours effectively improved (RSCSE‐RDB subscale: t(40) = ‐2.817, p = 0.007), anxiety and burden levels decreased (STAI‐Y1: t(40) = 3.170, p = 0.003; STAI‐Y2: t(40) = 2.327, p = 0.025; ZBI: t(40) = 2.290, p = 0.027), while depression scores did not change significantly (BDI‐II: t(40) = 1.164, p = 0.251). Correlation analysis showed that the change of STAI‐Y1 was positively associated with the change of STAY‐Y2 (r = 0.440, p = 0.004), and the increase of RSCE‐RDB subscale was positively associated with the improvement of caregiver burden (r = 0.430, p = 0.005).

Conclusion

Our study showed that the eHealth intervention improved the caregiver’s ability to deal effectively with the disruptive behaviours of patients, and this change was associated with a reduction of caregiver burden. The results and participation rates support the implementation of online psycho‐educational interventions to meet the need for knowledge of disease management and avoid detrimental effects on caregivers’ health.
Technology in the service of caregiver well‐being: an online psycho‐educational intervention combined with virtual reality
Authors: Festari Cristina , Bonomini Cristina , Rosini Sandra , Gattuso Maria , Solorzano Claudio Singh , Zanetti Orazio , Corbo Daniele , Agnelli Giancarlo , Ferrari Clarissa , Gasparotti Roberto , Morganti Francesca , Pievani Michela
Published: December 2023

Background

Care for community‐dwelling people with dementia (PwD) is frequently delegated to relatives, who find themselves in the role of informal caregivers (iCGs) with no practical knowledge to manage their loved ones. This situation puts iCGs at high risk for emotional distress. We will assess the efficacy of an online psycho‐educational program combined with an immersive virtual reality (VR) experience to reduce iCGs perceived stress by acting on the cognitive and affective components of empathy.

Method

Using covariate‐adaptive (by sex and baseline level of perceived stress) randomization, 100 iCGs of mild‐to‐moderate Alzheimer’s disease patients will be assigned to i) an online 6‐week psycho‐educational program (control arm); or ii) the same psycho‐educational program integrated with VR (experimental arm). VR consists of 360‐degree videos and allows caregivers to experience dementia symptoms from the patient’s perspective. The primary outcome will be a change in emotional distress, assessed with the Zarit Burden Inventory and the State‐Trait Anxiety Inventory. In addition, changes in brain activity while reading emotional stories (protocol modified from Ashar, 2017) will be assessed as a secondary outcome in a subsample of 50 participants who will undergo magnetic resonance imaging. Primary and secondary outcomes will be measured before and after the intervention. A 2‐month clinical follow‐up is also scheduled.

Result

To date, 20 iCGs (mean age: 58; range 30‐79; female: 75%; children: 55%) have been randomized to the 2 arms. The psycho‐educational program provides support for the home management of PwD, by offering knowledge on symptom management and enhancing strategies based on the cognitive component of empathy. During each session, iCGs are exposed to 30 minutes of empathy training with i) imagery exercises or ii) VR. The experimental intervention is expected to result in deeper disease comprehension and strengthen empathy’s cognitive component. At the network level, we expect to observe a greater activation of cognitive empathy circuits and a lower activation of affective empathy circuits in the experimental group.

Conclusion

To our knowledge, this will be the first randomized controlled trial assessing the synergistic effect of combining traditional psycho‐educational intervention with VR in iCGs and measuring both clinical and imaging markers.
Fastball ‐ a new functional biomarker of cognitive impairment
Authors: Stothart George , Alderman Sophie , Coulthard Elizabeth
Published: December 2023

Background

Fastball provides a new, rapid, objective EEG method for assessing cognitive function. Fastball is culturally, linguistically and educationally independent. Participants do not need to understand the task, or provide any response, and tasks take just minutes to complete. Fastball has recently been shown to be sensitive to memory deficits in Alzheimer’s disease (Stothart et al., Brain, 2021), and we present the latest findings in Mild Cognitive Impairment (MCI) patients.

Method

Healthy older adult controls (n = 56, ACE‐III = 96+‐3) and MCI patients (n = 46, ACE‐III = 82+‐10) completed a Fastball task designed to measure their recognition memory at baseline and at 12 month follow up. All EEG data were collected in patients' homes using low‐cost portable EEG. They also completed the ACE‐III and the Delayed Match to Sample 48, a validated neuropsychological measure of recognition memory.

Result

Between group comparisons, controlling for individual differences in EEG response magnitude, showed amnestic MCI patients had significantly reduced Fastball responses compared to non‐amnestic MCI patients (p = .002) and healthy older adult controls (p = .005). Fastball scores correlated with the ACE‐III memory subscale (r(46) = .44, p = 0.002) and no other ACE‐III subscale, demonstrating sensitivity and specificity to memory dysfunction. Fastball scores also correlated with performance on the Delayed Match to Sample 48 abstract subscale (r(46) = .37, p = .011). 12 month follow up is underway and data will be presented at AAIC 2023.

Conclusion

Fastball is a passive, rapid measure of memory dysfunction in Alzheimer’s disease that we have now demonstrated to be sensitive to early memory dysfunction in Mild Cognitive Impairment. Fastball data can be reliably collected in patients' homes using low‐cost portable EEG, and the approach holds great potential as a future diagnostic tool.
Strategies to develop, design, implement and support digital health equity in key underserved groups: protocol for a systematic review
Authors: Wilson Sarah , Tolley Clare , Ardle Ríona Mc , Beswick Emily , Lawson Lauren , Slight Robert , Slight Sarah , Hassan Nehal
Published: December 2023

Background

Digital health technologies (DHT) can be used to detect and remotely monitor digital biomarkers associated with prodromal dementia. However, there are growing concerns that DHT are not leading to demonstrable health benefits in all populations, particularly the underserved who are typically neglected in research resulting in worse health outcomes. One possible cause is digital exclusion, which refers to the unfair differences in access, use, motivation and reliability in DHT across different demographic groups. The UK regulatory bodies acknowledge the need to mitigate digital exclusion, leading to the development of inclusive digital strategies such as tailoring DHT to ensure it is appropriate to individuals in terms of affordability, culturally applicable, and accessible. This systematic review will synthesize the literature regarding strategies to improve digital inclusivity for underserved groups at risk of digital exclusion.

Method

This review will follow PRISMA guidelines and involve systematically searching four large databases (Medline, Embase, PsycINFO, Scopus). It has been registered on PROSPERO: CRD42022378199. Search terms will be used to identify relevant studies focusing on factors associated with digital exclusion, including: Culture (ethnicity, language, religion), Limiting conditions (visual and hearing impairments), Education, Age, Residence (rural or deprived areas, homelessness), and Socioeconomic status (low to middle‐income and unemployed individuals), summarised by the acronym CLEARS (Figure 1). Primary research English‐language studies using qualitative or mixed methods to explore facilitators and barriers to digital inclusion will be included. Studies will be independently screened by two additional reviewers using a computer software, Rayyan. The methodological quality of studies will be assessed using a checklist designed to assess qualitative and mixed methods. A narrative synthesis of data from included studies will be conducted.

Result

This review will integrate the evidence available on the facilitators and barriers associated with the design and implementation of digitally inclusive strategies for DHT in CLEARS groups. Key recommendations for digitally inclusive strategies to support health equity will also be produced.

Conclusion

The results of this review will be used to support digital health equity in research by providing recommendations for the development, design, and implementation of strategies to promote digital health equity in key underserved groups.
Cognitive screening based on EEG markers for clinical trial stratification
Authors: Braboszcz Claire , Chugani Karan , Dagnino Paulina Clara , Soria‐Frisch Aureli
Published: December 2023

Background

Global life expectancy is growing at an unprecedented rate, giving rise to multiple chronic diseases such as pathological cognitive impairment. The aim of Starlab is to provide a cognitive status report that can aid clinical trial professionals in detecting normal or abnormal brain condition using electroencephalography (EEG) biomarkers. The EEG markers deliver accurate screening of the older population based on the objective assessment of cognitive decline.

Method

Our reporting system is based on normative EEG values of cognitive status using open‐access datasets. The data consist of resting state EEG recordings of subjects diagnosed with Alzheimer’s Disease (AD), Mild Cognitive Impairment (MCI) and age matched Healthy Controls (HC). We extract spectral EEG features related to cognition with the goal of identifying those which accurately distinguish between the groups. For the features that are statistically significant, we build probability density functions for each group and calculate the group thresholds determined by the intersection of the distributions.

Result

Applying statistical testing on the different features extracted we found that ratios between slow and fast bands showed to be accurate at distinguishing HC and MCI groups versus AD groups. Moreover, alpha frequency features proved to be precise in differentiating HC from MCI and AD subjects. Thresholds are then calculated for each of these features for them to be delivered in a decision matrix for patient stratification.

Conclusion

Overall, this work provides a first version of a cognitive status reporting system based on EEG spectral biomarkers. The vision is that this reporting system can be used by clinical trial professionals as a decision support system for the recruitment of patients with cognitive decline.
Remote and in‐clinic digital cognitive screening tools outperform the MoCA to distinguish cerebral amyloid status among cognitively healthy older adults
Authors: Dion Catherine , Kunicki Zachary J. , Emrani Sheina , Strenger Jennifer , De Vito Alyssa N. , Britton Karysa J. , Harrington Karra D , Roque Nelson A , Sliwinski Martin J. , Salloway Stephen , Correia Stephen , Jones Richard N , Thompson Louisa I
Published: December 2023

Background

Existing cognitive screening measures fall short in capturing preclinical AD, and cognitive impairment is unrecognized or misdiagnosed in 27‐81% of older adult primary care patients. Digital assessment technology has the potential to deliver more efficient and sensitive cognitive screening, but requires rigorous validation first. We aimed to determine the accuracy of remote (M2C2 mobile app) and clinic‐based (TabCAT and DCTclockTM) digital tests to distinguish between older adults with and without AD pathologic change. We used the Montreal Cognitive Assessment (MoCA) as a reference standard comparison test.

Method

We recruited 73 cognitively normal participants with Aß PET status (Aß+, n = 25; Aß‐, n = 48, determined by clinical read) from the Butler Hospital Alzheimer’s Prevention Registry (mean age = 69.2 and education = 16.5; 71% female; 89% White). Participants completed M2C2 tasks at home 3 times per day for 8 days, followed by the TabCAT tasks, DCTclockTM, and MoCA at an in‐person study visit. We calculated the area under the curve (AUC) to compare cognitive task accuracy to distinguish Aß status. Multi‐day learning curves were used to examine differences in M2C2 task performance by Aß status over time.

Result

Among the M2C2 tasks, average performance on the Prices task (episodic memory) over 8 days showed the highest accuracy (AUC = .77) to distinguish Aß status. The Aß+ group tended to perform worse than the Aß‐ group on the Prices task over time (Figure 1). On in‐person screening measures (single time‐point), accuracy to distinguish Aß was greatest for the TabCAT Favorites task (AUC = .76), relative to the DCTclockTM (AUC = .72) and the MoCA (AUC = .71).

Conclusion

We showed that several brief digital screening approaches (memory‐specific tasks on the M2C2 and TabCAT) outperform the MoCA in distinguishing between cognitively healthy individuals with and without elevated cerebral Aβ. Although further validation in community and clinic‐based samples is needed, these results suggest that these digital cognitive assessments may be suitable for more widespread screening to detect early pathological changes in neurodegenerative disorders. Figure 1. M2C2 task performance over time (3 sessions daily for 8 days) by Aβ status.