bluuebunny/crossref_metadata_2025 huggingface dataset:
UK Biobank imaging adapted for a real‐world memory clinic sample
Authors: Griffanti Ludovica , Gillis Grace , O'Donoghue M Clare , Blane Jasmine , Pretorius Pieter M , Mitchell Robert , Aikin Nicola , Lindsay Karen , Campbell Jon , Semple Juliet , Martos Lola , Raymont Vanessa , MacKay Clare
Published: December 2022

Background

The Oxford Brain Health Centre (BHC) provides real‐world research data, aligned with the UK Biobank imaging study (UKB), routinely captured in a clinical service from patients under‐represented in dementia research. In this work we present how we 1) adapted the UKB MRI acquisition protocol to be suitable for memory clinic patients, 2) modified the imaging analysis pipeline to extract measures that are in line with radiology reports and 3) compare measures from BHC patients to the biggest brain MRI study in the world (ultimately 100,000 participants).

Method

Adaptations of the UKB acquisition protocol for BHC patients include dividing the scan into core and optional sequences to improve patients’ tolerance. We adapted the UKB structural MRI analysis pipeline to extract quantitative measures from the scans, taking into account the characteristics of a memory clinic population (e.g. high level of white matter hyperintensities, WMH, causing misclassifications in tissue‐type segmentation). We compared the measurements extracted from the scans to visual ratings from radiology reports and to reference distributions derived from UKB data.

Result

Of the 108 BHC attendees since August 2020 (average age 78.5 years, range 65‐101 years, 50.9% female), 100 (92.6%) completed the clinical scans, 100 (92.6%) consented to use of data for research, and 69 (63.9%) consented to additional research sequences, demonstrating that the protocol is well tolerated. Modified tissue‐type segmentation improved grey matter volume estimation, which showed stronger correlation with visual ratings of global atrophy after correction (r=‐0.34; p=0.001) than with the original analysis pipeline (r=‐0.31; p=0.002). Correlations between hippocampal volumes and MTA scale (r(L)=‐0.59, r(R)=‐0.71) and between WMH volume and Fazekas scale (r=0.78) were also significant (p<0.001). Because UKB participants are younger than memory clinic patients, additional scans on elderly healthy controls are planned to improve reference distributions to detect pathological deviations. Measures from BHC patients within UKB age range are comparable to those from UKB participants, with several patients falling in the lower percentiles.

Conclusion

We adapted UKB research imaging for clinical practice. Current and future work aims to integrate automated quantitative measures in the radiology reports and evaluate their clinical utility.
Diabetes and hypertension are associated with elevated beta‐amyloid burden: evidence from the population‐based Rotterdam Study
Authors: Neitzel Julia , van Arendonk Joyce , Steketee Rebecca M.E. , van Assema Daniëlle , Segbers Marcel , Ikram M. Arfan , Vernooij Meike W.
Published: December 2022

Background

Higher vascular risk increases the likelihood of developing dementia. Better understanding the association between vascular risk and Alzheimer’s disease (AD) pathology at the pre‐dementia stage is critical for developing effective strategies to delay cognitive decline. In this work, we estimated the impact of vascular risk on the presence and severity of in‐vivo measured brain beta‐amyloid (Aβ) plaques in participants from the population‐based Rotterdam Study.

Method

Vascular risk factors (hypertension, hypercholesterolemia, diabetes, obesity, physical inactivity, and smoking) were assessed twelve and seven years prior to 18F‐florbetaben positron emission tomography (PET) in 506 dementia‐free participants. Vascualr risk factors were associated with binary amyloid PET status or continuous PET readouts (SUVr values) using logistic and linear regression models respectively, adjusted for age, sex, education, APOE4 risk allele count, and time between vascular risk and PET assessment

Result

Participants’ mean age at time of amyloid PET was 68 years (range: 60‐90), 262 (51.8%) were women and 158 (31.2%) carried at least one APOE4 risk allele (Figure 1). The adjusted prevalence estimates of an amyloid‐positive PET status markedly increased with age (12% in 60‐69y vs. 45.5% in 80‐89y age‐groups) and APOE4 allele count (8.3% in non‐carriers vs. 34.8 to 58.8% in carriers of one or two risk allele(s); Figure 2). A diagnosis of diabetes seven years prior to PET assessment was associated with a higher risk of a positive amyloid status (OR[95%CI] = 4.07[1.66‐9.71], P = 0.002; Figure 3) and higher SUVr values, indicating more severe Aβ pathology (standardized beta = 0.478[0.205–0.750], P = 0.001; Figure 4). We found evidence for an association between hypertension and higher SUVr values in APOE4 carriers, but not in non‐carriers (interaction: standardized beta = 0.425[0.092–0.758], P = 0.013; Figure 5). Hypercholesterolemia, obesity, physical inactivity and smoking were not related to amyloid PET measures.

Conclusion

The current findings suggest a contribution of diabetes and hypertension to the pathophysiology of AD. Since both conditions respond well to lifestyle modification and drug treatment, further research should be conducted to examine the preventative effect of early risk management on the development of AD neuropathology.
Longitudinal changes of automated speech markers in MCI and mild AD
Authors: Cho Sunghye , Shellikeri Sanjana , Ash Sharon , Agmon Galit , Cousins Katheryn A Q , Gonzalez‐Recober Carmen , Nevler Naomi , Liberman Mark Y , Grossman Murray
Published: December 2022

Background

Mild cognitive impairment (MCI) and mild Alzheimer’s disease (mAD) are characterized by decline in memory and other cognitive domains, including language. Previous studies have shown that MCI and mAD patients produce impaired speech. In this study, we investigated longitudinal changes in lexical and acoustic speech features from natural speech of MCI and mAD patients using highly reliable automated methods.

Method

We analyzed 116 digitized 1‐minute picture descriptions produced by 24 MCI (65.8±9.2y, 9 females, mean mini‐mental state exam (MMSE) score at the first recording (T1)=25.4±1.1) and 19 mAD patients (66.9±8.8y, 5 females, mean MMSE at T1=21.9±1.1). The groups did not differ in demographic characteristics, disease duration, and mean inter‐sample interval. Using automated pipelines, we tagged the part‐of‐speech categories of all words, rated words for word frequency, familiarity, concreteness, and semantic ambiguity, and counted partial words and total number of words. Speech samples were segmented into speech and silent pause segments to calculate mean speech segment duration, pause rate, percent of speech out of total time, and articulation rate. Linear mixed‐effects models examined changes over time for each measure, controlling for disease duration at T1. The difference between the first and the last recordings (mean=24±10.9 months) in each measure was related to changes in MMSE, covarying for disease duration at T1.

Result

Patients’ adjectives (beta=‐0.04, p=0.006) and determiners (beta=‐0.06, p=0.01) decreased over time, whereas pronouns increased (beta=0.06, p=0.014). Patients produced more frequent (beta=0.004, p=0.043) and more familiar (beta=0.001, p=0.046) words over time. Patients articulated more slowly (beta=‐0.02, p=0.001) and produced more partial words (beta=0.04, p=0.004) and fewer total words (beta=‐0.9, p=0.018) over time. Patients produced shorter speech segments (beta=0.008, p=0.021), paused more frequently (beta=0.32, p=0.001), and produced less speech (beta=‐0.35, p<0.001) over time. All measures showed no group interaction. Patients whose MMSE scores decreased spoke more slowly (beta=2.25, p=0.04) and produced higher‐frequency words (beta=‐6.4, p=0.043) and more partial words (beta=‐0.72, p=0.028) compared with patients whose MMSE scores did not change.

Conclusion

MCI and mAD patients’ language changed over time, and this was significantly related to patients’ cognitive decline. These findings support the use of automated speech analyses in studying longitudinal changes in neurodegeneration.
Selecting appropriate meaningful change thresholds for trials of early (prodromal‐to‐mild) AD: A caregiver‐rated, anchor‐based analysis based on the Tauriel Study
Authors: Lansdall Claire J , Teng Edmond , McDougall Fiona , Delmar Paul , Smith Janice , Manser Paul T
Published: December 2022

Background

Clinically meaningful change thresholds for assessments used in Alzheimer’s disease (AD) trials, including the Clinical Dementia Rating Scale – Sum of Boxes (CDR‐SB), may differ by disease stage and are increasingly important to interpret efficacy. However, anchor‐based estimates for the CDR‐SB have largely used clinician‐ rather than caregiver‐rated anchors. We established meaningful change thresholds for the CDR‐SB using a caregiver‐rated anchor of global change in early (prodromal‐to‐mild) AD patients over an 18‐month clinical trial.

Method

Anchor‐based analyses of the Tauriel data (NCT03289143) were conducted to establish CDR‐SB thresholds for biomarker confirmed early AD patients. The Caregiver Global Impression of Change – Alzheimer’s Disease (CaGI‐Alz), a 7‐point caregiver‐rated instrument, provided 2 independent anchors of meaningful decline in memory and activities of daily living (ADLs) (Figure 1). The anchor category of interest for establishing minimal meaningful change thresholds was the ‘Somewhat worse’ category. Average score changes were generated for the ‘No change’ category for comparison. Baseline CDR‐SB and Week 25, 49, and 73 CaGI‐Alz and CDR‐SB data were analyzed; correlations of >0.3 were deemed acceptable for anchor‐based analyses.

Result

Our results focus on 49‐ and 73‐week time points based on strength of anchor‐measure correlation and group sample size (Table 1). At 49 weeks, prodromal participants in the ‘Somewhat worse’ category had average CDR‐SB changes of 1.54 (ADL anchor) and 1.08 (memory anchor), mild participants had changes of 2.22 (ADL) and 1.80 (memory), and the combined early AD population had changes of 1.97 (ADL) and 1.51 (memory). At 73 weeks, prodromal participants in the ‘Somewhat worse’ category had average CDR‐SB changes of 2.09 (ADL) and 1.52 (memory), mild participants had changes of 2.25 (ADL) and 2.32 (memory), and the combined early AD population had changes of 2.18 (ADL) and 2.01 (memory).

Conclusion

Although thresholds for meaningful change may differ across disease stages, AD is a continuum and the transition between prodromal to mild is often indistinct. In early (prodromal‐to‐mild) AD populations assessed over longer clinical trials, it may be appropriate to identify meaningful progression on the CDR‐SB using thresholds of 2–2.5 at the individual level.
Single‐Neuron Genome Sequencing in Alzheimer’s Disease Identifies Disease‐Specific Somatic Alterations and Insights into Pathogenesis
Authors: Miller Michael B. , Huang August Yue , Kim Junho , Zhou Zinan , Kirkham Samantha L , Maury Eduardo A , Ziegenfuss Jennifer S , Reed Hannah C , Rento Lariza , Ames Heather M , Oakley Derek , Frosch Matthew P. , Hyman Bradley T. , Lodato Michael , Lee Alice E. , Walsh Christopher A.
Published: December 2022

Background

Alzheimer’s disease (AD) is characterized pathologically by deposition of misfolded amyloid‐b and tau proteins. However, protein‐directed therapeutic strategies have shown limited clinical benefit, pointing to the need to examine pathogenesis from a broader lens.

Neurons each harbor somatic single nucleotide variants (sSNV) in their genomes, which increase with age, at a rate of ∼15 sSNV per year. In AD, DNA damage is increased, with potentially significant effects on the genome of each cell.

Method

We performed single‐cell whole‐genome sequencing on neurons from postmortem brain tissue from humans with AD and age‐matched controls, using two independent genome amplification methods (MDA and PTA), and analyzed the burden of somatic mutations. We also performed mutational signature analysis of the nucleotide changes and trinucleotide context to assess for mutagenic patterns.

Result

We found significantly increased sSNV in AD, with each neuron carrying hundreds of additional somatic mutations, with a distinct mutation pattern. AD neurons show an increase in Signature C, which contains distinct nucleotide changes including C>A variants. We found elevated 8‐Oxoguanine DNA lesions, evidence that these mutations may result from oxidative damage to DNA. Mutations also show a mechanistic role for gene transcription in the generation of sSNV. Somatic mutations are predicted to produce deleterious effects on the neuron, including gene inactivation and neoantigen‐stimulated immune attack.

Conclusion

Somatic mutations accumulate abundantly in Alzheimer’s disease, distributed across the genome. Our findings implicate multiple mutagenic forces in sSNV generation in AD, illuminating multiple upstream components of disease pathogenesis including DNA oxidation and transcription‐coupled DNA repair. Furthermore, elevated somatic mutation levels appear to produce a toxic cellular state, positioning neurons for dysfunction and death. These findings therefore identify somatic mutation accumulation as a novel process in neurodegeneration, through which we can dissect the cascade of events in Alzheimer’s disease pathogenesis.
Cognitive and Functional Trajectories in Prediagnostic Parkinson’s Disease
Authors: Bock Meredith A , Vittinghoff Eric , Bahorik Amber L , Leng Yue , Yaffe Kristine
Published: December 2022

Background

Cognitive and functional decline is typically considered a late manifestation of Parkinson’s Disease (PD). However, impactful non‐motor symptoms can occur prior to the typical motor symptoms due to prodromal neurodegeneration. Few studies have investigated prediagnostic trajectories of cognition and function.

Method

We studied 15,390 participants from two prospective cohort studies of community‐dwelling elders (one of men and one of women) followed up to 20 years. PD was repeatedly ascertained by self‐reported physician diagnosis over follow‐up. We excluded individuals with prevalent PD at baseline (n = 152). Global cognition (Modified Mini‐Mental State Examination or the Mini‐Mental Status Exam), executive function (Trails B), and functional status (interviewer administered IADL and physical function questionnaire) were repeatedly evaluated in both studies. Raw scores were z‐transformed to mean 0 and standard deviation 1. We estimated the associations of PD diagnosis with rates of change in cognition and function before and after PD diagnosis compared to healthy older adults using mixed‐effects models adjusted for age, education, race, body mass index, smoking, alcohol use, depression, and cardiovascular risk factors.

Result

Over follow‐up, 297 individuals developed incident PD (168 men and 129 women). Interactions between the terms in our model and sex were statistically significant for all three outcomes (p<0.001 for all), so we stratified results by sex. Compared to older men without PD, men who developed PD exhibited faster decline in global cognition (0.04 SD difference in annual change, p<0.001), executive function (0.05 SD difference, p<0.001), and functional status (0.06 SD difference, p<0.001) in the prediagnostic period. Women who developed PD compared to women without PD displayed faster decline in executive function (0.02 SD difference, p = 0.006) and functional status in the prediagnostic period (0.07 SD difference, p<0.001).

Conclusion

Individuals who develop PD exhibit decline in executive function and functional status during the prediagnostic phase that exceeds rates associated with normal aging. Men exhibit more cognitive decline prior to PD diagnosis compared to women. Better understanding the prodromal phase of PD may enable earlier diagnosis and open a window for the management of non‐motor symptoms to improve quality of life and facilitate the development of future neuroprotective treatments.
Sex differences in the association between hearing impairment and brain atrophy: findings from the UK Biobank
Authors: Fitzhugh Megan C , Pa Judy
Published: December 2022

Background

Hearing impairment is highly prevalent in older adults and was recently recognized as a modifiable risk factor for dementia. However, it is unknown if risk differs by sex and whether other issues associated with hearing, like social engagement or depression, impact these associations.

Method

UK Biobank data was used to identify 165,471 participants (57±8 years, 55% female) without dementia who had a hearing assessment at baseline. Hearing was assessed using a speech reception threshold task, with scores grouped into good, insufficient, and poor severity levels based on previously derived cut‐offs (Dawes et al., 2014). Cox proportional‐hazard models were used to investigate sex differences in the association between hearing impairment and dementia risk. Sensitivity analyses were conducted to determine if social engagement or depressive symptoms mediated these associations. In a subset of participants with MRI data (n=2,322, 62±7 years, 52% female), linear mixed models stratified by sex were conducted to examine if development of impaired hearing from baseline was associated with gray matter atrophy in auditory and limbic regions.

Result

Insufficient and poor hearing were associated with increased risk for dementia compared to good hearing (HR=1.76, 95%CI 1.43‐2.18 and HR=2.13, 95%CI 1.46‐3.11, respectively), but differed by sex. Women with insufficient (HR=1.73, 95% CI 1.25‐2.40) and poor (HR=3.08, 95%CI 1.80‐5.28) hearing had the greatest risk of dementia, whereas only men with insufficient hearing had increased risk (HR=1.78, 95%CI 1.34‐2.35; poor HR=1.60 95%CI 0.94‐2.73). These relationships were not mediated by social engagement or depression. In the MRI subset, women who developed or maintained impaired hearing had greater atrophy over 2.29 years in auditory pathway (e.g., primary auditory cortex, thalamus) and limbic (e.g., hippocampus, parahippocampus, amygdala) regions compared to women with good hearing. Men who developed impairment exhibited decreases over 2.30 years in a secondary auditory region only.

Conclusion

Women with impaired hearing have greater risk of dementia compared to men. These sex differences are not mediated by social engagement or depression. Women with impaired hearing exhibit greater atrophy in auditory and limbic regions, while men do not. Sex differences in gray matter atrophy may explain why women with impaired hearing are at greater risk of dementia.
Association of Liver Fibrosis with Cognitive Test Performance and Brain Volume Changes in the UK Biobank Study
Authors: Parikh Neal S , Kamel Hooman , Zhang Cenai , Rosenblatt Russell , Cohen David E , de Leon Mony J. , Gottesman Rebecca F , Iadecola Costantino
Published: December 2022

Background

Liver fibrosis is a chronic liver condition that, though frequently subclinical, has widespread systemic effects. We hypothesized that liver fibrosis is associated with worse cognitive performance and corresponding brain imaging changes.

Method

We examined the association of liver fibrosis with cognition and brain volumes among adults in the UK Biobank study, which prospectively enrolled approximately 500,000 people starting in 2007 and subsequently collected cognitive test and brain MRI data for some participants. We included participants with available liver fibrosis, cognitive test, and brain imaging data. Liver fibrosis was defined at baseline using validated cutoffs of the Fibrosis‐4 (FIB‐4) liver fibrosis score. The primary cognitive test outcome was the Digit Symbol Substitution Test (DSST), a multidomain test. Secondary cognitive test outcomes were executive function tests (Trails A, Trails B, Reaction Time) and memory tests (Numeric Memory, Pairs Matching). The primary imaging outcome was white matter hyperintensity volume; secondary outcomes were hippocampal volume and total brain volume. We used multiple linear regression models to evaluate the association of liver fibrosis with cognitive test performance and brain volumes while adjusting for potential confounders.

Results

Among 105,313 participants with cognitive test data, the mean age was 56.1 years and 56% were women. Standard liver chemistries were largely in the normal range. However, 2.0% (95% CI, 1.9‐2.1%) had liver fibrosis based on FIB‐4 scores. Cognitive tests were completed a median of 5.8 years after baseline liver fibrosis assessment. After adjusting for demographics, socioeconomics, education, body mass index, metabolic syndrome, hypertension, diabetes, dyslipidemia, and tobacco and alcohol use, liver fibrosis was associated with worse performance on the DSST (β = ‐0.40; 95% CI, ‐0.60, ‐0.20; P<0.001) (Figure). Liver fibrosis was associated with worse executive function but not memory test performance (Table). We included 34,730 participants with brain MRI, obtained a median of 9.3 years after baseline. In adjusted models, liver fibrosis was associated with lower hippocampal volume (β = ‐58.8; 95% CI, ‐94.7, ‐22.9; P = 0.001) and higher white matter hyperintensity volumes (β = 1142.8; 95% CI, 311.6, 1973.9; P = 0.007) (Table, Figure).

Conclusion

Liver fibrosis is associated with worse cognitive performance, perhaps explained by hippocampal volume loss and white matter hyperintensity burden.
Free Innovative Tool to Address Memory Concerns and Brain Health for All Communities
Authors: Kenny Brooks
Published: December 2022

Background

Over 60% of dementia cases are undetected, often due to fear, stigma, and lack of education about memory and brain health. To address this unmet need, UsAgainstAlzheimer’s developed BrainGuide, a free, web‐based consumer education platform designed to empower individuals to take the best next steps in managing their own or a loved one’s brain health.

Method

BrainGuide was built with nonprofit, advocacy, industry, medical and technology experts. It offers two memory questionnaires created with input from medical experts and adapted from validated tools in the healthcare community. The self‐assessment is based on MIS/MIS‐T and the caregiver assessment is based on the AD8. Both were adapted for use with a voice and web bot. BrainGuide is not intended to diagnose or provide treatments. Six personas representing individuals concerned about their or a loved one’s brain health, caregivers, and individuals living with Alzheimer’s, were created to curate resources for users to browse after completing a questionnaire. Twenty‐five original tailored factsheets and 70+ links to external resources are also available. BrainGuide’s development was informed by market research including qualitative and quantitative feedback from users. It runs on Amazon Web Services making it available to anyone with telephone or Internet access and was developed with in‐kind and financial support by Biogen.

Result

Since launching in March 2021, over 283,000 individuals have visited BrainGuide and 160,000 have completed a memory questionnaire; 79% of users are women, 78% of users are 60+ years and 17% are non‐white. 79% of individuals are taking the memory questionnaire for themselves, and the platform generates a summary to bring to a provider. 74% of users who took the questionnaire indicated that they felt more prepared to discuss brain health with a doctor through our post‐experience user survey.

Conclusion

Data collection is ongoing, to measure consumer engagement and behavior change. To date, we have collected data including consumer confidence in raising the topic of memory with loved ones and providers, the adoption among different audience segments and the ongoing engagement of users. This data provides insights for the field as we work to address challenges to early detection and diagnosis.
Co‐Creating an AI Virtual Assistant Prototype with People Living with Dementia
Authors: Fournier Lisa
Published: December 2022

Background

Joi is an Artificial Intelligence (AI) Virtual Assistant prototype to improve emotional well‐being for people living‐in‐place with dementia. The Virtual Assistant creates personalized joy pops for the person with dementia within a smart‐home living environment. The joy pops by the VA are triggered based on input from sensors in the smart home, including motion, sound, temperature, and light. The prototype is designed and personalized for the person to provide a moderately stimulating environment to reduce agitation, apathy, and anxiety.

Method

Based on reminiscence therapy intervention and a smart home environment, the prototype was co‐created with input from people living with dementia and their care partners. A literature review on stress‐related risk reduction strategies between people with dementia and their care partners was completed for input into the system philosophy. Surveys were used to gather the information from people living with dementia and their care partners, including the current and future state of the home environment and an assessment of meaningful objects.

Result

A personalized memory box was developed for each individual to house meaningful objects, such as photos, music, or other items deemed meaningful by the participants in the survey. In addition, the prototype was integrated into a smart home environment to show how smart technologies can be used for conversation prompts with AI versus a name prompt to initiate the AI instance.

Conclusion

The prototype can be used for continued development and testing to explore possibilities for living‐in‐place with dementia. This type of co‐creation encourages dementia citizenship and well‐being as well as values user input for prototyping from a vulnerable population.
Synthesizing Images of Tau Pathology from Images of Glucose Utilization
Authors: Lee Jeyeon , Burkett Brian J , Min Hoon‐Ki , Senjem Matthew L. , Mester Carly T. , Wiste Heather J. , Lundt Emily S. , Corriveau‐Lecavalier Nick , Dicks Ellen , Botha Hugo , Radford Jonathan Graff , Barnard Leland R , Gunter Jeffrey L. , Schwarz Christopher G. , Kantarci Kejal , Knopman David S. , Boeve Bradley F. , Petersen Ronald C. , Jack Clifford R. , Jones David T.
Published: December 2022

Background

In vivo tau‐positron emission tomography (PET) is an attractive biomarker for Alzheimer’s disease (AD) diagnosis and treatment. However, tau‐PET is less widely available than other modalities. In this study, we tested cross‐modality synthesis of tau‐PET brain images from fluorodeoxyglucose F‐18 (FDG)‐PET using a deep convolutional neural network (CNN).

Method

Participants (n=1,192) who had brain FDG‐PET with 18F‐FDG and tau‐PET with Flortaucipir (F‐18‐AV‐1451) were included for training and testing. This cohort spanned normal aging (ages 26‐98), pre‐clinical, and clinical AD and related disorders including the FTD and DLB spectrum. External validation was done using ADNI (n=288). The PET scans were co‐registered to the corresponding MRI and subsequently warped to Mayo Clinic Adult Lifespan Template (MCALT) space. Tau‐PET images were SUVR‐normalized to the cerebellar crus, and FDG to the pons. A 3D dense‐U‐net model was utilized as an architecture. Cross‐validation experiments were conducted using 5‐fold validations (60% training set, 20% validation set, and 20% test set) with mean squared error as the loss function.

Result

Our dense‐U‐net model successfully synthesized tau‐PET from metabolic images with good correlation and low prediction error for regional SUVRs (Figure 1A‐C). The model showed a robust prediction ability, performing accurately in an independent, external ADNI cohort (Figure 1D‐F). The model‐imputed tau‐PET significantly improved performance in classifying tau positivity (mean AUROC(±SD)=0.78±0.04 and 0.85±0.03 for FDG‐PET and synthesized tau‐PET, respectively) and diagnostic groups (cognitively unimpaired with abnormal amyloid‐PET vs. cognitively impaired with abnormal amyloid‐PET) compared to the original input FDG data (mean AUROC(±SD)=0.89±0.04, 0.85±0.05 0.91±0.04 for actual tau‐PET, FDG‐PET and synthesized tau‐PET, respectively) (Figure 2), suggesting enhanced clinical utility for metabolic images. The ADNI cohort also showed similar results (for tau positivity: AUROC=0.66 and 0.78 for FDG‐PET and synthesized tau‐PET, respectively; for CU A+ vs. CI A+: AUROC=0.86, 0.62, and 0.73 for actual tau‐PET, FDG‐PET, and synthesized tau‐PET; Figure 3).

Conclusion

We showed that using a CNN model to predict tau‐PET from FDG‐PET is feasible. The synthesized tau‐PET can augment the value of FDG‐PET, facilitating the multi‐modal diagnosis of AD.
Alzheimer’s Disease Proteinopathy and Synaptic Integrity: The Protective Role of Physical Activity
Authors: Lee Shannon Y. , Paolillo Emily W , VandeBunte Anna M. , Brinkmalm Ann , Blennow Kaj , Zetterberg Henrik , Kramer Joel H. , Casaletto Kaitlin B
Published: December 2022

Background

Alzheimer’s disease (AD) proteinopathy levels are associated with greater synaptic dysfunction markers in brain tissue and cerebrospinal fluid (CSF). However, it is less well known how physical activity (PA) affects this relationship. We aimed to examine the moderating role of PA on AD proteinopathy and synaptic marker outcomes in typically aging adults.

Method

43 cognitively normal older adults from the UCSF Memory and Aging Center (Meanage = 72.82; SDage = 6.51; 56% women; 83.7% non‐Hispanic White) self‐reported their physical activity levels via the Physical Activity Scale for the Elderly (PASE) questionnaire and completed lumbar punctures during their annual research visit. CSF was analyzed for p‐tau181 and Aβ42, as well as presynaptic (SNAP‐25, synaptotagmin‐1), postsynaptic (neurogranin‐36), and synaptic growth (GAP‐43) proteins in picograms per milliliter (pg/ml). Separate linear regression models assessed the interactive effect of PA and p‐tau181/Aβ42 ratios on levels of each synaptic marker, covarying for participant demographics.

Result

Greater p‐tau181/Aβ42 ratios correlated with worse synaptic integrity (r = 0.364‐ 0.412). Adjusting for age, body mass index, and education, there was a significant interaction between p‐tau181/Aβ42 and physical activity on synaptotagmin‐1 (p = 0.0065), neurogranin‐36 (p = 0.0318), and GAP‐43 (p = 0.0321) CSF protein levels, with SNAP‐25 approaching interaction significance (p = 0.0699). Probing the interaction by tertiles, at higher levels of physical activity, the negative relationships between AD proteinopathy and synaptic integrity outcomes were significantly attenuated.

Conclusion

Physical activity significantly moderates the relationship between AD proteinopathy and CSF biomarkers of synaptic integrity. Higher PA engagement may attenuate the adverse link between AD proteinopathy and synapse dysfunction. Our findings highlight the importance of exercise and active lifestyles in promoting and maintaining synapse function regardless of neuropathological burden.
White matter hyperintensities are an early marker for cognitive decline in cognitively healthy older adults
Authors: Morrison Cassandra , Dadar Mahsa , Villeneuve Sylvia , Collins Louis D
Published: December 2022

Background

Previous research suggests that white matter hyperintensities, amyloid, and tau contribute to cognitive decline. It remains unknown as to how these factors relate to one another and how they jointly contribute to cognitive decline in normal aging. The goal of this study was to examine the association between these pathologies and their relationship to cognitive decline.

Methods

Cognitively normal older adult data from the Alzheimer’s Disease Neuroimaging Initiative were examined. Participants were included if they had no subjective cognitive decline, had baseline white matter hyperintensity measurements, CSF Aß42, CSF pTau181, and cognitive scores. WMHs were segmented using a previously validated automatic technique (Dadar et al., 2018). Of the 230 participants included, only 199 had follow‐up cognitive scores. Linear regressions examined the influence of white matter hyperintensities, amyloid, and tau on baseline and follow‐up cognitive scores. Linear regressions also examined the association of amyloid and tau on white matter hyperintensities and between tau and amyloid.

Results

Increased baseline WMHs were associated with increased baseline ADAS‐13 scores (t=2.59, p=.01) and lower follow‐up executive functioning (t= ‐2.84, p=.005). Lower baseline Aß42 was associated with lower baseline (t=3.58, p<.004) but not follow‐up executive function. Baseline pTau was not associated with decline in cognition at baseline or follow‐up. At baseline, WMHs were not associated with pTau but were inversely related to lower baseline Aß42 (t=‐4.20, p<.001). Aß42 and pTau were not associated (t=0.51, p=.61).

Conclusion

White matter hyperintensities may be one of the earliest pathologies observed in healthy older adults that contribute to cognitive decline. The inclusion of white matter hyperintensities as an additional marker for early cognitive decline may improve our current understanding of age‐related changes in cognitively healthy older adults.
Amyloid status prediction by combining plasma p‐tau181 and NfL cut‐offs
Authors: Bun Shogyoku , Ito Daisuke , Sato Yoshiaki , Tezuka Toshiki , Takahata Keisuke , Yamamoto Yasuharu , Sano Yasunori , Kubota Masahito , Tabuchi Hajime , Mimura Masaru
Published: December 2022

Background

Plasma biomarkers have emerged as a promising tool for screening Alzheimer's disease(AD). However, no externally defined cut‐off values for any plasma biomarkers yet to exist to predict amyloid β (Aβ) status.

Method

Taking advantage of the different plasma p‐tau181 and NfL increase profiles, we used the two plasma biomarkers to establish preliminary cut‐off values (two cut‐offs for p‐tau181, one for NfL) for screening Aβ positivity. Participants with a clinical diagnosis of AD(N=20), mild cognitive impairment(MCI)(N=12), other neurodegenerative disorders(N=19), psychiatric disorders(N=3 with depression, N= 1 with delusional disorder), and healthy controls(N=37) were recruited from the Memory Clinic at Keio University Hospital. Static 18F‐Florbetaben (FBB) PET was conducted on all the participants. A trained neuroradiologist visually assessed the acquired images to determine Aβ positivity. Each participant's p‐tau181 value was plotted against NfL values. After visualizing their distribution stratified by the Aβ status, we conducted an exhaustive search to predict Aβ positivity. We first created a ROC curve for p‐tau181 alone and then made a 'quasi‐ROC' curve by combining two p‐tau181 cut‐offs(i.e., the higher and lower cut‐offs) and one NfL cut‐off. The optimal cut‐off values for each ROC curve were determined by the Youden Index.

Result

Of the 92 participants, 30(32.6%) were Aβ‐positive(Aβ+). Mean ages were 68.7 years(SD8.2) for Aβ‐ and 72.4(SD9.3) for Aβ+ group (p=0.02). Mean p‐tau181 values were 1.72pg/ml (SD0.75) for Aβ‐ and 3.58pg/ml (SD1.09) for Aβ+ group (p<0.001), whereas mean NfL values were 24.47pg/ml(SD13.77) vs 27.24(SD9.96) (p=0.01). The ROC curves yielded each found the optimal cut‐off values as follows: for plasma p‐tau181 alone, ptau‐181 value, true positive rate(tpr) and false positive rate(fpr) were 5.8 pg/ml, 0.767 and 0.065, respectively. For a combination of higher and lower p‐tau181 cut‐offs and one NfL cut‐off, each biomarker value and the corresponding tpr and fpr were 3.0pg/ml, 2.0/g/ml, 35pg/ml, 0.933, and 0.177, respectively.

Conclusion

Our results suggest combining two cut‐off values for plasma p‐tau181 and one cut‐off for NfL may yield an excellent discriminant capacity for Aβ positivity. Further research is needed to validate the result.
Intersecting PTMS regulate clearance of pathogenic tau by the CHIP ubiquitin ligase
Authors: Nadel Cory M , Gestwicki Jason E.
Published: December 2022

Background

Biochemical and cellular models of tau post‐translational modifications (PTMs) were generated to understand how pathogenic tau species evade the protein quality control machinery during the pathogenesis of neurodegeneration.

Method

A pathogenic fragment of 0N4R tau representing the species derived from caspase‐cleavage at Asp421 (tauC3) bearing native PTMs was purified from Sf9 insect cells, and its binding to the ubiquitin ligase CHIP was analyzed by ELISA. Differential scanning fluorimetry and fluorescence polarization assays were used to identify relevant sites of modification that alter the affinity of CHIP for tauC3. X‐ray crystallography was employed to define the molecular details of the interaction of the CHIP TPR domain with tauC3.

Result

Phosphorylation of tauC3 was shown to reduce the affinity of the CHIP‐tauC3 interaction and attenuate ubiquitination of tauC3 by CHIP. Phosphorylation of tauC3 at Ser416 was shown to be sufficient to significantly reduce the affinity of CHIP‐tauC3 interaction and promote tauC3 accumulation in cells. Introducing specific mutations into CHIP rescued binding to phosphorylated tauC3 and improved ubiquitination and clearance of tauC3.

Conclusion

C‐terminal phosphorylation at Ser416 of caspase‐cleaved tau inhibits tau clearance by the CHIP ubiquitin ligase and represents a targetable modality to promote clearance of pathogenic tau species during the pathogenesis of neurodegenerative diseases.
Novel Loci for Alzheimer Disease Identified by Genome Wide Association Study in Ashkenazi Jews
Authors: Li Donghe , Farrell John , Mez Jesse B. , Martin Eden R. , Bush William S. , Mayeux Richard , Haines Jonathan L. , Pericak‐Vance Margaret A. , Wang Li‐San , Schellenberg Gerard D. , Lunetta Kathryn L. , Farrer Lindsay A.
Published: December 2022

Background

Previous studies identified associations of Alzheimer’s disease (AD) risk primarily in outbred European ancestry (EA) populations. We focused on Ashkenazi Jews (AJs) who descended from a founder population in eastern Europe.

Method

We discriminated AJs in the multiethnic Alzheimer’s Disease Genetic Consortium (ADGC) TOPMed imputed GWAS dataset (n = 53,502) and whole genome sequencing (WGS, n = 16,815) and whole exome sequencing (WES, n = 20,504) datasets assembled by the Alzheimer’s Disease Sequencing Project using a reference GWAS dataset including persons with four AJ grandparents (n = 3,435). Principal component (PC) analysis was performed for each AD dataset combined with the AJ reference data, and a Gaussian mixture model was applied for population clustering. GWA analyses were performed by combining AJs discriminated from the ADGC and WGS subjects (G1) using genome‐wide data and from all three datasets using variants called from exome capture (G2). Separate analyses of individual common (MAF≥1%) and rare (MAF<1%) variants and gene‐based analyses including rare variants were performed using models adjusting for age, sex, and PCs.

Result

Totals of 2,956, 738 and 1,062 unique AJs were identified in the ADGC, WGS and WES datasets, respectively. After filtering duplicate and closely related individuals, the sample sizes were 1,355 cases and 1,661 controls for G1 and 1,504 cases and 2,047 controls for G2 analyses. Excluding the APOE region, G1 analyses revealed a genome‐wide significant (GWS) association (P<5.0×10−8) with the TREM2 R47H missense mutation (P = 9.66×10−9) and suggestive associations with rs541586606 near RAB3B (P = 5.01×10−8), rs545690149 near ZNF890P, (P = 5.77×10−8) and rs1225737296 near ANXA10 (P = 6.32×10−8). In G2 analyses, we obtained GWS associations with GBA intronic SNP rs3115534 (P = 3.20×10−13) and TREM2 R47H (P = 2.64×10−10), and suggestive associations with rs1003710 in SMAP2 (P = 1.91×10−7) and rs200698976 in ZNF890P (P = 3.49×10−7). No GWS rare variant associations were identified. Significant gene‐based association was identified with GIPR (7.34×10−7).

Conclusion

Among the novel findings, GBA was previously associated with Parkinson disease and Lewy body dementia (LBD). Remarkably, rs3115534 is located 35 bp from, but not in linkage disequilibrium with, N370S that is associated with LBD in AJs. Moreover, rs3115534 (MAF = 0.027 AJ controls) is rare in EAs (MAF = 0.0015). Our results highlight the efficacy of GWAS in founder populations.
Computerized cognitive interventions for preventing dementia in people with mild cognitive impairment: A systematic review with meta‐analyses
Authors: Zuschnegg Julia , Schoberer Daniela , Häussl Alfred , Russegger Silvia , Ploder Karin , Fellner Maria , Hofmarcher‐Holzhacker Maria , Roller‐Wirnsberger Regina , Paletta Lucas , Koini Marisa , Schüssler Sandra
Published: December 2022

Background

People with mild cognitive impairment (MCI) are faced with a higher risk of developing dementia, but with a “window of opportunity” for prevention and treatment. Computerized cognitive interventions (CCIs) might constitute a beneficial non‐pharmacological treatment approach. This systematic review evaluated evidence of CCIs performed individually with a computer, tablet‐PC, game consoles, virtual reality (VR), or augmented reality (AR) on cognition in community‐dwelling people with MCI.

Method

A systematic review and meta‐analyses of randomized controlled trials (RCTs) was performed. The systematic literature search was conducted in MEDLINE, CINAHL, Embase, Cochrane CENTRAL, IEEE Xplore Digital Library, ISI Web of Knowledge, Scopus and PsycINFO, and included an additional search for gray literature. The search was completed by backward citation tracking. The methodological quality of the included RCTs was independently assessed by two reviewers. Comparable studies were pooled using the random‐effects model.

Result

A total of 18 randomized controlled trials (RCTs) were identified. 12 RTCs were used for conducting meta‐analyses which showed significant effects of CCIs for people with MCI in memory (SMD 1.12, CI 95% [0.08, 2.16]), working memory (SMD 0.85, CI 95% [0.32, 1.38]), attention/concentration/processing speed (SMD 0.61, CI 95% [0.21, 1.02]), executive functioning (SMD 0.96, CI 95% [0.26, 1.66]), and language (SMD 1.63, CI 95% [0.20, 3.06]), but no significant improvement in global cognition. Pooling follow‐up evaluations was not possible, but one of two studies showed continuing significant differences for the intervention group after 6 months post intervention in memory and working memory. CCIs were conducted predominantly with computers, followed by tablet‐PCs, VR, AR, and mixed reality.

Conclusion

This review demonstrated beneficial effects of CCIs on domain‐specific cognition in people with MCI. Therefore, CCIs might be a valuable treatment option to maintain cognition and prevent progression to dementia. However, further research is necessary, especially on CCIs applied with emerging technologies like VR or AR. Furthermore, various outcome measurements used in the studies were challenging for the pooling of study results, which highlights the need for a predefined set of important cognitive outcomes and tools for future RCTs.
Experiences of people with Alzheimer’s disease, relatives, and dementia trainers on the usability of a tablet‐based dementia training
Authors: Schüssler Sandra , Zuschnegg Julia , Paletta Lucas , Russegger Silvia , Fellner Maria , Ploder Karin , Strobl Bernhard , Sekulic Maja , Koini Marisa , Hofmarcher‐Holzhacker Maria , Roller‐Wirnsberger Regina
Published: December 2022

Background

Non‐pharmacological interventions for people with dementia, like tablet‐based cognitive trainings, are increasingly popular to counteract the disease progression. Usability research on such trainings in the field of dementia is essential to raise acceptance and increase training intensity, as regular practice may contribute to their effectiveness. The aim was to explore the experiences of people with Alzheimer’s disease (PwAD), relatives, and dementia trainers regarding the usability of a tablet‐based dementia training.

Method

This qualitative study is part of an ongoing randomized controlled trial (project multimodAAL) which investigates the effects of an individually performed tablet‐based dementia training program (i.e., physical and cognitive exercises) in PwAD living at home. Individual interviews were conducted with people with mild AD (n=5), relatives (n=5) and dementia trainers (n=5) who had been performing the training for at least 6 months. A qualitative content analysis was conducted.

Result

Participants were predominantly women (73.3 %), with an average age of 73.4±11.4 years for PwAD, 66.2±10.7 years for relatives, and 43.1±10.4 years for trainers. Participants confirmed a good feasibility of the video‐provided physical exercises (e.g., coordination, strength), but some PwAD reported feeling unchallenged. Relatives and trainers wished for exercises to be more motivating (e.g., direct motivational address by the gymnast in the video, colorful sportswear). Regarding cognitive exercises, participants appreciated the varied and alternating types of exercises (e.g., puzzle, quiz) within the training sessions. Trainers and relatives recognized that PwAD particularly enjoyed exercises related to topics of their past/biography (e.g., hobbies, previous occupation) and to religious/seasonal traditions (e.g., Easter). Relatives and trainers highlighted that most PwAD needed support during the physical and cognitive exercises in terms of (technical) guidance, motivation/feedback/praise, as well as hints/tips/thought‐provoking impulses to perform their training successfully and to avoid frustration and cancellation of the training. Some suggested to extend the program regarding written and verbal support (e.g., hint button, voice assistant). Furthermore, participants emphasized a good sensitivity of the tablet‐PCs’ touch screen.

Conclusion

Results show that the presented tablet‐based dementia training is received well by participants, but there is still potential for (technical) enhancements regarding support through the exercises and motivational strategies.
DEMENTIA CAREGIVER SUPPORT PROGRAM IN VIETNAM: DEVELOPMENT, IMPLEMENTATION AND FIRST RESULTS
Authors: Huong Tran Thi Thu , Tam Pham Thi Thanh , Luu Phan Thi , An Nguyen Thi Thai , Liem Do Thanh , Truc Nguyen Tran Thanh , Thang Tran Cong , Weschke Sarah , Klein Olga A. , Kilimann Ingo
Published: December 2022

Background

Previous studies on support programs including psychoeducation, care training, and counselling have shown to be beneficial for family dementia caregivers with the potential to reduce care giver burden. In this pre‐post study, we aimed to assess the effects of a new support program to reduce caregivers’ burden.

Methods

We developed and conducted a 4‐week support program (4 sessions, 1.5 hours each). An 8‐module course developed by the German Center for Neurodegenerative Diseases (DZNE) and the German Alzheimer’s Society was culturally adapted to fit into the Vietnamese context. Caregivers of people with dementia were invited to participate in the program at Hospital 30‐4 in Ho Chi Minh City, Vietnam.

Caregiver burden was assessed with the 22‐item Zarit Burden Interview (ZBI) at baseline and after the intervention using the Wilcoxon signed‐rank test.

Results

A total of 15 caregivers underwent the study. The mean age was 52.7 years, 67% of patients were women, the mean time duration of care was 16 (±9.5, max 30) months. Wilcoxon signed‐rank test indicated that median ZBI scores post‐intervention (median = 40) were not statistically significant difference to the median pre‐intervention (median = 44, Z = 34.5, p = 0.26).

Conclusion

Our study showed no statistically significant change of burden, however, a tendency towards a reduction of the ZBI score after the intervention. The reasons for not reaching significance might be the small sample size of the intervention. Furthermore, the ZBI assessment directly after the end of the program might miss the effect of the intervention as participants will need time for the implementation of new coping strategies.