bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimated Age of Amyloid Onset in Participants with Early‐ versus Late‐Onset Alzheimer’s Disease: Results from the LEADS & ADNI Studies
Authors: Blazhenets Ganna , Mundada Nidhi , Lee JiaQie , Landau Susan M. , Koeppe Robert A. , Carrillo Maria C. , Dickerson Brad C. , Jagust William J. , Apostolova Liana G. , Rabinovici Gil D. , La Joie Renaud
Published: December 2023

Background

Aβ deposition is thought to start decades prior to symptom onset. Previous studies have shown that mathematical modeling enables reconstruction of Aβ‐PET trajectory and age estimation at Aβ‐PET positivity in Aβ‐positive patients. We aimed to apply this approach to determine Aβ duration and estimate age at Aβ‐PET positivity in sporadic early‐ (<65yo) and late‐ (≥65yo) onset AD (EOAD/LOAD).

Method

We combined PET data from the Longitudinal Early‐Onset AD Study (LEADS, n = 288) and ADNeuroimaging Initiative (ADNI, n = 915). First, we selected Aβ+ (baseline Centiloids ≥24) cognitively impaired patients with ≥2 Florbetaben‐PET scans to compare baseline and longitudinal amyloid‐PET in EOAD versus LOAD using linear mixed effects regression (Figure 1). Then, we used ADNI participants with ≥2 Florbetapir‐PET scans to assess the relationship between Aβ‐PET Centiloids and time (Figure 2). We estimated the Aβ temporal trajectory by integrating a reciprocal of the spline model from the accumulation rate and Centiloidmid‐point. Finally, we used the resulting Aβ trajectory to estimate Aβ duration and age at Aβ‐PET positivity onset for patients with EOAD and LOAD (Figure 3).

Result

EOAD patients had higher baseline Aβ burden than LOAD patients. Amyloid‐PET increased at similar rates in the two groups (Figure 1), allowing us to operate under the assumption that EOAD and LOAD follow the same Aβ trajectory, with a temporal shift. Aβ trajectory was estimated in ADNI Florbetapir‐PET, showing an almost linear dependency between Centiloids and Aβ duration (Figure 2). The model suggests that Aβ‐PET positivity (CL = 24) is reached after 7 years, and an additional 26 years are needed to reach 100 CL. When applied to the Florbetaben sample, we determined that 75yo LOAD patients became Aβ‐PET positive around 52yo, while 60yo patients with EOAD dementia were Aβ‐PET positive around age 31 (Figure 3).

Conclusion

Based on available data, the dynamic of Aβ accumulation seems similar in EOAD and LOAD, with a temporal shift indicating that EOAD patients might transition to Aβ‐PET‐positive in their early 30s. Prospective studies on early phases of Aβ accumulation in EOAD patients will be important for validation of these findings since existing data is limited.
Transcriptomic signatures of regional selective vulnerability in ALS and FTLD‐TDP
Authors: Spencer Barbara E , Phatnani Hemali , Lee Eddie B , Irwin David J. , McMillan Corey T ,   the NYGC ALS Consortium
Published: December 2023

Background

Differential gene expression in the brain has been identified in both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP‐43 (FTLD‐TDP) relative to controls. However, direct comparisons of ALS and FTLD‐TDP are rare. We hypothesize that identification of distinct transcriptomic signatures between ALS and FTLD‐TDP may provide insight into regional selective vulnerability of TDP‐43. Here, we directly compare gene expression in frontal cortex between FTLD‐TDP and ALS cases, accounting for cell‐type proportion differences due to neurodegeneration.

Method

Frontal cortex RNA‐seq samples passing extensive quality control metrics were downloaded from the New York Genome Center ALS Consortium, including non‐neurological controls (n = 42) and individuals with neuropathological diagnoses of ALS (n = 118) or FTLD‐TDP (n = 27). A total of 59,782 genes were quantified for each sample. Scaden was used to deconvolve this bulk RNA‐seq data into cell type proportions. Infrequently expressed genes were filtered and data was normalized by total count. Generalized linear model estimates of dispersion were calculated accounting for potential confounders including cell type proportions, RIN, contributing site, age at death, and sex to identify differentially expressed genes (DEGs) between ALS and FTLD‐TDP as well as each neurological group relative to controls. A gene ontology enrichment analysis for biological processes was performed for each DEG set. We report DEGs and enrichment surviving FDR p<0.05.

Result

653 DEGs were identified in FTLD‐TDP compared to ALS within the frontal cortex samples. The majority of these DEGs were also differentially expressed between only one of these neurological groups and controls. However, 281 of these DEGs were uniquely differentially expressed in ALS compared to FTLD‐TDP, not differentially expressed between either neurological group and controls. Gene ontology enrichment analyses for biological processes revealed that the 198 genes uniquely upregulated in FTLD‐TDP compared to ALS (not different from controls) mapped to pathway terms including those related to immune and inflammatory responses as well as vascular functions, while the 83 genes uniquely upregulated in ALS compared to FTLD‐TDP related to retina development.

Conclusion

This case‐case comparative study will provide insight into the candidate mechanisms underlying regional selective vulnerability in FTLD‐TDP relative to ALS that may drive individual‐level cognitive/behavioral presentations of TDP‐43 proteinopathies.
Cerebrospinal Fluid Protein Levels in Patients with Neurodegenerative Diseases Correlates with Cognitive and Motor Function
Authors: Szabo Marcell P , Haselhuhn Taryn R , Kwan Justin Y , Snyder Allison
Published: December 2023

Background

Blood brain barrier (BBB) dysfunction is suggested to have a causal role in neurodegenerative disorders. Cerebrospinal fluid (CSF) total protein (TP) is a proxy for CSF albumin quotient, which is an indicator of BBB breakdown. Normative values for CSF TP are based on young and healthy individuals, and there is a lack of understanding of how this biomarker changes with aging and neurodegeneration. The aim of this study is to examine the CSF profile in a cohort of patients with ALS‐FTD spectrum disorders and to determine relationship between the CSF profile and cognitive and motor measures in these patients.

Method

CSF from participants with ALS‐FTD spectrum disorders enrolled in the NIH protocol “Investigating Complex Neurodegenerative Disorders related to Amyotrophic Lateral Sclerosis and Frontotemporal Dementia” were included (n = 63). We described the distribution of the CSF profile in these participants and compared the findings with existing literature. We then examined the relationship between CSF measures and functional rating scales and cognitive and motor measures.

Result

The average total protein was 47.77 mg/dL (SD = 38.29). The average CSF glucose was 66.00 mg/dL (SD = 12.80). There was a negative correlation (p = 0.0102) between CSF TP and the ALS Functional Rating Score. We will further investigate the relationship between the CSF profile and measures of cognitive and motor performance.

Conclusion

Our findings show that CSF TP is elevated in patients with ALS‐FTD spectrum disorders and higher CSF TP level correlated with greater disease severity in ALS. We will further investigate the relationship between CSF TP and other measures of cognitive and motor function.
Regional cerebral blood flow is associated with PET and plasma biomarkers of tau pathology in middle age
Authors: Houck Alexander L , Lao Patrick J. , Alshikho Mohamad J , Turney Indira C , Pyne Jeffrey , Benavides Andrea , Hale Christiane , Gutierrez Jose , Simoes Sabrina , Manly Jennifer J. , Brickman Adam M.
Published: December 2023

Background

Cerebrovascular dysfunction and vascular brain injury are associated with risk and progression of clinical Alzheimer’s disease (AD), but it is unclear whether they contribute directly to disease pathogenesis. Animal models of small vessel cerebrovascular disease suggest that transient cerebral hypoperfusion may promote tau pathology independent of amyloidosis. In the current study, we used pulsed arterial spin labeling (PASL) magnetic resonance imaging (MRI) to examine the association of regional cerebral blood flow (CBF) with two biomarkers of tau pathology, plasma phosphorylated tau 181 (ptau181) concentrations and PET MK6240 SUVR, in middle aged adult participants from the Offspring Study of Mechanisms for Racial Disparities in Alzheimer’s Disease.

Method

At the time of analysis, 469 Offspring Study participants (54.0±10.6‐years‐old; 64% women; 67% Latinx, 22% non‐Latinx Black, 6% non‐Latinx white) had available PASL and ptau181 plasma concentrations (Quanterix Simoa HDx platform). Sixty‐four participants (59.9±5.4‐years‐old age; 67% women; 64% Latinx, 22% non‐Latinx Black, 8% Latinx white) with PASL CBF data received tau PET imaging with MK6240 and mean SUVR was computed across all grey matter regions for each participant. Voxelwise correlational analyses were run to examine the relationship between ptau181 concentrations and regional CBF and between tau PET SUVR and regional CBF.

Result

Increased ptau181 concentrations were associated with clusters of decreased CBF in frontal grey matter, striatum, hippocampus, and periventricular white matter. These correlations were asymmetrical, with the largest clusters found in the left hemisphere. Higher PET SUVR was associated with clusters of lower CBF in frontal, parietal, and occipital grey matter.

Conclusion

These findings demonstrate a codependency between regional blood flow and tau pathology, indexed by fluidic and imaging biomarkers. Future studies will clarify the directionality and possible causality of these associations, but these cross‐sectional findings are consistent with a hypothesis that subtle diminished blood flow gives rise to tau abnormalities.
APOE4 affects cortical microstructural alterations in Alzheimer’s disease: evidence from an autopsy‐confirmed cohort.
Authors: Torso Mario , Ridgway Gerard R , Valotti Michele , Hardingham Ian , Chance Steven A ,   National Alzheimer’s Coordinating Center and Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Apolipoprotein E ε4 (APOE4) is one of the most studied genetic risk factors for developing Alzheimer’s disease (AD). However, it is still not fully understood how APOE4 contributes to cortical neurodegeneration. We investigate ante‐mortem cortical microstructural changes in carrier and non‐carrier patient MRIs with autopsy‐confirmed Alzheimer’s disease neuropathological changes (ADNC).

Method

Forty‐nine participants with ADNC and ante‐mortem MRI were obtained from the National Alzheimer’s Coordinating Center (NACC; n = 34) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 15). Participants were grouped based on APOE4 presence (22 non‐carriers and 27 carriers). Thal phase, CERAD neuritic plaque assessment, Braak NFT, and combined ABC score, were used as AD neuropathological hallmarks.

Structural and diffusion MRI (dMRI) were used to calculate cortical diffusivity measures in five different functional macroregions: Primary Sensory, Unimodal, Limbic/Proisocortex, Heteromodal and Primary Motor (Ffytche & Wible 2014, PMID:24936089; Mesulam 1998, PMID:9648540). For each macroregion, cortical mean diffusivity and three neuropathology‐inspired cortical diffusivity measures were calculated: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+) (Torso et al. 2022, PMID:36281682).

Clinical, demographic and neuropathological data were used to characterize groups (Table). Group differences in diffusion metrics were tested with GLM adjusting for ABC score, interval between MRI scan date and autopsy date, scanner manufacturer, dMRI b‐value, age and sex, with false discovery rate correction (pFDR<0.05).

Result

The cortical diffusivity investigation revealed higher Primary Sensory (auditory, visual, sensory) AngleR values in APOE4 carriers (Figure). The APOE4 carrier group was significantly younger and showed higher Thal phase, CERAD neuritic plaque, Braak stage and ABC scores.

Conclusion

Cortical diffusivity measures can detect differences in cortical microstructure of APOE4 Carrier and Non‐carrier patients, suggesting a wider pattern of cortical damage in APOE4 carriers that involves Primary Sensory areas (lateral occipital, postcentral, pericalcarine, transverse temporal).

Consistent with previous findings, the diffusion‐derived metric AngleR appears particularly sensitive to subtle effects, such as the early cortical changes associated with amyloid deposition and neuroinflammation (Torso et al. 2022, PMID:36281682), perhaps linked to the APOE4 modulation of the pattern of cortical microstructural neurodegeneration.
Association Analysis of Common Structural Variants in the Alzheimer’s Disease Sequencing Project
Authors: Lee Songmi , English Adam C , Xia Rui , Peloso Gina M. , Bis Joshua C , Lin Honghuang , Choi Seung Hoan , Heard‐Costa Nancy , DeStefano Anita L. , Sedlazeck Fritz J , Fornage Myriam
Published: December 2023

Background

Structural variants (SV), genomic rearrangements of >50 base pairs, are an important source of genetic variation and have a great impact on gene expression and protein function. However, their contribution to the genetic architecture of Alzheimer’s Disease (AD) has not been comprehensively investigated. Identification of SVs by short‐read alignment can be inaccurate and biased. We used a novel SV calling pipeline that leverages assembly‐based methods and graph‐based representation, to identify SVs with high accuracy in the diverse sample of the Alzheimer’s Disease Sequencing Project (ADSP). We further examined the association of common SVs with AD.

Methods

We applied Biograph for SV calling on the ADSP 17K whole genome sequence data. After filtering out low‐quality SVs and performing sample‐level quality control, we identified 222,956 deletions, 177,139 insertions, and 10,558 inversions in 12,908 individuals (6,304 AD cases; 6,604 controls). We performed association analyses of common SVs (MAF > 1%) with AD using a logistic mixed‐effects model adjusting for sex, technical covariates, principal components, and relatedness. Statistical significance was evaluated using a Bonferroni‐corrected threshold (P< 9.19.x10−7).

Results

There were 28,634 deletions, 25,522 insertions, and 198 inversions with MAF > 1%. We identified 2 intronic deletions significantly associated with AD. The first deletion is located in CCDC88B, encoding a protein that regulates T‐cell maturation and inflammation. The second deletion is located in CCDC11, predicted to be part of the spliceosomal complex. Among 11 insertions significantly associated with AD, 3 mapped to exonic sequences. A relatively common insertion located in an exon of FOXO6 showed the most significant association with AD (P = 1.41×10−12). FOXO6 is a member of Forkhead transcription factors that have been implicated in aging. Along with its high level of expression in the hippocampus, mice lacking FOXO6 had impaired memory consolidation. We identified one inversion suggestively associated with AD (P = 3.32×10−6) and located in an intron of PDE5A. PDE5A inhibitors have been reported as potential therapeutic targets for AD.

Conclusion

Using novel data structures and algorithms to call SV, we discovered 14 SVs significantly associated with AD. Validation and gene prioritization of these findings are warranted.
Alzheimer’s disease blood tests of amyloid‐β 42/40, p‐tau217, p‐tau181 and p‐tau205 ratios in a diverse community‐based population: Preliminary results from SEABIR
Authors: Bateman Randall J.
Published: December 2023

Background

Alzheimer’s disease (AD) blood tests that can identify and quantify amyloid plaques, tau tangles, and cognitive and clinical decline are needed in clinical practice, including primary care. However, these tests require validation in diverse groups and real‐world settings. The goals of the Study to Evaluate Amyloid in Blood and Imaging Related to Dementia (SEABIRD) were to enroll 1120 participants to determine the accuracy and validity of blood amyloid‐β (Aβ) and phosphorylated tau (p‐tau) tests in a diverse, community‐based sample of older adults compared with amyloid PET, and to explore the impact of key factors (age, race, years of education, cognition, APOE genotype, and medical conditions) on validity estimates.

Method

SEABIRD measured blood plasma Aβ42/40 ratio and ratios of phosphorylated to non‐phosphorylated p‐tau217, p‐tau181, and p‐tau205 (%p‐tau) in a diverse population of older adults. In addition, cognitive screening with the AD8® dementia screen and Montreal Cognitive Assessment (MoCA) were obtained. Approximately 25% of participants were selected for amyloid PET and CDR as a reference standard.

Result

Of the 859 participants enrolled in this ongoing study, 20.6% self‐identified as Black or African American and the percentage of APOE ε4 carriers was 30.2%, as expected for a population‐based sample (Table 1). For a subset of 76 participants with completed amyloid PET and all blood measures, plasma Aβ42/40 had ROC‐AUC with amyloid PET status of 0.85, %p‐tau217 of 0.97, %p‐tau181 of 0.83, and %p‐tau205 of 0.81 (Figure 1). Spearman correlations with amyloid PET SUVR were ‐0.59 for plasma Aβ42/40, 0.69 for p‐tau217 ratio, 0.43 for p‐tau181 ratio and 0.48 for p‐tau205 ratio.

Conclusion

These preliminary results demonstrate that AD blood tests have similar accuracies in a diverse population‐based sample to those reported in AD research cohorts. These findings suggest that rapid screening and diagnosis of amyloid pathology with AD blood tests is possible in a broader population with higher comorbid disease burden and greater diversity than typical AD research cohorts. Screening with AD blood tests could accelerate clinical trial recruitment and increase the representativeness of clinical trial populations, which may improve the generalizability of clinical trial results.
Friends with benefits: Sharing large‐scale transcontinental brain MRI databases in LatAM‐FINGERS and US POINTER
Authors: Da Graça Morais Martin Maria , Landau Susan M. , Damian Andres , Vemuri Prashanthi , Bérgamo Yanina , Suemoto Claudia Kimie , Calandri Ismael Luis , Caramelli Paulo , Lopera Francisco , Allegri Ricardo Francisco , Lovato Laura , Delgado Carolina , Nitrini Ricardo , Brucki Sonia Maria Dozzi , Duque Lissette , Baieti Ana Charamelo , Custodio Nilton , Leon‐Salas Jorge M , Acosta Daisy M , Velazquez Ivonne Z. Jimenez , Cusicanqui María Isabel , Sosa‐Ortiz Ana Luisa , Vellila Lin , Salinas‐Contreras Rosa Maria , Espeland Mark A. , Snyder Heather M , Carrillo Maria C. , Kivipelto Miia , Baker Laura D , Crivelli Lucía ,   US POINTER and LatAm‐FINGERS
Published: December 2023

Background

Multicentric initiatives to study brain cognition in the elderly offers us a unique collection of brain imaging data accompanied by detailed neuroclinical and neuropsychological evaluations. U.S. POINTER and LatAm‐FINGERS, part of the World Wide FINGERS, are both large‐scale investigations of lifestyle interventions and its impact on cognitive function. These large‐scale detailed data may offer an unprecedented opportunity to compare diverse populations.

Method

Baseline MRI of subjects from multiple US centers (POINTER‐US), distributed in 5 geographical regions, and from 9 latin‐american countries (LatAm‐FINGERS). The protocols vary from basic (3D T1, 3D FLAIR,T2* GRE, Cor T2 hippocampus, DWI) to advanced which also included ASL, rs‐FMRI and DTI. Demographic information and clinical, cognitive and neuropsychological assessment were also included.

Result

MRI data was collected from 662 participants in the United States (about 65% of the total anticipated U.S. POINTER neuroimaging sample) and from 542 subjects from 9 countries in latin‐america (about 80% of the total anticipated LatAm‐FINGERS neuroimaging sample), with around 1200 participants scanned (table1).

All participants have 3D T1, 3D FLAIR, T2* GRE images and either DWI or DTI images.

Comparative demographics from the 2 datasets shows similar mean age, a predominance of females, and slight differences in education (table 2). This will allow us to compare multiethnic and multicultural volumetric and functional brain MRI information, as well as disease markers, associated with thorough neurological and clinical assessment. Reasons for not acquiring MRI were mainly due to claustrophobia or scanner unavailability.

Conclusion

This is an exceptional opportunity to have comparative large‐scale databases, with anatomical and functional brain imaging from different populations, allowing us to study real world diverse brain data and better understand its relationships with demographics, health and risk characteristics, and cognition.
Who benefits from MRI in memory clinics? A clinical and research perspective from the Oxford Brain Health Clinic
Authors: Griffanti Ludovica , Dembele Mohamed , Gillis Grace , Mitchell Robert , Pretorius Pieter M , O'Donoghue M Clare , Blane Jasmine , Martos Lola , Raymont Vanessa , Mackay Clare
Published: December 2023

Background

With the advent of disease modifying treatments for dementia, it is essential to restructure memory clinic services to provide accurate and early diagnosis to enable precision therapies and recruitment to clinical trials. The Oxford Brain Health Clinic (BHC) offers a comprehensive clinical and embedded research assessment in the patient pathway, including a research‐quality brain MRI scan (using the UK Biobank protocol), well‐tolerated by patients (Griffanti et al., 2022, Neuroimage:Clinical). In this study we investigated whether the images obtained from BHC patients were of sufficient quality for clinical/diagnostic purposes (i.e. to provide a radiology report) and research purposes (i.e. suitable to extract quantitative measures with automated software) and whether the scan quality was related to patients’ characteristics (capacity, frailty, anxiety, cognitive impairment ‐ CI), to inform future triage to Brain Health Clinics.

Method

T1 and FLAIR scans from 138 BHC patients were reported by a radiologist and independently rated as high, medium or low quality for research purposes (consensus between 2 raters). The following patients’ characteristics were evaluated: capacity (yes/no), Rockwood Clinical Frailty Scale (more frail if 5 or more), anxiety before/during the scan (low/not‐low), Addenbrooke’s Cognitive Examination III (ACE‐III, score above or below 82). A two‐sided Fisher‐Freeman‐Halton test was run to test the association between scan quality (3 classes) and patients characteristics (2 classes for each independent variable). Bonferroni‐adjusted post‐hoc comparisons were performed between scan quality classes using 2×2 Fisher’s Exact Tests.

Result

The radiologist was able to provide a clinical report for all scans. Over 90% of scans were rated high or medium quality for research purposes (Fig.1). No significant associations were observed between patients’ characteristics and FLAIR quality. T1 quality was significantly associated with patients’ capacity (p = 0.001, more low‐quality images from patients lacking capacity, Fig.2) and frailty (p = 0.014, more low‐quality images from frailer patients, Fig.3).

Conclusion

Research‐quality MRI scans in memory clinic are useful for both clinical and research purposes. For research comprised of high‐quality MRI, relatively generous thresholds relating to frailty and capacity could be considered to balance the trade‐off between inclusivity (i.e. increasing representativeness) and adherence to protocols.
Describing the effects of iron dyshomeostasis on cognitive function and dementia in UK Biobank
Authors: Winchester Laura M , Newby Danielle , Sproviero William , Gallacher John , Bauermeister Sarah , Nevado‐Holgado Alejo J
Published: December 2023

Background

Iron dyshomeostasis is a feature of neurodegenerative disease. In circulating blood, changes in iron are associated with dementia disease phenotypes, while in brain tissue increased iron is associated with dementia progression. In UK Biobank, whole body imaging includes variables derived from the brain swMRI data which are indicative of iron in brain tissue. Complete blood counts per participant include hemoglobin concentration indicative of iron in oxygen transportation. Using the cognitive assessment and participants with all‐cause dementia we aimed to understand how measured changes in iron would affect dementia in a large UK‐based cohort.

Method

Using cross–sectional analysis at shared time points in UK Biobank data collection we compared both the iron phenotypes with cognitive measures. Firstly, the baseline values at the primary assessment centre visit where 478,082 participants were tested for cognitive function and red blood cell measures. Secondly, at Visit 2 (n = 5861), where brain imaging derived T2* measures and complete blood count (hemoglobin concentration) were captured alongside the repeated cognitive measures. Each linear regression model includes cognitive function (outcome) and iron measures (exposure) with correction for age and sex. Adjusted models include correction for education years, assessment centre and ethnicity.

Result

We found association between low hemoglobin and all‐cause dementia (beta = ‐0.125, p <0.001). This association was replicated with poorer cognitive function and low haemoglobin analysing cognitive function tests (including verbal and numerical reasoning and reaction time) and mean corpuscular hemoglobin, (p<0.05). Using quantile sets of hemoglobin concentration we found a non‐linear effect, whereby both high and low iron had a negative association on cognitive outcome (verbal reasoning ‐0.029,‐0.019, p’s = 0.002,0.049). Using MRI T2* we found associations between newer cognitive function tests, matrix pattern puzzles and symbol digit substitution (p <0.0001) as well as verbal reasoning (p = 0.015). These cognitive function measures were strongly associated with the T2* hippocampus region.

Conclusion

We have shown an association between dementia and low hemoglobin concentration. We have demonstrated the complexities of this iron homeostasis relationship, showing how lower cognitive function is associated with both increased and reduced iron concentration in blood and how iron changes in brain effect different cognitive traits.
Occurrence of sleep disorders, anxiety, and depression among patients with mild cognitive impairment and Alzheimer’s disease in diverse populations: A large nationwide electronic health record cohort study
Authors: Sánchez‐Soliño Olga , Yue Emma Xiaomeng , Boroje Isabella , Vinikoor‐Imler Lisa C
Published: December 2023

Background

Patients affected with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) often experience anxiety, depression, and sleep disturbances. Some of the published studies reported a higher incidence of these disorders in minority populations. The objectives of this study were to characterize the occurrence of sleep disorders, anxiety, and depression among patients with MCI and/or AD, stratified by gender, age and race/ethnicity in the United States clinical practice setting.

Method

A retrospective cohort study was conducted using electronic health records and insurance claims from the Optum® Market Clarity database containing data from more than 63 million people in the US insured through Medicare, Medicaid, and other insurance providers. The study included patients diagnosed, utilizing ICD diagnosis codes, with MCI and/or AD between January 2017 and September 2021. Prevalence of depression, anxiety, and sleep disorders, as well as associated medication prescriptions, were identified in the 12 months before and after MCI and/or AD diagnoses. The occurrence of these diagnoses and prescriptions was evaluated stratified by gender, age, and race/ethnicity.

Result

A total of 197,346 patients were diagnosed with MCI (56.9% female, mean age of 70.0 [SD 14.8]) and 144,321 with AD (63.9% female, mean age of 79.3 [SD 8.2]) at the baseline. Overall, a large proportion of MCI and AD cases had depression (pre‐MCI diagnosis: 40.3%; post‐MCI diagnosis: 44.8%; pre‐AD diagnosis: 32.2%; post‐AD diagnosis: 38.3%), anxiety (pre‐MCI diagnosis: 36.2%; post‐MCI diagnosis: 40.2%; pre‐AD diagnosis: 26.4%; post‐AD diagnosis: 31.5%), and sleep disorders (pre‐MCI diagnosis: 36.2%; post‐MCI diagnosis: 39.3%; pre‐AD diagnosis: 23.2%; post‐AD diagnosis: 25.4%). Occurrences of depression and anxiety were highest among females. Among individuals with MCI and/or AD, the gap between the proportion experiencing depression and the proportion prescribed an antidepressant was greatest for African American males and females. This was not observed for anxiety and anti‐anxiety medications.

Conclusion

A large proportion of individuals with MCI and/or AD also had depression, anxiety, and sleep issues. Further understanding of the populations with these comorbidities and their associated prescriptions by different ages, sex, and races/ethnicities is important when supporting patients with MCI and AD.
Neuroinflammatory biomarkers in neurodegenerative disease: Insights from the ONDRI Cohort
Authors: Sumra Vishaal , Dilliott Allison Ann , Frank Andrew R , Lang Anthony E , Roberts Angela C , Troyer Angela , Levine Brian , Arnott Stephen R. , Tan Brian , Fischer Corinne E. , Marras Connie , Kwan Donna , Munoz Douglas , Tang‐Wai David F. , Finger Elizabeth , Rogaeva Ekaterina , Orange Joseph B , Ramirez Joel , Sunderland Kelly M , Zinman Lorne , Binns Malcolm , Borrie Michael , Masellis Mario , Freedman Morris , Montero‐Odasso Manuel , Ozzoude Miracle , Bartha Robert , Swartz Richard H. , Tartaglia Carmela ,   The ONDRI Investigators
Published: December 2023

Background

Neuroinflammation (NI) has been implicated in both the pathogenesis of and neuroprotection against neurodegenerative diseases (NDs)(Psenicka et al., 2021). Plasma glial fibrillary acidic protein (GFAP), and Neurofilament light (NFL) are measures of astrogliosis and neurodegeneration, respectively. Amyloid beta (Aβ)42/40 ratio (Aβ42 concentration to total Aβ concentration) below 0.068 is associated with AD pathology (Baldeiras et al., 2018). Neuroimaging‐based inflammatory biomarkers have been proposed, including free‐water diffusion (FWD)(Pasternak et al., 2009). Here we investigated FWD as a candidate biomarker for NI in AD compared to non‐AD dementia using Aβ42/40 ratio in a subset of data from the Ontario Neurodegenerative Disease Research Initiative (ONDRI).

Method

FWD maps were generated in 370 subjects (126 non‐AD and 244 AD). MRI processing included ICVmapp3r for brain extraction and bias field correction, Synb0, Topup and Eddy for dMRI preprocessing and MATLAB for freewater mapping. Plasma Aβ42, Aβ40, GFAP and NFL were measured using the Simoa Human Neurology 4‐Plex E assay, and cognition was estimated using the Montreal Cognitive Assessment (MoCA). Linear regression was used to estimate the ability for FWD in the left (LcGM) and right (RcGM) cortical grey matter to predict GFAP, NFL and MoCA score in AD and nonAD based on Aβ42/40 threshold of 0.068.

Result

FWD correlated with GFAP (LcGM; R = 0.4, p = 0.0013 and RcGM; R = 0.37, p = 0.0069), and MoCA total score (LcGM; R = ‐0.29, p = 0.001 and RcGM; R = ‐0.27, p = 0.001), but not with NFL across the whole group. This relationship was largely driven by the AD group wherein FWD predicted GFAP (LcGM: R = 0.12, p = 0.02, RcGM approaching significance R = 0.1, p = 0.06), and MoCA Total score (LcGM: R = ‐0.33, p<0.0001), RcGM: R = ‐0.25, p<0.0001). The nonAD group did not show this relationship. FWD did not predict NFL in the AD and nonAD group.

Conclusion

In patients with Aβ42/40<0.068, suggestive of AD, FWD in cGM was more strongly related to GFAP than NFL, and predicted cognition, a pattern that was not observed in nonAD patients. Our results suggest distinct patterns of NI in AD compared with nonAD that can be detected with FWD and with a multi‐modal approach could further understanding of differences in pathophysiology across NDs.
A study of DNA methylation in the prefrontal cortex of heterozygous GBA1 mutant mice
Authors: Weymouth Luke Stephen , Imm Jennifer L , Sander Millie , Brown Jonathan T , Lunnon Katie , Smith Adam R.
Published: December 2023

Background

Epigenome‐wide association studies (EWAS) of DNA methylation are being undertaken in Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) post‐mortem brain to identify novel disease mechanisms. However, there is considerable heterogeneity in clinical and neuropathological manifestation, as well as the contribution of post‐mortem factors, which can confound smaller studies. The heterozygous GBA1 (D409V/WT) mouse model of DLB presents α‐synuclein deposition, cognitive decline and cholinergic dysfunction. We have undertaken the first systematic investigation of DNA methylation in these mice to identify changes related to α‐synuclein deposition. We have also explored the effect of varying post‐mortem interval (PMI) on DNA methylation patterns, to allow us to better interpret human studies.

Method

In total we profiled DNA methylation using the Illumina Infinium Mouse Methylation BeadChip array in 58 mice, corresponding to 28 GBA1 D409V/WT and 30 WT mice aged 8‐23 months. Within each age group we divided mice into 5 further groups to also explore the effect of PMI: +0hrs, +24hrs, +48hrs, +72hrs & +96 hrs respectively. The mice were culled and those in the +0hrs group were immediately dissected with the prefrontal cortex being flash frozen and stored in the freezer. Mice assigned to other PMI groups were culled and stored at 4 degrees for the relevant PMI before dissection and flash freezing. DNA was extracted, bisulfite treated and then profiled for DNA methylation.

Result

Of the 58 mice that were sourced it was ensured that D409V/WT mice and WT mice were balanced between the 5 PMI groups. We have investigated the effect of phenotype, neuropathology and PMI on DNA methylation levels using linear regression models.

Conclusion

Teasing apart the effect varying PMI has on DNA methylation in post mortem brain samples will be a great aid when analysing such data going forward in large human EWASs. We have collated an in vivo study cohort to investigate DNA methylation patterns in the heterozygous D409V/WT mouse compared to WT, and interrogated the effect PMI has on the quality of methylation data. More broadly our study of PMI will have relevance to interpreting the results of human EWAS of DLB and other dementias.
Validation of QyScore’s® fully automated quantitative image segmentation tools against expert manual gold‐standards
Authors: Gordon Elizabeth , Borrot Mathilde , Villa Luca , Jubault Thomas , Guizard Nicolas ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), and Organization for the Advancement of Structured Information Stand (OASIS)
Published: December 2023

Background

Quantitative imaging provides valuable information for early detection, disease progression and treatment response monitoring. Manual segmentation is the current gold‐standard, but is prohibitively labour‐intensive for large scale use, such as in clinical routine, and suffers from individual variability. Thus, there is a substantial unmet need for validation of automatic segmentation techniques that perform as accurately as this labour‐intensive manual gold‐standard.

Method

The validation cohort consisted of 50 individuals with multiple diagnoses, wide age range (18‐86 yrs), balanced for sex and acquired on multiple scanners for improved generalizability of quantification results (Table 1). Three expert neuroradiologists each manually segmented the caudate, putamen, globus pallidus, thalamus, cerebellum, brainstem, and lateral ventricles on 3DT1 images using itk‐SNAP (http://www.itksnap.org/) software. A consensus expert segmentation was then derived using the STAPLE (Simultaneous Truth and Performance Level Estimation) algorithm (Wakefield et al., (2004)) for each region and compared with the fully automated segmentations produced using QyScore®, a CE‐marked and FDA‐cleared neuroimaging medical device. Performance was investigated using the Dice Similarity Coefficient (DSC) and concordance assessed with plotted linear regression.

Result

Mean, standard deviation and confidence intervals of the DSC demonstrated a high degree of agreement between the consensus manual gold‐standard and QyScore®’s automated segmentations (Table 2). Importantly, this agreement remained consistent following stratification by field strength, demonstrating generalizability to most clinical imaging centres. For 1.5T scanners the mean DSC was 0.81, 0.89, 0.79, 0.86, 0.94, 0.93 and 0.91 for the caudate, putamen, globus pallidus, thalamus, cerebellum, brainstem, and lateral ventricles respectively. For the 3T scanners, this was equivalent or marginally better at 0.84, 0.89, 0.82, 0.86, 0.94, 0.94, and 0.93 respectively. In addition, strong concordance was demonstrated between the volumes, expressed as a percentage of intracranial volume (%ICV), obtained by the automated medical device QyScore® and the consensus of the manual gold‐standard segmentation (Figure 1: Table 2).

Conclusion

QyScore® produces fast reliable automated segmentations with comparable accuracy to expert neuroradiologists. These findings support the implementation of QyScore® in clinical trials and in clinical routine to provide quantitative image analysis in support of diagnosis and monitoring of disease progression and treatment response.
International implementation of Cognitive Stimulation Therapy in Brazil, India and Tanzania: Findings from the CST‐International study
Authors: Fisher Emily , Mograbi Daniel C. , Ferri Cleusa P , Santos Raquel L , Naylor Renata , Brum Paula Schimidt , Bertrand Elodie , Benevides Pedro , Vaitheswaran Sridhar , Venkatesan Shreenila , Natarajan Nirupama , Krishna Murali , Chandra Mina , Shaji K S , Mkenda Sarah , Urasa Sarah , Walker Richard , Dotchin Catherine , Paddick Stella‐Maria , Walker Jess , Oliver Benedict , Stoner Charlotte , Spector Aimee E
Published: December 2023

Background

There is a pressing need for effective and affordable interventions to support quality of life and cognition in people with dementia. Many psychosocial interventions are developed but few are delivered at scale and in routine practice. Group Cognitive Stimulation Therapy (CST) is the only non‐pharmacological treatment recommended by the National Institute for Health and Care Excellence (NICE) to improve cognition and wellbeing in mild to moderate dementia, and its global implementation has been recommended by Alzheimer’s Disease International. CST has been culturally adapted for use in at least 36 countries, but this has not resulted in widespread delivery in routine practice.

Methods

Methodology consisted of four phases 1) Exploring barriers to implementation through stakeholder engagement with clinicians, policy‐makers, people with dementia and caregivers; 2) Development of implementation plans for each country; 3) A mixed‐methods pre‐post study of CST in each country (total n = 103), exploring feasibility, acceptability, cost and outcomes including cognition and quality of life; and 4) Refinement of implementation strategies, with an aim of creating ongoing and sustainable CST programmes.

Results

Implementation plans were developed for each country based on stakeholder engagement. CST delivery took place virtually in Brazil and India due to the Covid‐19 pandemic. We will present the barriers and facilitators to CST implementation in different settings based on the Consolidated Framework for Implementation Research (CFIR), and reflect on the success of implementation strategies. These include subsidising cost and travel, establishing a caseload of participants to receive CST, promotion and marketing of CST groups, educating family caregivers on the role of psychosocial interventions and enlisting their endorsement, and developing a ‘train the trainer’ model for CST group leaders. We will discuss the feasibility and acceptability of in‐person and virtual CST in varied settings, drawing on quantitative and qualitative findings from the pre‐post study of CST.

Conclusion

It is crucial to not only culturally adapt the content of a psychosocial intervention, but also tailor implementation strategies for unique settings, considering economic realities, health equity and healthcare access. Key next steps to widespread CST implementation are long‐term funding arrangements and endorsement from regional or local guidelines.
Comparison of clinicopathologic features of Limbic and Diffuse Transactive Response DNA‐binding Protein 43 pathology in Alzheimer’s disease neuropathologic spectrum
Authors: Carlos Arenn Faye , Machulda Mary M. , Rutledge Matthew H. , Nguyen Aivi T. , Reichard Ross R. , Dickson Dennis W. , Petersen Ronald C. , Josephs Keith A
Published: December 2023

Background

Increasing evidence suggests that transactive response DNA‐binding protein 43 (TDP‐43) pathology in Alzheimer’s Disease (AD), or AD‐TDP, can be diffuse or limbic‐predominant. Understanding whether diffuse AD‐TDP has genetic, clinical, and pathological features that differ from limbic AD‐TDP could have clinical and research implications. We aimed to better characterize the clinicopathologic features of diffuse AD‐TDP and differentiate it from limbic‐predominant AD‐TDP pathology.

Method

Three hundred sixty‐three participants were prospectively recruited and followed in the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group and died between May 1999 and August 2021. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. At postmortem evaluation, they showed Alzheimer’s disease neuropathologic changes and TDP‐43‐immunoreactive inclusions. The distribution of TDP‐43 pathology was assessed using the Josephs 6‐stage scheme. Participants with TDP‐43 stages 1‐3 were classified as Limbic, while those with stages 4‐6 were classified as Diffuse. Neuropathologically defined frontotemporal lobar degeneration cases were excluded. Multivariable logistic regression was used to identify clinicopathological features that predicted diffuse TDP‐43 pathology at postmortem. We hypothesized that the Diffuse group would show impairment in cognitive domains beyond episodic memory and more hippocampal sclerosis.

Results

The cohort was 61% female and old at onset (median:76 years [IQR:70‐82]) and death (median:88 years [IQR:82‐92]). Fifty‐four percent (n = 197) were classified as Limbic and 46% (n = 166) as Diffuse. A “clinical” multivariate logistic regression fit to 85 participants with all clinical variables of interest showed that later age at onset (OR:1.09, 95%CI:1.01‐1.19;P = 0.03), longer disease duration (OR:1.17, 95%CI:1.02‐1.36;P = 0.03) and higher Neuropsychiatric Inventory scores (OR:1.14, 95%CI:1.01‐1.28;P = 0.03) all independently increased the odds of being Diffuse, while higher Trails Making Test‐B (OR:0.99, 95%CI:0.98‐0.99;P = 0.02) and Block Design Test scores (OR:0.91, 95%CI:0.85‐0.99;P = 0.023) independently decreased the odds of being Diffuse. A “pathology” multivariate logistic regression fit to 233 cases with all neuropathological data revealed that widespread amyloid‐β pathology corresponding to Thal phases 3‐5 all significantly decreased the odds of diffuse pathology by 80‐90%, while hippocampal sclerosis increased it sixfold (OR:6.18, 95% CI:2.93‐13.03;P<0.001).

Conclusions

Diffuse AD‐TDP shows clinicopathological features that differ from Limbic AD‐TDP, which could have public health implications relating to treatment and research on AD and dementia.
The association between AD biomarkers and neuropsychiatric symptoms in subjective cognitive decline; the SCIENCe project
Authors: Trieu Calvin , van Harten Argonde C. , van Leeuwenstijn Mardou S. S. A. , Kroeze Lior A. , Ebenau Jarith L. , Verberk Inge M.W. , Sikkes Sietske A.M. , Verfaillie Sander C.J. , Giessen Elsmarieke , Teunissen Charlotte E. , van der Flier Wiesje M.
Published: December 2023

Background

Neuropsychiatric symptoms (NPS) are increasingly recognized as non‐cognitive manifestation of Alzheimer’s disease (AD). However, the relationship between AD‐related pathology and NPS remains unclear. We aimed to investigate the cross‐sectional association between Alzheimer biomarkers and neuropsychiatric symptoms (NPS) in individuals with subjective cognitive decline (SCD) presenting at a memory clinic. In addition, we evaluated personality traits and education as potentially modifying factors of this association.

Method

We included 346 individuals with SCD (age: 62.9±7.8) from the SCIENCe cohort, including 92 amyloid positive participants (age: 66.4±7.0, Female: 44.6%, MMSE: 28.5±1.3) and 254 amyloid negative participants (age: 61.6±7.7, Female: 40.6%, MMSE: 28.6±1.3). Amyloid status was determined by amyloid PET or CSF biomarkers according to visual read or established cut points. Neuropsychiatric symptoms were assessed using the Geriatric Depression Scale (GDS; n = 282), the Center for Epidemiological Studies‐Depression (CES‐D; n = 225), the Hospital Anxiety and Depression Scale – anxiety subscale (HADS‐A; n = 225) and the Neuropsychiatric Inventory Questionnaire (NPI‐Q; n = 198). We used linear regression analyses, adjusted for age and sex, to assess the association between amyloid status and NPS. In secondary analyses, we tested for interactions between amyloid status and (1) neuroticism (Dutch Personality Questionnaire), (2) somatization, (Four‐Dimensional Symptom Questionnaire), and (3) educational level (Dutch Verhage scale).

Result

Amyloid status was not associated with GDS, CES‐D, HADS‐A and NPI‐Q scores in univariable analyses. When we evaluated effect modification, we found an interaction between amyloid status and neuroticism in the association with NPI‐Q (p<0.05), indicating a positive association between amyloid status and NPS in participants with a low level of neuroticism (β: 2.56±2.24), and a negative association in participants with a high level of neuroticism (β: ‐4.09±3.23).

Conclusion

In this cross‐sectional analysis in individuals with SCD, amyloid status was hardly associated with neuropsychiatric symptoms. In future studies, we focus on amyloid status as determinant of change in NPS over time.