bluuebunny/crossref_metadata_2025 huggingface dataset:
Higher cortical thickness/volume in Alzheimer’s‐related regions: Protective factor or risk factor?
Authors: Williams McKenna E. , Elman Jeremy A. , Bell Tyler Reed , Fennema‐Notestine Christine , Franz Carol E , Hagler Donald J. , Kremen William S.
Published: December 2023

Background

Neuroimaging signatures based on cortical thickness or volume in regions vulnerable to Alzheimer’s disease (AD) pathology are tools developed to identify brain changes specific to mild AD. Lower thickness/volume signatures (indicating comparatively thinner cortex) are commonly associated with risk of future decline. In contrast, some evidence suggests a biphasic pattern of changes wherein higher, rather than lower, cortical thickness is associated with very early AD pathology. Understanding the difference between high cortical thickness indicating a risk versus a protective factor carries important implications for early identification of AD. We examined whether integrating information from a novel AD brain signature based on gray matter mean diffusivity (MD)—previously shown by our group to be sensitive to early AD‐related changes and predictive of thickness/volume‐based signatures over a decade later—can aid in the interpretation of when high cortical thickness/volume is a risk versus a protective factor for future AD‐related changes.

Method

Participants were 572 men in the Vietnam Era Twin Study of Aging (VETSA) who were cognitively unimpaired (CU) at baseline (mean age = 56 years; range = 51‐60). A validated thickness/volume signature and novel gray matter MD signature, each a weighted average of MRI‐based morphometry in eight AD‐related brain regions, were used in longitudinal mixed models predicting brain and cognitive outcomes. Subgroup analyses included all CU participants with high baseline thickness/volume signatures, regardless of subsequent cognitive status (n = 147).

Result

Among individuals with high thickness/volume signature scores at baseline, those that additionally had high values on MD signature scores showed significantly lower thickness/volume signatures and lower episodic memory performance 12 years later compared to the high thickness/volume‐low MD group. In contrast, group differences in global mean cortical thickness remained stable across waves. Groups did not differ in level of young adult cognitive reserve.

Conclusion

Gray matter MD differences may capture heterogeneous subgroups among individuals with high cortical thickness/volume. Findings are in line with a biphasic model in which increased cortical thickness in AD‐related regions may precede future decline. An AD signature based on cortical MD can be used alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes.
Scaling Digital Biomarker Discovery with the Cloud and Wearable Devices
Authors: Ford Colby T , Corkey Jon
Published: December 2023

Background

In clinical trials and other disease research, biomarkers provide a valuable indication of drug performance and disease progression. Traditionally, these biomarkers may include genomic factors, lab test results, and more, but we now can easily expand into longitudinally collected digital biomarkers from consumer smart devices.

Method

The Amissa platform, built on the Microsoft Azure cloud, enables the collection of high frequency data from consumer smartwatches (such as the Apple Watch and Samsung Galaxy watch devices). The API‐driven cloud architecture enables secure sensor data collection including location, gyrometry/accelerometry, activity monitoring/pedometry, and biosensors such as oxygen saturation and heart rate. This solution allows for sub‐minute capture frequency while balancing device battery drain. The ISO 27001:2013‐compliant platform is globally scalable through an innovative cloud‐native design that ensures security and compliance.

Result

Caregivers, researchers, and healthcare providers can now monitor loved ones/patients through consumer‐grade wearables, providing a cost‐effective, accurate, and flexible solution for biomarker discovery, data collection, and remote monitoring.

Conclusion

The Amissa platform successfully enables digital biomarker development and helps to address disparities in clinical trials and research studies of underrepresented groups through decentralized data collection. Plus, the platform address security and privacy considerations while enables collaborative research participation and flexible study designs.

Note: In this presentation, we will discuss the NIH‐funded work of Amissa and the cloud‐first approach taken to build the world’s first global‐scale platform for disease research using wearable devices. We will cover technical design patterns, considerations for privacy and security, the effect of decentralized data collection on addressing health disparities and inclusion in clinical trials, and the future of digital biomarker discovery in Alzheimer’s disease and related dementias.
Plasma biomarkers of Alzheimer’s disease in dementia with Lewy bodies
Authors: Bolsewig Katharina , Gonzalez Maria Camila , Ashton Nicholas J. , van Unnik Annemartijn A. J. M. , Blujdea Elena R. , Aarsland Dag , Zetterberg Henrik , Padovani Alessandro , Bonanni Laura , Mollenhauer Brit , Schade Sebastian , Vandenberghe Rik , Poesen Koen , Kramberger Milica G. , Paquet Claire , Bousiges Olivier , Cretin Benjamin , Willemse Eline A.J. , Teunissen Charlotte E. , Lemstra Afina W. ,   European‐Dementia with Lewy Bodies (E‐DLB) Consortium
Published: December 2023

Background

Alzheimer’s disease (AD) co‐pathology is a common feature in dementia with Lewy bodies (DLB) and associated with a more rapid decline. Here, we aimed to evaluate plasma biomarkers as alternatives for CSF biomarkers for the detection of amyloid pathology, and for their diagnostic and prognostic value in DLB.

Method

Plasma Aβ42/40, GFAP, NfL, pTau181 and pTau231, were measured by SIMOA in patients with DLB (n = 342), AD (n = 131), and healthy controls (n = 89) from the E‐DLB consortium cohort. Associations of biomarkers with CSF Aβ42 status were assessed with ANCOVA corrected for age and sex. ROC analyses were performed to assess biomarker’s performance for amyloid detection and differential diagnosis. Associations of biomarkers with cognitive impairment and decline were determined by linear regression and mixed effects models.

Result

Altered Aβ42/40 (β = ‐0.0076, 95%CI:‐0.0137 to ‐0.0016, p<.05), pTau181 (β = 0.2503, 95%CI: 0.0555 to 0.4451, p<.05) and pTau231 levels (β = 0.2269, 95%CI:0.0347 to 0.4191, p<.05) were associated with amyloid pathology in DLB, as assessed by CSF Aβ42. The combination of these biomarkers differentiated amyloid normal from abnormal DLB patients with an AUC of 0.728 (sensitivity = 64.6%, specificity = 75.0%). pTau181 best differentiated these groups as a single marker (AUC = 0.700, sensitivity = 62.5%, specificity = 73.1%). The combination of Aβ42/40, NfL and pTau231 differentiated DLB from AD with an AUC of 0.726 (sensitivity = 73.3%, specificity = 68.8%). In DLB, increased GFAP (β = ‐8.9, 95%CI:‐11.7 to ‐6.1, p<.001), NfL (β = ‐7.2, 95%CI:‐10.0 to ‐4.4, p<.001), pTau181 (β = ‐2.6, 95%CI:‐4.0 to ‐1.2, p<.001) and pTau231 (β = ‐2.4, 95%CI:‐3.7 to ‐1.2, p<.001) were associated with lower baseline MMSE scores and increased GFAP (annual change of ‐2.1 MMSE points (95%CI:‐2.9 to ‐1.3, p<.001) and NfL (annual change of ‐2.1 MMSE points (95%CI:‐3.0 to ‐1.3, p<.001) predicted faster cognitive decline.

Conclusion

Plasma Aβ42/40, pTau181 and pTau231 were associated with amyloid abnormality in DLB. Their utility for differential diagnosis and identifying amyloid pathology in DLB was modest. Our findings suggest a prognostic value of GFAP and NfL for cognitive decline in DLB.
What does ‘super‐ageing’ mean to high‐functioning Australian older adults?
Authors: Powell Alice , Page Zara A , Close Jacqueline CT , Sachdev Perminder S. , Brodaty Henry
Published: December 2023

Background

‘Super‐ageing’ has been used to refer to older adults who maintain high level cognitive abilities into advanced age. However, there is no universally accepted definition of this phenomenon and it is unclear what older adults think of the term, how it is defined and what benefits studying such individuals may bring.

Method

Interviews and focus groups were conducted using a combination of in‐person meetings and online video conferencing with 8 overtly high‐functioning older community members aged between 81 and 101 living in Australia. Interviews were transcribed and thematically analysed.

Result

Key themes were independence, having enough cognitive ability to ‘manage yourself’ and ‘do all the things you want to do’ (such things would be different for each individual), contributing meaningfully to society and remaining engaged particularly with younger members of the community. For this group, it was important to not be physically incapacitated or in chronic pain but physical challenges could be coped with if cognition was intact. Longevity in itself was not important. Some elders emphasised broader concepts of valuing older individuals in society, the necessity of individuals and societies to prepare for the challenges of ageing and the notion of being a role model to younger adults.

Conclusion

Super‐ageing is a highly individual construct to this small sample of high‐functioning older adults. Functional independence is central but lacking in most research definitions. Some elements that are very important for these older people, such as living a meaningful life or being socially engaged, have not been considered in existing definitions.
Impacts of depression, apathy, and anxiety on cognitive function in older adults with subjective cognitive decline
Authors: Makino Taeko , Umegaki Hiroyuki , Kuzuya Masafumi , Taki Yasuyuki
Published: December 2023

Background

Although previous studies showed that neuropsychiatric symptoms are associated with cognitive decline, the results are controversial. We investigated the impacts of depression, apathy, and anxiety on cognitive function in older adults with subjective cognitive decline (SCD).

Method

Altogether, 464 subjects aged 65‐85 years who had SCD were enrolled in this study. All participants were evaluated with the short version of Geriatric Depression Scale (GDS15), Starkstein’s Apathy Scale (AS), the anxiety subscale of the Hospital Anxiety and Depression Scale (HADS), and 9 cognitive tasks assessed using the Mini‐Mental State Examination, Logical Memory and Visual Reproduction subtests of the Wechsler Memory Scale‐Revised, Verbal Fluency Test, Digit Span, Visual Memory Span and Digit‐Symbol subtests of the Wechsler Adult Intelligence Scale‐III, Stroop Test, and Trail Making Test. We performed a Pearson correlation analysis to examine the associations between depression, apathy, and anxiety, and a multiple linear regression analysis, adjusted for age, sex, educational level, and global cognitive state to determine the impacts of depression, apathy, and anxiety on cognitive function.

Result

Pearson correlation analysis revealed a low‐ to moderate‐grade relationship among depression, apathy, and anxiety, as shown by the correlation between GDS15 and AS (r = 0.49, p < 0.01), GDS15 and HADS (r = 0.36, p < 0.01), and AS and HADS (r = 0.18, p < 0.01). The multiple linear regression analysis, with each cognitive task score as dependent variable, indicated a significant association of the HADS with lower scores on Logical Memory I (beta = −0.18, p < 0.001) and II (beta = −0.14, p = 0.002), after adjusting for the subjects’ age, sex, educational level, and global cognitive state.

Conclusion

Our results suggest that anxiety may be associated with immediate and delayed memory functions in older adults with SCD.
Feasibility of ADappt: towards personalized communication and prediction in early Alzheimer’s disease in memory clinics
Authors: Hendriksen Heleen M.A. , de Rijke Tanja J. , van Gils Aniek M. , de Beer Marlijn , Bouwman Femke H. , Hempenius Liesbeth , van Maurik Ingrid S. , Pel‐Littel Ruth , Meester Hanneke F.M. Rhodius‐ , Roks Gerwin , Smets Ellen M.A. , van der Flier Wiesje M. , Visser Leonie N.C.
Published: December 2023

Background

ADappt is a Web‐based toolkit (www.ADappt.health) to support personalized communication and prediction in memory clinics. In the context of an iterative development process with professionals, patients, and care partners, we assessed feasibility, satisfaction, and usability of ADappt in the clinical workflow.

Method

We conducted a feasibility pilot in four Dutch memory clinics. Three neurologists, one geriatrician, two specialized nurses and two medical doctors (12±7y clinical experience) participated and recruited 21 patients (69±8yrs, 19%F) and 21 care partners (60±15yrs, 81%F). For professionals, ADappt‐modules comprised a 1) topic list, 2) shared decision‐making conversation guide, 3) overview of diagnostic tests, and 4) risk calculation tool. Prior to their visit, patients and care partners were informed about ADappt‐patient tools: 1) educational video‐animations, and 2) question prompt list. All participants completed questionnaires on feasibility, satisfaction, and usability after the first (n = 17) and/or the disclosure (n = 7) consultation. Professionals were interviewed afterward.

Result

Professionals reported good usability (68±14, range 50‐83, System Usability Scale, 0‐100) and high satisfaction (71±10, range 50‐85, scale 0‐100). They most often used the overview of diagnostic tests (67%) and reported this module as most helpful (3.8±0.4, range 3‐4, scale 1‐5). Patients and care partners were highly satisfied with the clinician‐patient consultations in general (81±14, range 50‐100, Patient Satisfaction Questionnaire, scale 0‐100). Of those who reported to know and have used the patient tools (54%), 97% would recommend them, whereby most used the question prompt list (84%) and a smaller proportion the video‐animations (64%). Recommendations from the interviews to improve feasibility include: 1) the development of more concrete instructions for professionals on how to use ADappt, and 2) a better alignment of patient tools with the patient journey and general information provided by that particular memory clinic.

Conclusion

Stakeholders reported good usability and high satisfaction regarding ADappt. Points of attention to foster feasibility in the clinical workflow are: 1) improved training for professionals and 2) improving the accessibility of patient tools. We take these matters into account while preparing for the next step: a prospective validation study in the memory clinic setting to study the influence of ADappt on patient satisfaction.
Attention‐deficit/hyperactivity disorder in old age and the risk of dementia: A national cohort study in Israel
Authors: Levine Stephen Z , Rotstein Anat , Beeri Michal S , Weinstein Galit , Reichenberg Abraham , Sandin Sven , Kodesh Arad
Published: December 2023

Background

Evidence of the association between Attention‐Deficit/Hyperactivity Disorder (ADHD) and the risk of dementia is scarce, inconsistent, and subject to potential sources of bias that are as yet unconsidered. Our objective was to examine the association between ADHD and dementia risk.

Method

A prospective national cohort study born 1933‐1952, without a dementia diagnosis for two years, were followed up for incident dementia from 2002‐2020. Information was from electronic health records in a healthcare maintenance organization in Israel. ADHD diagnosis was classified as present from the age of the first diagnosis, otherwise absent. Competing risk Cox regression models were fit to quantify the risk of incident dementia with the Hazard Ratio (HR) and their associated 95% Confidence Intervals (CI) with inverse probability weights, age as the underlying time‐scale, unadjusted and, in the primary analysis, adjusted by 18 covariates.

Result

Of 110,196 participants aged 50‐70 years in 2002, 56,914 (51.6%) were female. During follow‐up there were a total of 746 (0.7%) cases of ADHD, and 8,339 (7.6%) of incident dementia. The percentage of incident dementia was 13.1% (N = 98) among those with ADHD present and 7.5% (N = 8,241) among those with ADHD absent. In the primary analysis, the group with ADHD was statistically significantly (P<.05) associated with a higher risk of dementia (unadjusted: HR = 3.57, CI = 2.89, 4.42; adjusted HR = 2.73, CI = 2.04, 3.65) compared to the group with ADHD absent. Eight of ten sensitivity analyses replicated the statistically significant association observed in the primary analysis. Psychostimulant medication offset the association between ADHD and dementia risk to null, and evidence of reverse causation was mild.

Conclusion

ADHD is associated with increased dementia risk. Policymakers, caregivers, patients, and clinicians may wish to monitor ADHD in old age reliably.
Differential gene expression analysis in individuals with depression in Alzheimer’s disease using RNAseq
Authors: Sinclair Lindsey I , Ballard Clive G , Bennett David A. A
Published: December 2023

Background

Depression in individuals with Alzheimer’s disease (AD) is common, distressing, difficult to treat, may increase carer burden and is inadequately understood. It occurs more frequently in AD than in older adults without dementia. The underlying biology remains obscure.

We aimed to identify patterns of differential gene expression in individuals with depression in AD compared to individuals with AD but no history of depressive illness.

Method

We used data from the Religious Orders Study and the Memory and Aging Project: the ROSMAP cohort. Individuals with other disorders which could have caused cognitive impairment e.g. Parkinson’s disease(n = 122) or clinically significant head trauma (n = 234) were excluded, and those with bipolar disorder(n = 13). Those with neuropathological or consensus clinical evidence of a dementia other than Alzheimer’s disease were also excluded (n = 116).

Depression caseness was defined as a highly probable/probable clinical diagnosis of depression made by the assessing clinician at a study visit or a CESD score of >7 at a study visit. Individuals with treated depression (n = 301) who were taking antidepressants but never met depression caseness criteria and 380 individuals with subthreshold depressive symptoms on the CESD but a clinical assessment that depression was “not present” were also excluded.

RNAseq data was available from the DLPFC and posterior cingulate. The posterior cingulate analysis is ongoing. Fastq files were quality controlled using fastqc and Picard following HISAT2 alignment to GRCh38. After exclusion of files which failed QC fastq files were aligned to the GRCh38 transcriptome using Salmon. Files with low transcriptome alignment (<28%) were also excluded. Differential gene expression analysis was carried out in Rstudio using DEseq2.

Result

After exclusions and QC, data was available for 15 individuals with depression & AD and 25 individuals with AD but no depression for the DLPFC. Age, RIN, sex and Braak stage were included in the analysis model. After adjustment of the p value for multiple comparison 64 genes were differentially expressed in depression including Fbox proteins, nucleosome assembly proteins and voltage‐gated channel proteins. KEGG pathway analysis is underway

Conclusion

We have identified genes differentially expressed in depression in AD which may allow better understanding of this condition.
Sex‐dependent effects on the association between air pollution and longitudinal changes in CSF and plasma biomarkers of Alzheimer’s disease
Authors: Vilor‐Tejedor Natalia , Escalante Armand González , Rodríguez‐Fernández Blanca , Genius Patricia , Milà‐Alomà Marta , Ortiz‐Romero Paula , Cirach Marta , Nieuwenhuijsen Mark , Sunyer Jordi , Minguillon Carolina , Fauria Karine , Kollmorgen Gwendlyn , Carboni Margherita , Molinuevo Jose Luis , Navarro Arcadi , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo
Published: December 2023

Background

A growing body of research links environmental factors with neurodegeneration and premature mortality. However, the biological mechanisms through which the different pollutants may be affecting Alzheimer’s disease (AD) pathology in the early asymptomatic stages of AD and the downstream consequences are unknown. We aimed to evaluate the association between air pollution and longitudinal change rates of cerebrospinal fluid (CSF) and plasma biomarkers of AD in cognitively unimpaired individuals.

Method

The study included 195 middle‐aged cognitively unimpaired participants from the ALFA+ study, many within the Alzheimer’s continuum, with baseline and one follow‐up measurement of biomarkers of primary pathology of AD such as cerebrospinal fluid (CSF) β‐amyloid (Aβ) Aβ42/40 ratio (exploratory Roche NeuroToolKit assays [Roche Diagnostics International Ltd, Rotkreux, Switzerland]), plasma Aβ42/40 (Quanterix Simoa Neurology 4‐Plex E Advantage Kit), and CSF phosphorylated tau181 (p‐tau181) (Roche Elecsys® Phospho‐Tau [181P] CSF assay). Land use regression models were used to estimate individual levels of air pollution, including nitrogen oxide (NO2) and particulate matter (PM2.5, PM10), at the participants’ residential area. General linear models corrected by age, sex, APOE‐ε4 status, and time between measurements were conducted to assess the association between environmental exposures and biomarker changes. Sex‐specific effects were also investigated by including an interaction term.

Result

Higher levels of exposure to PM2.5 were significantly associated with greater longitudinal reduction in plasma Aβ42/40 (β = ‐0.188, padjusted = 0.024). In addition, significant interactions between sex and NO2 (padj = 0.016), PM2.5 (padjusted = 0.008), and PM10 (padjusted = 0.007) on longitudinal change rates of plasma Aβ42/40 were found. Results showed that as the level of exposure increased, men presented reductions in plasma Aβ42/40 levels while women did not show significant changes (Figure 1). No significant results were found for longitudinal change rates of CSF biomarkers.

Conclusion

These results reinforce the role of air pollution as a sex‐dependent environmental risk factor for AD pathology in asymptomatic individuals. Although more research is needed to elucidate the mechanisms involved in these associations, our results may inform better personalized prediction and prevention practices.
Can the proposed research criteria for prodromal behavioural variant FTD be a bridge between neurologists and psychiatrists for early diagnosis?
Authors: El‐Jaafary Shaimaa Ibrahim , Ortuño Roman Romero
Published: December 2023

Background

The early diagnosis of the behavioural variant of frontotemporal dementia (FTD) is very challenging to clinicians. This type of dementia has a wide range of clinical variability, and the psychiatric presentation adds to the complexity of the differential diagnosis. The need for early precise diagnosis of FTD in the prodromal phase is increasing for tailored interventional strategies, better guidance, early counselling, and enrolment in clinical trials. However, its application in clinical practice needs good collaboration between psychiatrists and neurologists. We aimed to review the literature for studies highlighting the need for such collaboration.

Method

We performed a scoping literature review on early diagnosis of FTD, including suggested new biomarkers and psychometric studies supporting the diagnosis.

Result

The search identified a recent publication on proposed research criteria for prodromal bvFTD. These criteria were developed and validated by the ALLFTD Consortium. For the early detection of FTD, the investigators stressed the need to refine the definitions of neuropsychiatric disorders in neurodegenerative diseases differentiating them from primary psychiatric disorders, to conduct psychometric assessment to detect executive dysfunctions in patients presented with psychiatric disorders, lowering the threshold of suspicion, applying some tests for social cognition, and to use plasma and CSF biomarkers to support the diagnosis. It was considered important to use culturally adapted psychometric batteries for assessment of executive function and social cognition.

Conclusion

Collaboration between neurologists and psychiatrists will be needed to translate research criteria into clinical practice for the early diagnosis of patients with FTD. The current search for feasible biomarkers to improve the diagnostic utility is important and should be encouraged among psychiatrists as well as neurologists.
Multi‐omic profiling of isogenic ApoE3/3 and ApoE4/4 iPSC‐derived astrocytes uncovers altered lipid metabolism and mitochondrial function of ApoE4 astrocytes
Authors: Koppes Sascha , Feringa Femke M , Robert Aiko , Kruijff Iris Daphne , Olivier‐Jimenez Damien , Erlebach Lena , Thompson Leslie M. , Kronenberg‐Versteeg Deborah , Ori Alessandro , Mohammed Yassene , Giera Martin , van der Kant Rik
Published: December 2023

Background

As the main genetic risk factor for AD, glial ApoE4 has been implicated in a number of early disease relevant processes, such as lipid dyshomeostasis, mitochondrial dysfunction and altered immune function. This ApoE4 glial phenotype is not yet well characterized and this hampers the rationale design of ApoE4‐targeting interventions.

Method

We characterize the phenotypes of ApoE3/3 and ApoE4/4 iPSC‐derived astrocytes by multi‐omic profiling. In addition, we use lipidomic and metabolic profiling of interventions in ApoE4 astrocytes to define compounds that normalize lipid counts and metabolic function.

Result

In the ApoE4 astrocytes we observe strong accumulation of cholesterol esters (storage product of cholesterol) and triglycerides (storage products of fatty acids), in comparison to the ApoE3 astrocytes. Interestingly, our proteomic and transcriptomic profiling of these cells reveal an increase in cholesterol synthesis, despite the already high levels of cholesterol esters in the cell. Moreover, our proteomic and transcriptomic results display an increase in mitochondrial pathways, such as beta‐oxidation, TCA cycle and oxidative phosphorylation and a decrease in glycolysis. Not only mitochondrial function is altered but also mitochondrial organization, as we see an upregulation of the most relevant proteins for mitochondrial fusion, MFN1, MFN2 and OPA1. Our lipidomic and metabolic profiling of ApoE4 astrocytes after treatment with a number of different interventions reveals new insights into these altered lipid metabolic pathways.

Conclusion

Our multi‐omic profiling of iPSC‐derived ApoE3/3 and ApoE4/4 astrocytes uncovers that ApoE4 astrocytes have altered lipid metabolism, mitochondrial function and mitochondrial organization. Treatment with interventions reveals new insights into these altered pathways.
Associations between accelerated long‐term forgetting of Complex Figure Drawing, cerebral amyloid deposition, brain atrophy and serum neurofilament light in 73‐year‐olds
Authors: Lu Kirsty , Keshavan Ashvini , Baker John , Nicholas Jennifer M , Street Rebecca E , Keuss Sarah E , Coath William , James Sarah‐Naomi , Weston Philip SJ , Murray‐Smith Heidi , Cash David M , Malone Ian B , Wong Andrew , Fox Nick C , Richards Marcus , Crutch Sebastian J , Schott Jonathan M
Published: December 2023

Background

Accelerated Long‐term Forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). ALF may be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer’s disease pathology in older adults, and how memory selectivity may influence which material is forgotten.

Method

Participants in ‘Insight 46’, a sub‐study of the MRC National Survey of Health and Development (British 1946 birth cohort), completed cognitive and neuroimaging assessments at two time‐points (baseline at age ∼70; follow‐up ∼2.4 years later). At follow‐up, we assessed Complex Figure Drawing (copy; immediate recall; 30‐minute recall; 7‐day recall). Complex Figure items were categorized as ‘outline’ or ‘detail’ (Fig1), to test the hypothesis that forgetting the outline of the structure would be more sensitive to the effect of brain pathologies.

ALF scores were calculated as the proportion of material retained after 7 days, relative to 30 minutes. Rates of cerebral atrophy between baseline and follow‐up were quantified from T1‐weighted MRI using the Brain Boundary Shift Integral (BBSI). β‐amyloid status (positive/negative) was determined from 18F‐Florbetapir‐PET. Baseline serum neurofilament light (NfL) was quantified (Quanterix Simoa assay).

Multivariable regression models were used to investigate the effects (mutually adjusted) of β‐amyloid status, BBSI and NfL on ALF in n = 316 clinically‐normal individuals (50% female; 22% β‐amyloid positive; 30% APOE‐ε4 carriers), and to explore interactions between these predictors, adjusting for potential confounders including prospectively‐collected childhood cognitive ability and education.

Result

‘Outline’ items were better retained than ‘detail’ (Fig1). β‐amyloid‐positive participants had poorer ALF scores for ‘outline’ (but not ‘detail’) items (Fig1C; Table 1). Unexpectedly, higher NfL was associated with scores for ‘outline’ items (Table 1). Greater rate of cerebral atrophy predicted poorer retention among participants with elevated β‐amyloid and higher NfL (Table 1; Fig2).

Conclusion

These results provide evidence of associations between biomarkers of brain pathologies and ALF in 73‐year‐olds. Interactions between different biomarkers merit further exploration. ALF may be a sensitive outcome measure for therapeutic trials in preclinical AD. Better retention of ‘outline’ (vs. ‘detail’) items illustrates the strategic role of memory selectivity.
Higher Dietary Inflammatory Index scores are associated with higher beta‐amyloid deposition in the Framingham Heart Study
Authors: Lent Debora Melo , Beiser Alexa S. , Yuan Changzheng , Jacques Paul F , Ghosh Saptaparni , Thibault Emma G. , Fakhri Georges El , Decarli Charles , Johnson Keith A. , Vasan Ramachandran S , Seshadri Sudha , Himali Jayandra Jung , Jacob Mini E
Published: December 2023

Background

High Inflammatory content of diet enhances systemic chronic inflammation, a pathway which plays an important role in the development and progression of dementia. We investigated the cross‐sectional relationships between long‐term Dietary Inflammatory Index (DII) scores and beta‐amyloid(Aβ) and tau Positron Emission Tomography(PET) among participants of the community‐based Framingham Heart Study(FHS).

Method

343 adults (mean age 58 years [standard deviation (SD)], 10; 51% women]) completed a validated 126‐item Food Frequency Questionnaire (FFQ). We created a DII score (based on the published method by Shivappa et al. 2014) based on previous studies linking individual dietary factors to six inflammatory markers (i.e. C‐reactive protein, interleukin (IL)‐1β, IL‐4, IL‐6, IL‐10 and tumor necrosis factor‐alpha), consisting of 34 components. A cumulative DII score was calculated by averaging across two FFQs (administered at FHS Generation 2(GEN2) examination cycles 8(2005‐2008) and 9(2011‐2014), and at Generation 3(GEN3) examination cycles 2 (2008‐2011) and 3 (2016‐2019). Cumulative DII scores were examined as a continuous variable and using median‐split(‐1.11). Aβ and tau PET examinations were conducted(2016‐2021) using synthesized 11C‐Pittsburgh compound B(PiB) and/or F‐18‐flortaucipir(FTP) tracers. Examination cycles 9(GEN2) and 3(GEN3) were considered as study baseline. We used linear regression to relate the cumulative DII score to Aβ (Fronto‐lateral‐retrosplenial uptake(FLR) and precuneus) and tau (entorhinal, inferior temporal, rhinal, cortical composite and global composite) PET regions.

Result

Higher cumulative DII scores, as compared to DII scores below the median, were associated with higher amyloid precuneus region (β±SE, 0.023±0.011,p = 0.042) after adjustment for age, age‐squared, sex, camera and time between DII exam and PET scan exam. No other relationships were observed between DII and Aβ and tau PET. Interaction analyses showed interactions between DII (median‐split) and age (median‐split 58y) when testing association between median‐split DII and Aβ regions and tau global composite region. Stratified analyses showed relationships between higher DII vs. below median DII and higher amyloid FLR and precuneus region (0.055 ± 0.055,p = 0.037; 0.050±0.022,p = 0.022,respectively) among individuals aged 58y>, but not among individuals <58y (‐0.004±0.006,p = 0.947;0.000±0.000,p = 0.999,respectively). There were no significant interactions by sex and apolipoproteinE4 status in the association between DII and Aβ and tau PET.

Conclusion

Higher DII scores were associated with increased Aβ deposition.
Investigating lysosomal exocytosis as a pathway of beta‐amyloid release from neurons
Authors: Tsang Adrianna R , Seah Claudia , Krupa Jordan M , Pasternak Stephen H
Published: December 2023

Background

The endosomal‐lysosomal system has long been linked to the production of beta‐amyloid (Aβ), but the specific intracellular compartments involved in Aβ secretion remain contentious. Conventionally, lysosomes are associated with Aβ degradation, yet studies have also shown that lysosomes are a site of Aβ accumulation. Lysosomal exocytosis is a major secretory pathway in non‐neuronal cells, but few studies have investigated this pathway in neurons. This project examined the role and mechanism of lysosomal exocytosis in neurons, and we hypothesized that lysosomal exocytosis is a pathway for Aβ secretion from neurons.

Methods

We have established human iPSC‐derived neurons in culture, including cells bearing the APP Swedish mutation. Cells were transduced with pH sensitive fluorescent (pHluorin/pHmScarlet) tagged compartment markers to examine neurosecretory granules (synaptophysin), early endosomes (Rab5), late endosomes (Rab9) and lysosomes (LAMP1). Cells were loaded with fluorescent exogenous Aβ or Amytracker to label endogenous Aβ. We then stimulated secretion with ionomycin and used live cell Total Internal Reflection Fluorescence (TIRF) microscopy to examine molecular events occurring within 250 nm to the plasma membrane. shRNA against proteins known to be involved with lysosomal secretion (Rab27b, Munc13‐4 and synaptotagmin‐7) were used as controls. Imaris software was used to analyze the number and timing of lysosomal secretory events and the secretion of Aβ.

Results

As previously reported, exogenous Aβ in wild‐type cells and endogenous Aβ in APP Swedish cells accumulates in lysosomes, but not in early endosomes. TIRF microscopy captured videos of lysosomes approaching and fusing with the plasma membrane. Fusion appears as a reduction in normal fluorescent LAMP1 signal and an increase in pH sensitive fluorescent protein marker signal (reflecting the loss of luminal acidity due to fusion). Intracellular Aβ was released from neurons as lysosomes fused with the plasma membrane, seen as a simultaneous decrease in fluorescent Aβ labelling. Silencing of Rab27b significantly reduced lysosomal exocytosis and Aβ secretion, which confirmed that this is a lysosomal process.

Conclusion

Our results demonstrate that lysosomal exocytosis is a novel secretion pathway for Aβ in human neurons and identify potential pharmacological targets that regulate clearance of Aβ.
GFAP Upregulation by Astrocytes May Attenuate Phospho‐Tau Levels in a Tauopathy Mouse Model
Authors: Muñoz‐Castro Clara , Healey Molly A. , Jaisa‐Aad Methasit , Jayakumar Rojashree , Alla Srinija , Kashlan Zane D. , Noori Ayush , Fan Zhanyun , Calvo‐Rodriguez Maria , Das Sudeshna , Hudry Eloise , Hyman Bradley T. , Serrano‐Pozo Alberto
Published: December 2023

Background

Astrocytes react to amyloid‐β plaques and phospho‐tau (pTau) neurofibrillary tangles in the Alzheimer’s disease brain but their net effect on these Alzheimer’s neuropathological hallmarks remains controversial. A well‐known feature of these so‐called “reactive astrocytes” is the upregulation of the intermediate filament glial fibrillary acidic protein (GFAP), which is thought to be necessary for astrocyte process motility and glial scar formation. Here we asked whether this cytoskeletal remodeling helps reactive astrocytes control the burden of pTau species and/or protect synapses and neurons.

Method

We overexpressed human GFAP isoform 1 specifically in astrocytes of 4‐month‐old, sex‐balanced, THY‐Tau22 mice (Thy1.2‐MAPT
G272V/P301S 1N4R, GFAP mice, n = 11)—when neurofibrillary tangles start to appear in the hippocampal CA1 subfield—using a viral transfer strategy with single retro‐orbital intravenous injection of AAV‐PHP.B (2.5×1011 vg) and the gfaABC1D promoter. We euthanized the mice at 11 months of age (i.e., prior to the tauopathy plateau) and performed immunohistochemical and/or biochemical analysis of astrocyte, tau, and synaptic markers. Negative control groups consisted of THY‐Tau22 littermates injected with either phosphate‐buffered saline (PBS mice, n = 9) or an AAV‐PHP.B vector encoding the enhanced green fluorescent protein (EGFP mice, n = 10).

Results

Immunohistochemistry confirmed the astrocyte‐specific expression of human GFAP with an apparent integration in their intermediate filament network. We observed statistically significant reductions or marginally significant trends toward decrease in hippocampal SDS‐soluble levels AT8/pTauSer202/Thr205 and AT8‐immunoreactive area fraction, and a shift of AT180/pTauThr231 from SDS‐soluble (decreased) to TBS‐soluble (increased) hippocampal protein fractions, in GFAP vs. EGFP and/or PBS mice, but no changes in soluble or insoluble total tau or AT270/pTauThr181 across groups. In the cortex, we detected no changes in soluble or insoluble total tau, AT8/pTauSer202/Thr205, or AT270/pTauThr181 levels, nor in AT8‐immunoreactive area. Lastly, we found no significant differences across groups in brain weight, cortical or hippocampal areas, nor in the cortical levels of synaptophysin, Psd95, or the glutamate transporters Eaat1/Glast‐1 and Eaat2/Glt‐1.

Conclusion

Our findings indicate that GFAP upregulation by astrocytes—a classic feature of reactive astrogliosis—may attenuate neuronal pTau burden in a tauopathy mouse model. Ongoing work will further elucidate whether this aspect of reactive astrocytes impacts pTau‐induced neurodegeneration.
Association of β‐amyloid, microglial activation, hypermetabolism and hypertrophy in Alzheimer’s disease
Authors: Cai Yue , Shi Dai , Lan Guoyu , Chen Linting , Jiang Yanni , Ma Shaohua , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Plasma β‐amyloid (Aβ) Aβ42/Aβ40 measured by immunoprecipitation and liquid chromatography‐mass spectrometry assay has been demonstrated useful to identify Aβ PET positive individuals, but the concordance and discordance about the positivity of plasma Aβ42/Aβ40 (Plasma+/‐) and Aβ PET (PET+/‐) have not been fully characterized. Moreover, the association of Aβ deposition, cortical thickness (CTh), glucose metabolism, and microglial activation among different Plasma/PET profiles is poorly understood.

Method

In this study, we classified 173 ADNI participants into Plasma‐/PET‐ (N = 48), Plasma+/PET‐ (N = 43), and Plasma+/PET+ (N = 73) group based on thresholds of composite Aβ PET (18F‐florbetapir, FBP) standardized uptake value ratio (SUVR) (≥1.11) and plasma Aβ42/Aβ40 (≤0.1218). Part of them had longitudinal 18F‐fluorodeoxyglucose (FDG) PET, structural MRI, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) data. Baseline and slopes of FBP SUVRs of 68 Freesurfer‐defined ROIs were compared between different Plasma/PET groups. The associations of regional FBP SUVRs, CSF sTREM2, regional glucose metabolism (reflected in FDG‐SUVR), and CTh (measured using structural MRI) were investigated in different Plasma/PET groups.

Result

Plasma Aβ42/Aβ40 might become positive earlier than Aβ PET (Fig.1A, McNemar’s test, p<0.001). Longitudinally, Plasma+/PET‐ participants showed faster rates of Aβ accumulation in bilateral BANKSSTS, supramarginal, and superior parietal cortices whereas demonstrated no difference in baseline FBP SUVRs than Plasma‐/PET‐ participants (Fig.1D‐E). Higher CSF sTREM2 level and faster rate of CSF sTREM2 increase were related to slower rates of Aβ accumulation in BANKSSTS (standardized β (βstd) = ‐0.418, p = 0.002) in Plasma+/PET+ but not in Plasma+/PET‐ individuals (Fig.2A and D). In contrast, thicker CTh (Fig. 4B‐C) and higher glucose metabolism (Fig. 4H‐I) in supramarginal and superior parietal cortices were coupled to faster rates of CSF sTREM2 increase in Plasma+/PET‐ rather than in Plasma+/PET+ individuals.

Conclusion

These findings suggest that plasma Aβ42/Aβ40 might become abnormal earlier than Aβ PET, and plasma Aβ42/Aβ40 positive Aβ PET negative (Plasma+/PET‐) individuals accumulate Aβ plaques faster than Plasma‐/PET‐ individuals. Activated microglia may play a role in reducing fibrillar‐Aβ increasing rates in late amyloidosis stage, whereas it may be related to hypertrophy and hypermetabolism in early amyloidosis stages.
Metabolic changes in preclinical AD as detected by magnetic resonance spectroscopy
Authors: Falcon Carles , Garcia Marina , Julia‐Sape Margarida , Montesinos Paula , Sanchez‐Gonzalez Javier , Blennow Kaj , Zetterberg Henrik , Kollmorgen Gwendlyn , Carboni Margherita , Suarez‐Calvet Marc , Grau‐Rivera Oriol , Gispert Juan Domingo ,   ALFA study
Published: December 2023

Background

Biochemical changes, which may precede morphological changes, could be of great relevance in profiling preclinical AD. We aimed to investigate metabolic changes using magnetic resonance spectroscopy (MRS) in three AD‐relevant regions: right hippocampus, right angular gyrus, and right precuneus, focusing on myoinositol due to its role in glial activity (osmoregulation‐neuroinflammation).

Method

Three hundred sixty‐six participants from the ALFA+ cohort underwent three single‐voxel MRS (PRESS sequence, TR = 2000ms; TE = 100ms chosen to invert myoinositol peak for more precise quantitation; volume of interest (VOI): 20×20×20mm3 [25×20×16mm3 for hippocampus]). Figure 1 shows VOI location and MRS samples. Concentrations of N‐acetyl‐containing compounds (NAA) that is a neuronal marker, total creatine (Cr) related to brain energy, myoinositol (mI), choline‐containing compounds (Cho) related to cell proliferation, and glutamate/glutamine were calculated with LCModel in arbitrary units (using water reference) with the default settings and basis set adapted to the acquisition conditions. Concentrations were corrected for VOI CSF content. Remaining VOI gray matter percentage was used as a confounder in all analyses, jointly with age, sex, and APOE‐e4 status (carrier/non‐carrier). We investigated the correlation of MRS metabolite concentrations with CSF concentrations of Aβ42/40 and ptau‐181 as biomarkers for AD (Elecsys®; Roche Diagnostics). For completeness, we also checked the dependency of MRS metabolites on age. MRS not meeting QA criteria were discarded (Cramer‐Rao lower bounds >20 for any of the metabolites or imprecise VOI location). The statistical threshold was set to p<0.05 for all the analyses.

Result

Table 1 shows characteristics of the subsamples with MRS in each location. Higher myoinositol levels in hippocampus and angular gyrus were associated with lower CSF Ab42/40, but not in the precuneus, where it was associated with higher Cr/Cho ratio. Higher Cr and NAA were positively associated with higher CSF p‐tau181 levels in the angular gyrus. NAA was negatively associated with age on cortical regions, as well as Cr on the angular gyrus. Table 2 summarizes the main results.

Conclusion

MRS allowed determination of differential metabolite changes in AD‐related regions in preclinical AD. Further research is warranted to better characterize the nature of these metabolic changes and determine their impact on longitudinal outcomes of these participants.
Neurobehavioral Manifestations and Outcomes in Autoimmune Encephalitis: A Retrospective Study
Authors: Nanthasi Witsarut , Jitpapaikulsarn Jiraporn , Senanarong Vorapun , Prayoonwiwat Naraporn , Rattanabannakit Chatchawan
Published: December 2023

Background

Autoimmune encephalitis (AE) could present with heterogeneous clinical manifestations. Neurobehavioral symptoms were presented diversely in each type of AE and may be misdiagnosed with psychiatric disorders. This study aimed to investigate and categorize the clinical manifestations and evaluate the treatment outcomes in patients with AE.

Methods

A retrospective chart review study of AE was done at Siriraj Hospital, Mahidol University. The data between 2009‐2022 were extracted. Thirty‐seven patients were diagnosed with AE. Clinical manifestations were collected and classified into four categories: neurological, cognitive, neuropsychiatric manifestation, and autonomic dysfunction.

Results

Among 37 patients who were diagnosed with AE, 32 patients (87.2%) were seropositive with ten different antibodies identified, and five patients (12.8%) were seronegative. The most commonly identified antibodies were anti‐NMDAR (n = 13, 33.2%) and anti‐LGI1 antibodies (n = 8, 20.5%). The neurological manifestation was most presented (92.3%), followed respectively by neuropsychiatric symptoms (76.9%), cognitive impairment (69.2%) and autonomic dysfunction (23.1%). The most frequent clinical features (>30%) were seizure (69.2%), memory impairment (64.1%), sensorium disturbance (51.3%), executive dysfunction (51.3%), abnormal movement (46.2%), and sleep problem (33.3%). All patients with anti‐NMDAR encephalitis had at least one neuropsychiatric symptom, which predominated in behavioral change (92.3%) compared with patients with other antibodies or seronegative (p = 0.02), such as agitation, aberrant motor behaviors, sleep and appetite change. Autonomic dysfunction was found only in anti‐NMDAR encephalitis patients (p<0.01), whereas the proportion of cognitive impairment and neurological deficit were not different among those with or without anti‐NMDAR antibodies. In this study, none of the patients presented solely psychiatric symptoms. The median following‐up duration after diagnosis was 38 weeks (IQR 14‐137). Treatment outcomes at 6‐12 months showed improvement or resolution of symptoms, but five patients (13.5%) developed emerging mood changes, particularly depression and irritability. Cognitive performance measured by Montreal cognitive assessment demonstrated improvement at 6 months of follow‐up (from 15.12±6.89 to 24.00±3.86, p<0.01) but not at 12 months.

Conclusions

AE had various manifestations. Most of them had a combination of symptoms in the neurological, psychiatric, cognitive, and autonomic domains. A sole neuropsychiatric manifestation was rarely presented in AE. The symptoms showed improvement at 6‐12 months after treatment.