bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain Reserve Score on Acute Trauma Head CT is Correlated with Pre‐TBI MCI/Dementia and is an Independent Predictor of Post‐TBI Cognitive Outcome
Authors: Gardner Raquel C. , Huie Russell , Yaffe Kristine , Manley Geoffrey T. , Yuh Esther C.
Published: December 2023

Background

Pre‐injury brain reserve may contribute to the substantial heterogeneity observed in cognitive outcome after mild traumatic brain injury (mTBI), including risk for cognitive decline and dementia. However, no tools exist to quantify pre‐injury brain reserve in an acute trauma setting, thereby limiting research. We aimed to develop and validate a visually‐rated Brain Reserve Score (BRS) to quantify baseline brain reserve on head CTs obtained to rule out intracranial trauma in adults presenting acutely with mTBI.

Methods

Data are from the Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK‐TBI) and TRACK‐Geriatric TBI (TRACK‐GERI) studies, multi‐center prospective cohort studies of adults age 18+ presenting within 24 hours (TRACK‐TBI) or adults age 65y+ presenting within 72 hours (TRACK‐GERI) of TBI who received head CT and multi‐domain clinical follow‐up for one year. BRS was developed by adapting existing MRI visual rating scales of global cortical atrophy, hippocampal atrophy, and white matter change for use in trauma head CTs and then by refining the scoring guide to optimize rater reliability. To establish concurrent validity, we assessed correlation of BRS with pre‐injury cognitive status (measured in TRACK‐GERI using informant‐reported Clinical Dementia Rating interviews). To establish predictive validity, we assessed association of BRS with good versus poor 12‐month cognitive outcome in TRACK‐TBI using logistic regression adjusted for baseline demographics, medical/psychiatric comorbidities, injury characteristics, and trauma severity on CT.

Results

Final BRS score ranged from 0‐10 (10 is highest burden of neuropathology); inter‐ and intra‐rater reliability were moderate‐substantial (weighted kappa 0.54‐0.80). Among N = 100 TRACK‐GERI participants BRS was significantly correlated with pre‐injury CDR (r = 0.37, p<0.01). Among N = 656 TRACK‐TBI participants, BRS of 6+ was independently associated with poor 12‐month cognitive outcome (fully adjusted odds ratio 4.35, 95% confidence interval 1.35‐13.99, p = 0.01).

Conclusion

BRS is a reliable visually rated score of brain reserve on acute trauma head CT that correlates with pre‐injury cognitive status and independently predicts poor cognitive outcome one year post‐mTBI. BRS may be a useful tool to facilitate inclusion of older adults in acute TBI research thereby advancing clinical care and research on mechanisms of accelerated post‐TBI cognitive decline and dementia.
Balance in idiopathic normal pressure hydrocephalus: microstructural brain correlates and relation to Alzheimer’s biomarkers.
Authors: Bommarito Giulia , Griffa Alessandra , Armand Stéphane , Herrmann François , Assal Frederic , Ville Dimitri Van De , Allali Gilles
Published: December 2023

Background

Patients with idiopathic normal pressure hydrocephalus (p‐iNPH) present with balance impairment, which contribute to falls and could improve after cerebrospinal fluid shunting procedure. Structural brain correlates of balance in iNPH have not been investigated yet. Moreover, as gait, balance changes after shunting could be affected by Alzheimer’s disease (AD) biomarkers. The aim was to assess the relationship between postural control and brain structural damage or AD biomarkers in p‐iNPH before and after CSF tap test (CSFTT), a prognostic test to predict response to shunting.

Method

thirty‐eight healthy controls (HC) and 23 p‐iNPH were consecutively recruited and underwent balance assessment, and MRI including diffusion weighted images before and after CSFTT (data after CSFTT available for 19 p‐iNPH). Center of pressure (COP) trajectories parameters and diffusion metrics were derived in both groups, during eyes open (EO) and eyes closed (EC) conditions. AD biomarkers were available for p‐iNPH. Repeated‐measures ANOVA (with one within‐subjects factor: EC/EO, and one between‐subjects factor: group) was used to compare posturographic measures. Non‐parametric correlation analysis was used to assess their relatioship with WM tracts diffusion metrics and AD biomarkers.

Result

COP speed in the antero‐posterior direction and sway area were worse in p‐iNPH compared to HC, and during EC compared to EO condition (group x factor interaction: F(1,59) = 5.02, p = .029 and F(1,59) = 4.95, p = 0.30, respectively), Fig.1. Orientation dispersion index and intracellular volume fraction of forceps minor and anterior thalamic radiation, tracts already related to balance in ageing, positively correlated to COP parameters during EC task in p‐iNPH (0.43<R<0.48, 0.02<p<0.046) and negatively in HC (‐0.44<R←0.21, 0.005<p<0.195). The relationship inverted after CSFTT in p‐iNPH, with a negative correlation found between sway area and forceps minor ODI (R = ‐0.47, p = .050), Fig.2. In p‐iNPH, no significant correlation was found between amyloid‐beta or phosphorylated‐tau and changes in posturography parameters after CSFTT (Fig.3).

Conclusion

postural control is impaired in p‐iNPH, especially during EC condition, suggesting an altered somatosensory function integration. Such impairment relates to microstructural damage of periventricular tracts, with a partial normalization of the relationship after CSFTT. Changes in balance after CSFTT do not seem to be affected by AD biomarkers.
Within‐ and Between‐Session Changes on Motor Learning and Amyloid Status
Authors: Duff Kevin , Schaefer Sydney Y , Hoffman John M.
Published: December 2023

Background

There is a growing body of literature that suggests that motor learning may be indicative of Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD). For example, motor learning may provide unique information for enriching clinical trials in MCI and AD if it is related to biomarkers of interest. The current study sought to examine motor learning patterns relative to amyloid deposition in the brain.

Method

One hundred fifty‐four older adults who were cognitively intact or had amnestic MCI or mild AD participated. Each participant completed a motor learning task that consisted of six trials of moving beans with a spoon between three cups, and the total time to complete the task was measured. This task was repeated at two additional visits, about one week and one year later. Each participant also completed an amyloid positron emission tomography (PET) scan within a month of the motor testing. Based on FDA‐approved prescribing and visual interpretation information, the amyloid PET scan was classified as positive (n = 94) or negative (n = 60). A second repeated‐measures analysis examined trial one at the initial, one‐week, and one‐year visits to look for between‐session changes based on amyloid status.

Result

Within the initial visit, both groups significantly improved their response time on this motor learning task across the six trials (p<0.001) and those classified as amyloid negative performed significantly faster than their amyloid positive peers (p = 0.01). However, there was no significant time by amyloid status interaction (p = 0.92). Like in the within‐session results, there were main effects of time (p<0.001) and amyloid status (p = 0.003), but there was not a significant interaction of the two (p = 0.37).

Conclusion

Older individuals who are amyloid positive performed worse on this motor learning task than their amyloid negative peers, both within the same session and between sessions. Additionally, notable learning was present in both groups within the same session, but this was somewhat reduced in the amyloid positive individuals across sessions. Even though there was no clear interaction between time and amyloid status, motor learning tasks may provide unique information in identifying individuals for clinical trials who are more likely to be amyloid positive.
Evolution of behavioral and psychological symptoms of dementia in the logopenic variant of primary progressive aphasia
Authors: Tastevin Tastevin , Laforce Robert , Lavoie Monica , Poulin Elizabeth , Sablonnière Justine De La , Carrier‐Auclair Julie
Published: December 2023

Background

The logopenic variant of primary progressive aphasia (lvPPA) is known to be associated with behavioral and psychological symptoms of dementia (BPSD) such as depression and apathy. However, few data are available regarding the evolution of BPSD, particularly in advanced stages and end of life, which is often of great concern for patients and families.

Method

We performed a retrospective chart review in a cohort including 42 deceased patients with a diagnosis of lvPPA. Symptoms of BPSD were assessed from disease onset to death by three experienced raters and, when possible, interviews were performed with proxies of patients to complete the missing data.

Result

Depression and anxiety were mostly prevalent at the early stages but decreased over time. In particular, at one‐year after first visit, 36% of the patients were affected by anxiety symptoms and 19% were suffering from depressive symptoms. Apathy increased with the follow‐up with a peak at 5 years from the first clinical visit (46% of the patients). Other BPSD such as rituals, hyperorality, or agitation were less prevalent throughout the disease. Nevertheless, patients frequently presented with dishinibition during the follow‐up (between 20‐36% of the patients during the 5 years following the first visit).

Antidepressants were used in around 20‐28% of the patients from first visit to later stages, followed by anxiolytics (3‐22%). Antipsychotics were mostly used in the advanced stages. At the first visit, 42% of the patients were treated with acetylcholinesterase inhibitors. During the follow up, this rate fluctuated between 40‐64%.

Conclusion

Affective symptoms were most prevalent in prodromal and early stages, whereas in the advanced stages, lvPPA was mostly characterized by apathy. Dishinibition was also frequent during the follow‐up. These findings could support a psychiatric assessment in the early stages, since depression and anxiety are known to respond well to psychotropic treatment.
An Automated Montreal Cognitive Assessment MoCA‐Report for Optimal Clinical Management of Alzheimer’s Disease and Initial Eligibility Assessment for Newly Approved Therapies
Authors: Klil‐Drori Sivan , Bodenstein Katie C , Ghantous Youssef , Nasreddine Ziad S
Published: December 2023

Background

The Montreal Cognitive Assessment (MoCA) is one of the cognitive screening tools most frequently used in primary care. Early detection of Alzheimer’s disease will allow rapid intervention, including initiation of recently approved disease modifying therapies, which carry potential benefits for patients, e.g., maintained cognition and function, along with improved prognosis. However, patients with cognitive impairment detected in primary care are commonly referred to specialty clinics for further evaluation. This causes large volume of referrals and long waiting‐time to cognitive specialists which delay diagnosis and treatment. Therefore, an automated report of cognitive screening with rapid interpretation of the results may allow primary care clinicians to identify the patients with high probability for Alzheimer’s disease and potential eligibility to approved therapies.

Method

We completed an extensive literature review and gathered data derived from the MoCA that is relevant for clinical management and suitability for approved disease‐modifying therapies. Following this, we developed an automated report for the digital‐MoCA software that will present pertinent information that is applicable for clinical management, staging, conversion to other useful well‐known scales, and initial assessment of eligibility for approved disease modifying therapies.

Result

Based on published studies, we developed a detailed MoCA‐Report to be automatically generated upon completion of the digital‐MoCA. The MoCA‐Report presents the patients’ score on each subtest as well as the total score in comparison to normative data, the Memory Index Score (MIS), MoCA score conversion to Clinical Dementia Rating Scale, Mini Mental State Examination, and risk for amyloid pathology. The MoCA‐Report also includes relevant information on staging, risk for driving errors, and possibility of conversion to dementia. It is designed to provide primary care clinicians assistance in clinical management, initial identification of eligibility for disease modifying therapies, and selection of referrals to specialty clinics, thus improving patient care and supporting the healthcare systems.

Conclusion

The MoCA‐Report integrates information and interpretation of cognitive screening in an automated modality, with minimal use of staff and time. Rapid interpretation of the cognitive screening in primary care may support clinical management in a timely manner and promote early detection and intervention for patients with Alzheimer’s disease.
The influence of Area Deprivation Index on cognition in cognitively‐normal adults as measured by Principal Component Analysis of Neuropsychological Data
Authors: Conner Drew C , Botchway Albert , Scaife Steve , Unnam Pavani , Roller Hunter R , Zec Ronald F , Ala Tom , Hascup Erin R. , Trivedi Mehul Alkesh
Published: December 2023

Background

Previous research has demonstrated that neighborhood disadvantage is associated with worse health outcomes including increased risk for dementia. The Area Deprivation Index (ADI) measure represents the theoretical domains of income, education, employment, and housing quality, which allows for the ranking of neighborhoods based on socioeconomic disadvantage. In the present study, we hypothesized that greater neighborhood disadvantage (i.e., higher ADI scores) would be associated with lower cognitive function after controlling for age, education, and sex.

Method

Principal component analysis (PCA) was used to examine the component structure of a neuropsychological test battery administered to 852 adult participants enrolled in the Southern Illinois University Longitudinal Cognitive Aging Study (SIU LCAS). The vast majority of the cohort was White/Not Hispanic (>98.0%) and female (72.4%). Mean age and education were 67.5 years and 14.8 years, respectively. Linear regression analysis was used to examine the relationship between ADI and PCA cognitive component scores after controlling for age, education, and sex.

Result

PCA identified four cognitive components, which were labeled speed/flexibility, visuospatial skills, word list learning/memory, and story memory (immediate and delayed recall). Regression analysis revealed that all three demographic variables were significantly associated with each cognitive component score (p<0.001). After controlling for age, gender, and education, higher ADI scores were associated with lower cognitive component scores for only the speed/flexibility component (p = 0.03). Age, education, and sex accounted for 23% of the variance in the speed/flexibility component. ADI accounted for only an additional 0.4% of the variance in the speed/flexibility component. There was no significant relationship between ADI scores and the visuospatial skills, word list learning/memory, and story memory components.

Conclusion

Our results suggest that the relationship between greater neighborhood disadvantage and poorer cognitive function are very subtle and may only be present for some, but not all, cognitive domains. One major limitation in the present study was that collection of cognitive data and ADI calculations were not synchronous. More studies are needed to better understand the relationship between neighborhood disadvantage and cognitive functioning.
Estimating the prevalence of mild cognitive impairment from clinical notes in U.S. Veterans
Authors: Jasuja Guneet , Li Xuyang , Aguilar Byron J. , Shishova Ekaterina , Morin Peter J , Berlowitz Dan , Miller Donald R , O'Connor Maureen K. , Nguyen Andrew H. , Zhang Raymond , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming
Published: December 2023

Background

Individuals with mild cognitive impairment (MCI), a noticeable decline in cognitive abilities, are at increased risk of developing Alzheimer’s disease (AD) or other dementia. Risk factors for dementia, such as obesity, stroke, depression are highly prevalent among U.S. veterans We report on the trends in the prevalence of MCI using clinical notes over the past 5 years in the Veteran Affairs, the largest integrated healthcare system in the U.S.

Method

Prevalent cases of MCI were identified from VA clinical notes for all Veterans aged 50 years and older in VA care from fiscal years (FYs) 2015‐19. VA clinical notes are maintained in searchable text integration utility files (TIU) available in the VA Corporate Data Warehouse (CDW). Pharmacy clinical notes were excluded. “Mild cognitive impairment” keyword was searched in clinical notes to identify patients with MCI. We validated the keyword “mild cognitive impairment” in 199 clinical notes. The positive predictive value for this validation was approximately 91%. For each FY, age and sex adjusted rates directly standardized to the 2010 U.S. Census general population were estimated.

Result

A total of 308,930 prevalent cases of MCI were identified from VA clinical notes from FYs 2015‐19. Standardized prevalence rates for MCI increased steeply, with prevalence of 0.9% in FY 2015, increasing to 1.31% in FY 2019. Standardized age adjusted MCI prevalence rates also increased sharply for male (0.77% in FY 2015 to 1.10% in FY 2019) and female veterans (1.01% in FY 2015 to 1.50% in FY 2019) with rates higher for females than males for each FY.

Conclusion

We observed recent trends of increasing prevalence rates for MCI among veterans identified from VA clinical notes. Considering the increased risk of dementia among individuals with MCI, our study finding of increasing prevalence of MCI among veterans highlights the critical need for effective interventions and treatment to target veterans with MCI.
Radiopharmaceutical selection for tau PET imaging
Authors: Ozsahin Ilker , Onakpojeruo Efe Precious , Uzun Berna , Ozsahin Dilber Uzun , Butler Tracy A
Published: December 2023

Background

The accumulation of pathologically misfolded tau is a feature that is shared by a group of neurodegenerative disorders that are collectively referred to as tauopathies. AD is the most prevalent of these tauopathies. Neurofibrillary tangles are characterized by the presence of hyperphosphorylated protein (tau), and senile plaques are characterized by the presence of amyloid peptide aggregates. PET imaging is fully quantitative and enables accurate spatial assessment. However, as a result of non‐specific binding and the limited spatial resolution of PET scanners, this technique requires not only the presence of tau inclusions in a brain region but also sufficient density and spatial extent of those inclusions in order to generate a sufficient signal‐to‐noise ratio. With the development of tau‐specific ligands for use with PET, it is now possible to investigate the role that tau pathology plays in the development and progression of these disorders. The purpose of this study is to analyze, compare, and rank the currently available tau PET tracers for imaging in research and routine clinical settings.

Method

We proposed using the fuzzy Preference Ranking Organization Method for Enrichment of Evaluations (PROMETHEE), a multicriteria decision‐making (MCDM) tool. First‐generation tau PET tracers ([18F]AV1451, [11C]PBB3, [18F]THK5117, [18F]THK5351, [18F]THK5317, and [18F]THK5105) and second‐generation compounds ([18F]MK‐6240, [18F]JNJ‐067, [18F] PI‐2620, [18F]RO‐948 (previously referred to as [18F]RO69558948), [18F]PM‐PBB3, [18F]GTP1, [18F]JNJ‐64349311 ([18F]JNJ311), [11C]RO‐6931643, and [11C]RO‐6924963) were selected to investigate in this study. The evaluation is based on relative parameters, such as specificity, target binding accuracy, neocortical uptake, radiation exposure, brain penetration, free fraction in plasma, defluorination, and adverse reactions, and the importance that is placed on each of these parameters is weighted differently.

Result

The results from this study show that [18F]RO‐948 is the most favorable tau PET ligand, while[18F]THK5105 is the least favorable one based on the considered weighted criteria in this study.

Conclusion

Fuzzy PROMETHEE can be used as a decision‐aid system to select the proper radiopharmaceuticals for tau PET imaging. This study can be extended to include more tracers and criteria and might help researchers and concerned readers to select the optimal tau PET tracer.
Proposal for Efficient Access to Cognitive Screening: using MoCA‐XpressO Pre‐screen, MoCA‐Duo Videoconference Screen, and MoCA‐Report for Post‐screen Interpretation
Authors: Klil‐Drori Sivan , Bodenstein Katie C , Ghantous Youssef , Nasreddine Ziad S
Published: December 2023

Background

The continuously aging population worldwide results in increased prevalence of cognitive decline and growing demand for cognitive screening. This demand is expected to increase with newly approved disease modifying therapies. However, scarce resources for professional cognitive assessments, requires efficient screening tools that are accessible and easily applied. Therefore, a simple process of brief self‐administered cognitive pre‐screening, videoconference‐screening, and an automated report with result interpretation, may be highly efficient and will increase access to cognitive screening.

Method

We integrated validated novel tools for accessible, home‐based cognitive pre‐screening and screening. It includes development and validation of the Montreal Cognitive Assessment (MoCA)‐XpressO: a brief self‐administered cognitive pre‐screening tool, and cognitive screening via MoCA‐Duo: videoconference version of MoCA. Finally, we developed the MoCA‐Report, an automated summary of MoCA‐Duo with result interpretation according to various cognitive domains and suggestions for further inquiries.

Result

The MoCA‐XpressO includes assessment of memory tasks, logical tasks, and processing speed. Validation of MoCA‐XpressO showed high accuracy (AUC 0.85) therefore may identify the healthy population with no objective cognitive impairment: the “worried‐well” who will not require further screening. Cognitive screening can then be applied via MoCA‐Duo only to selected patients with identified cognitive impairment. MoCA‐Duo by videoconferencing carries significant benefits: (1) allows home‐based validated assessment; (2) allows matching between patients and certified raters across the globe, with similar country of origin and language, which is highly valuable in cognitive evaluations. Ultimately, post‐screening interpretation is provided automatically by MoCA‐Report which presents interpretation of the scores according to normative data, present the Memory Index Score (MIS), conversion to Mini Mental State Examination and Clinical Dementia Rating scores, optional cognitive manifestations, prediction of conversion to dementia, prediction of amyloid pathology, and potential risk for driving errors. It will also explore potential eligibility for newly approved disease modifying therapies.

Conclusion

The estimated increase in the prevalence of dementia, and newly approved disease modifying therapies are expected to increase demand for cognitive screening. Integration of self‐administered cognitive pre‐screening by MoCA‐XpressO, and videoconference cognitive screening via MoCA‐Duo including an automated report with result interpretation, propose efficient and comprehensive cognitive screening for high volume of patients.
A novel approach to measure dyadic patterns of subjective cognitive changes: its association to Alzheimer’s disease biomarkers and ability to predict clinical progression in cognitively normal older adults
Authors: Vannini Patrizia , Gagliardi Geoffroy Pierre , Cacciamani Federica , Mimmack Kayden J.
Published: December 2023

Background

Discrepancy in the dyadic relationship of subjective cognitive change has revealed both increased/heightened awareness and decreased awareness/unawareness in the predementia stages of Alzheimer’s Disease (AD). The dyadic relationship is often calculated using the mean discrepancy between an individual and their study partner’s scores on a memory complaints questionnaire. However, participants may display heightened awareness on some questions and unawareness on others, canceling out each other’s effect and masking subtle changes in either direction. Here, we present a new item‐level methodological approach allowing us to examine individual subtle changes in these two awareness dimensions separately. Moreover, we compared them to AD pathology and investigated their ability to predict clinical progression.

Method

A total of 503 ADNI participants (Table.1) with baseline clinical dementia rating (CDR) = 0 and baseline CSF (Aβ1‐42 and t‐tau) were included. A subset (N = 329) had at least two follow‐up CDR time points to compute clinical progression. A traditional score was calculated as the average discrepancy between the partner and participant’s responses on the Everyday Cognition questionnaire, with positive scores indicating heightened awareness and negative scores indicating unawareness. An unawareness (resp., heightened awareness) sub‐score was computed by applying a ceiling (resp., floor) at zero to item‐level differences before averaging. Each measure was compared by AD pathology, adjusted for age and sex. Survival analyses examined the relationship of the new scores with clinical progression.

Result

CSF t‐tau, but not Aβ1‐42, was a significant independent predictor of the traditional and unawareness scores in models adjusting for each other. There was no significant interaction between the two (Table.2). Survival analyses showed a one‐point improvement on the unawareness sub‐score associated with an 84% reduction in progression hazard (HR = 0.16, p<0.001), or equivalently. A one‐point decline and 525% increase in progression hazard, with no significant effect for the heightened awareness score.

Conclusion

Decomposing the traditional awareness score into two sub‐scores, allowed the investigation of the relationship between AD and awareness with more specific, sensitive measures. Of these, the unawareness sub‐score was associated with t‐tau and a strong predictor of clinical progression, providing further support that discordant self‐ and informant‐reported cognitive decline may provide important clinical information.
Dyadic patterns of subjective cognitive decline relate to Alzheimer’s disease biomarkers differently in preclinical and prodromal clinical states
Authors: Houston Michelle L , Zhang Panpan , Liu Dandan , Hohman Timothy J. , Blennow Kaj , Zetterberg Henrik , Jefferson Angela L. , Gifford Katherine A.
Published: December 2023

Background

Subjective cognitive decline (SCD) may provide an early indicator of evolving neurodegenerative disease. Dyadic SCD patterns, or understanding the self/patient’s in relation to an informant/loved one’s endorsement of SCD, may more accurately reflect underlying Alzheimer’s disease (AD) pathology in particular. We related dyadic discrepancies in SCD to markers of core AD pathology, including amyloid‐β42 (Aβ42) and phosphorylated tau (p‐tau).

Method

Vanderbilt Memory and Aging Project participants free of clinical dementia [n = 150, 72±7years, 37% mild cognitive impairment (MCI)] and their informants completed the Everyday Cognition questionnaire. Dyadic discrepancy (self‐reported score minus informant‐reported score) was calculated. Positive scores indicate self>informant SCD and negative scores indicate informant>self SCD. Participants also underwent fasting lumbar puncture to obtain cerebrospinal fluid (CSF) for quantification of Aβ42 and p‐tau. Linear mixed‐effects regression models related dyadic score to individual CSF biomarkers adjusting for age, sex, self‐reported race/ethnicity, cognitive status, apolipoprotein E‐ε4 status (positive, negative), and depression symptoms (Geriatric Depression Scale) with false discovery rate (FDR) corrections for multiple comparisons. Models were repeated with a diagnosis x biomarker interaction.

Result

SCD discrepancy in the negative direction (informant>self‐SCD) was associated with higher CSF p‐tau (β = ‐0.64, pFDR<0.001). Cognitive status modified the association between discrepancy score and Aβ42 (β = 10.81, pFDR = 0.02). Stratified analyses by cognitive status revealed that MCI participants with negative discrepancies (informant>self‐SCD) had lower Aβ42 levels (β = 5.592, pFDR = 0.02), indicating more cerebral amyloid deposition. The opposite pattern was observed in cognitively unimpaired participants, though findings did not survive FDR correction (β = 1.16, p = 0.03, pFDR = 0.24). Additionally, in MCI participants, negative SCD discrepancy was associated with higher p‐tau levels (β = ‐0.7223, pFDR = 0.02). All significant results survived outlier exclusion. See Figure for details.

Conclusion

Dyadic SCD discrepancy correlates with AD biomarkers differently in preclinical and prodromal states. In MCI, greater informant‐SCD related to more amyloid and p‐tau deposition, likely due to patient anosognosia and increasing functional changes noted by others. Conversely, in an earlier, preclinical stage before the onset of overt problems, more self‐SCD appears indicative of greater amyloid pathology. Results are consistent with the purported pathological cascade of AD and highlight the relevance of considering dyadic SCD to inform underlying disease.
A novel anti‐amyloid‐beta oligomer antibody reduces plaque burden and slows cognitive decline in 5xFAD mice
Authors: Wang Yubin , Huang Lei , Bujold Matthew , Tang Lingyun , Du Xin
Published: December 2023

Background

The soluble amyloid‐beta (Aβ) oligomers are the more toxic form of Aβ as compared with monomers and insoluble fibrils. Lecanemab, a humanized monoclonal antibody (mAb) with high affinity for Aβ oligomers, reduced cognitive decline in patients with early Alzheimer’s disease in a phase 3 clinical trial. Here we report a novel fully‐human anti‐Aβ oligomer mAb with profiles similar to Lecanemab.

Method

AlivaMab human F(ab’)2 transgenic mice were immunized with Aβ oligomers to generate Aβ oligomer selective mAbs. The antibodies were screened for, and ranked, based on their selectivity for Aβ oligomer over monomer and ability in mediating the uptake of Aβ oligomers by microglia. Pharmacokinetics (PK) and brain penetration of lead mAb candidates was determined in mice. In vivo efficacy was evaluated in 7‐month old 5xFAD mice with weekly intraperitoneal injection of antibody lead at 1, 3, or 10 mg/kg dose levels for 4 months. After completion of dosing, open field and novel object recognition tests were performed on the treated mice and amyloid plaque burden in the brain was measured by Campbell‐Switzer stain and ELISA.

Result

Lead antibody 17P04 exhibited higher oligomer selectivity than that of mAb158 (mouse parental antibody of Lecanemab which served as reference antibody control) and induced antibody‐dependent cell‐mediated phagocytosis of Aβ oligomers in mouse microglia cells. PK study in mice showed that 17P04 had longer half‐life in the plasma and the brain, and demonstrated higher brain penetrance in comparison with mAb158. Subchronic treatment of 5xFAD mice with 17P04 reduced Aβ plaque burden in the brain in a dose dependent manner, reversed the abnormal activity of 5xFAD mice in open field test, and reduced cognitive decline as evaluated by novel object recognition.

Conclusion

We identified a novel fully‐human anti‐Aβ oligomer antibody with superior Aβ oligomer selectivity, half‐life and brain exposure. Lead antibody 17P04 demonstrated high efficacy in plaque clearance and cognitive protection in 5xFAD mice.
Exploring the Social Connection of Young Caregivers of People Living with Dementia in Ontario
Authors: Redublo Tyler Christian , Alvares Allison , Farahani Mehrdad
Published: December 2023

Background

Caregiving at a young age can have negative effects on relationships, mental health, and emotional regulation. Notably, dementia caregivers are at higher risk of experiencing social isolation due to their caregiving responsibilities (1‐3). However, there is a lack of knowledge of the experiences of young caregivers of people living with dementia (YCPLWD). Our project is the first to recognize YCPLWD as a unique population and seeks to improve their social connection, which is how individuals connect with each other, and it is comprised of multiple aspects (4) (Figure 1). Our project goals are to:

1. Describe the experiences of social connection among YCPLWD.

2. Identify barriers and facilitators to social connection.

Method

Our project applies the Toronto Translational Framework (5) (Figure 2), a patient‐centric approach to identify person‐centered needs in healthcare and co‐create innovative solutions. Qualitative data will be collected through 2‐4 focus groups, each with 6‐8 YCPLWD. Participant criteria include English‐speaking post‐secondary students (aged 18‐24 years) who have provided care to a person(s) living with dementia in the past 12 months and are currently living in the Greater Toronto and Hamilton area. Participants will be recruited using both convenience and snowball sampling. Focus groups will be audio‐recorded, transcribed verbatim, then analyzed using Braun & Clarke’s thematic analysis (6) to identify significant themes.

Result

Focus group discussions will focus on (1) experiences with and the impact of social connection, and (2) facilitators and barriers to social connection. These sessions will enable YCPLWD to co‐create knowledge with their peers and share unique insights about the social experience of caregiving. Moreover, focus group findings will be mapped onto Liougas et al.’s framework (4) to verify how YCPLWD experience and articulate different aspects of social connection, including resources, activities, and subjective feelings.

Conclusion

This project will recognize YCPLWD as a vulnerable population with unique and specific needs. Given the heterogeneity of dementia caregiving experiences, YCPLWD may face various challenges that can be further understood. Moreover, by exploring barriers and facilitators to social connection, this project will inform the development of novel resources to educate and support YCPLWD.
Evaluation of the association between circulatory markers of neuroinflammation and Alzheimer’s disease pathology
Authors: Peretti Débora Elisa , Ribaldi Federica , Boccalini Cecilia , Marizzoni Moira , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Frisoni Giovanni B , Garibotto Valentina
Published: December 2023

Background

Increasing evidence suggests that neuroinflammation and astrogliosis have a prominent role in the spread of pathology and the development of cognitive impairment in Alzheimer’s disease (AD). Circulating plasma markers of neuroinflammation, such as the glial fibrillary acid protein (GFAP), have recently become available, and early observations suggest a robust association with brain pathology. Positron emission tomography (PET) is a molecular imaging technique that allows visualisation and quantification of AD pathology in vivo. The aim of this study was to evaluate the association between GFAP and AD pathology, and its interaction with cognitive decline.

Method

121 subjects from the Geneva Memory Centre underwent amyloid and tau PET, blood collection, and mini‐mental state examination (MMSE). Amyloid uptake was calculated as centiloid whereas tau was quantified as standardised uptake value ratio. Association of centiloid and tau with GFAP was assessed using a multivariate linear regression model, corrected for age, gender, and MMSE. Mediation analysis described the mediating effect of GFAP on the association between centiloid and tau. Ninety‐four subjects had a follow‐up MMSE after at least 12 months. Linear regression was used to assess the effect of GFAP on the annual rate of change of MMSE (corrected for centiloid, global tau, age, and gender). Mediation analysis was used to test whether the relationship between rate of MMSE change and tau could be explained by a mediation of GFAP.

Result

The mean (SD) age of the participants was 72.6 (7.6) years, and 61 of 121 subjects were men. GFAP was significantly associated with increased tau, but not with centiloid. GFAP partially mediated the effect of centiloid on global tau (mediated proportion = 14%, p = 0.03). The rate of MMSE change was significantly associated with GFAP, and global tau, but not with centiloid. Moreover, GFAP partially mediated the effect between global tau SUVR and change of MMSE scores (52%, p<0.01).

Conclusion

Elevated GFAP is associated with tau. GFAP also partially explains the effect of amyloid pathology on tau accumulation and of tau pathology on subsequent cognitive decline. These results support neuroinflammation and astrogliosis as a relevant contributor to AD pathology, which can be monitored in blood.
White matter changes with cerebrovascular disease and Alzheimer’s disease pathologies
Authors: Raghavan Sheelakumari , Tian Jianqiao , Reid Robert I. , Przybelski Scott A. , Lesnick Timothy G. , Lowe Val J. , Machulda Mary M. , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Radford Jonathan Graff , Vemuri Prashanthi
Published: December 2023

Background

White matter (WM) plays an important role in cognitive function and undergoes substantial changes due to aging and increase in AD and AD related dementia (AD/ADRD) pathologies. While recent work proposed measurement of global WM changes from diffusion MRI as biomarkers for Cerebrovascular disease (CVD) such as PSMD and free water, there needs to be a better understanding of WM changes due to AD/ADRD pathologies. The goal of our recent work was to understand white matter changes with CVD and AD – common pathologies in AD/ADRD ‐ utilizing data from Mayo Clinic Study of Aging and Mayo ADRC.

Method

Using diffusion MRI (dMRI) in 718 participants from Mayo Clinic Study of Aging (mean age = 71.1 years, 56% male), we investigated relationships between commonly used dMRI measures and vascular risk as well as global amyloid PET. In a subset of 233 participants who were amyloid‐PET positive and also competed Tau‐PET (flortaucipir) from Mayo Clinic Study of Aging and Mayo ADRC, we investigated associations between regional flortaucipir SUVRs in Braak stages and regional WM changes.

Results

We found greater frontal lobe WM damage with increasing vascular risk across all dMRI measures. We previously validated the strong relationship between the genu of the corpus callosum (anterior interhemispheric connections) dMRI measurements made on antemortem scans and cerebrovascular pathology observed on postmortem tissue (Nguyen et. al. Acta Neuropathologica 2022) supporting the utility of genu of the corpus callosum dMRI measures as a potential CVD biomarker. Also, we found greater posterior WM damage with increasing amyloid burden. Among the 233 amyloid positive participants, we found spatially dependent WM degeneration associated with regional flortaucipir SUVRs in Braak stages with greater extent of posterior WM damage. Further, dMRI measurements of the WM damage provided complementary information about disease staging and progression of AD in addition to flortaucipir SUVR measurements.

Conclusions

Anterior WM measurements may be more specific to CVD and posterior WM changes are seen with increasing AD pathological burden. Our results suggest that WM changes observed with CVD and typical AD may be different and have clinical utility for differential diagnosis and disease staging.
PHysical ACtivity and Aminoacids in MCI: their role in progression towards DEmentia. Study design for “PHACADE”: a monocentric, prospective, non‐pharmacologic interventional study
Authors: Villani Emanuele Rocco , Manni Barbara , Galli Chiara , Fabbo Andrea
Published: December 2023

Background

Mild cognitive impairment (MCI) is a condition in which individuals shows overt cognitive impairment with minimal impairment of instrumental activities of daily living (IADLs). Individuals with MCI have a 10‐fold increased risk of developing dementia as compared to cognitively normal individuals. Several factors are involved into progression from MCI to dementia and sarcopenia is one of them. Hence, physical exertion is an appropriate treatment for people with MCI. But older adults should integrate physical activity with a nutritional programme. The aim of our project is to evaluate the effect of physical training alone and combined physical training and dietary intervention on MCI progression towards AD.

Method

open‐label single centre trial. It compares two cohorts of patient with MCI during a follow‐up period of 2 years: 200 participants are divided in two cohorts (50 intervention group, 150 control group, 1:3 ratio). Inclusion criteria are being > = 65 years old with a diagnosis of MCI made upt to 6 months before the enrolment. Exclusion criteria are Tinetti Scale score of > = 24, Clinical Frailty Scale (CFS) < = 5 and concomitant psychiatric disorders or chronic alcoholism. For each participant in the control group, a twice a week plan of up to 40 minutes of aerobic exertion is conducted by a technician with a degree in sports science belonging to the UOC Medicina dello Sport of AUSL Modena Physical activity programme lasts two months and is scheduled at month 4, and then rescheduled at month 10, month 16 and month 21. In addition to the same twice‐a‐week physical activity exertion plan scheduled for the control group, a supplementation of essential amino acids pharmacological preparation, according to WHO daily ratio is furnished for participants in the intervention group. The main endpoint is to evaluate the efficacy, in terms of incidence rate ratio of developing an overt AD over a 24‐months period.

Result

currently, the project has been approved by the ethic committe (AOU 0026789/22)) and the enrolment is ongoing.

Conclusion

this study will provide more evidence about the efficacy and the feasibility of integrated physical exertion and nutrition programme in MCI population.
Clinical correlates of psychotropic therapy use in early‐onset Alzheimer’s disease ‐ experiences from the Serbian Centre for Memory Disorders
Authors: Stojmenovic Gorana Mandic , Stojkovic Tanja , Stefanova Elka , Obradovic Dragan , Šarčević Maksim , Kostic Vladimir S
Published: December 2023

Background

Early‐onset dementia (EOD) is conventionally considered to include patients with disease onset before 65 years of age, with Alzheimer’s disease (AD) being the most common form of EOD. Our aim was to investigate the clinical correlates of psychotropic therapy use in early onset AD (EOAD).

Method

This observational retrospective study included 135 consecutive EOAD patients who were diagnosed according to current criteria from April 1, 2012. until April 1, 2017. year at the Neurology Clinic, University Clinical Centre of Serbia. Neuropsychiatric symptoms were assessed using Neuropsychiatric inventory, Hamilton scale for depression and anxiety, and apathy scale.

Result

The frequency of psychotropic therapy use in our EOAD group was high with 85.18% patients receiving these drugs. Patients often received combinations of psychotropic drugs, 40% of patients received two psychotropic drugs (the most common was a combination of antidepressants and benzodiazepines). Clinical correlates of benzodiazepine administration in our group were agitation, irritability and anxiety. Antipsychotics use correlated with hallucinations, anxiety, irritability and sleep disorders. Psychotropic therapy was not associated with faster cognitive deterioration in EOAD patients, while more frequent functional deterioration correlated with the use of antipsychotics. The use of antipsychotics in patients with EOAD was not associated with serious side effects and reduced life expectancy.

Conclusion

The frequency of psychotropic therapy use in our EOAD group was high. Psychotropic therapy was not associated with faster cognitive deterioration, serious side effects and reduced life expectancy in our EOAD patients.
An Integrated Approach to Dementia Support: Sage House
Authors: King Rachel , Surrell Isabelle , Sharpe Benjamin , Pereira Antonina
Published: December 2023

The rising prevalence of dementia, economic costs and growing demand on secondary care services has highlighted the need to start evaluating how we support individuals with dementia and their care givers (Wittenberg et al., 2019). In 2016 the World Alzheimer’s report recommended a shift to post‐diagnostic support services being based in primary and community led care (Prince et al., 2016). As outlined in the WHO global action plan these services need to be accessible, integrated and comprehensive, empowering people with dementia to live in the community for longer (World Health Organisation, 2017).

A model of support that meets this directive is an Integrated Dementia Support Approach (IDSA), exemplified by a centre called Sage House. Sage House is an integrated hub for dementia support, offering a range of services for individuals with dementia and caregivers that spans across the dementia journey from diagnosis to day care. This provision includes access to assessment, information, cognitive and social enrichment, and care services in one carefully designed setting.

In order to gain a better understanding of the potential of IDSA, a series of research projects were co‐designed with Dementia Support as part of their National Ambition Programme. Three research projects were developed to examine the impact of this integrated approach on outcomes such as wellbeing, quality of life and health economics. The first of these studies is a mixed‐method exploratory service evaluation, that combines survey and interview methods to understand the lived experience of attending Sage House for individuals with dementia and caregivers.

Overall, the integrated approach was rated highly, with participants highlighting how the approach was practical and helped to reduce stress. This included reducing the load related to locating services and optimising time by being able to access multiple services in the same visit. Moreover, the continuity helped to facilitate the development of friendships and a sense of familiarity and safety. The evaluation also gave insight into how this innovative approach can impact well‐being, quality of life and engagement with health and social care services. Findings are discussed in light of the potential of this impactful integrated approach to Dementia care.