bluuebunny/crossref_metadata_2025 huggingface dataset:
Automated Brain Volumetry Analysis for Differential Diagnosis of Frontotemporal Dementia Subtypes
Authors: Cho Hyeonwoo , Park Mina , Lee Seung Hyun , Jung Wooseok , Kim Dong‐Hee , Kim Jinyoung , Lee Yeha ,   for the Frontotemporal Lobar Degeneration Neuroimaging Initiative*
Published: January 2025

Background

Clinical diagnosis of frontotemporal dementia (FTD) can be challenging, requiring an accurate tool dedicated to this diagnostic hurdle. Since FTD exhibits distinct regional atrophy patterns on magnetic resonance imaging (MRI), AI‐aided automated brain volume analysis could enhance the clinical diagnostic assessment of FTD, including the detection of the disease and the classification of subtypes, which encompass behavioral variant (BV), semantic variant (SV), and progressive non‐fluent aphasia (PNFA). In this study, we leverage automated brain volumetry software to approach both FTD detection and the differential diagnosis among its subtypes.

Method

A total 258 patients with FTD (BV = 57, SV = 40, PNFA = 34) and 127 Normal Control (NC) were identified from the frontotemporal lobar degeneration neuroimaging initiative (NIFD) data sets with available MRI. We obtained 104 areas of patient’s normalized regional brain volumes using VUNO‐Med DeepBrain. Comparative analyses were conducted to explore differences in regional volume distribution between FTD and NC, as well as among FTD subtype based on their known atrophy patterns. Additionally, regional normative percentiles were utilized as features for classification using the XGBoost algorithm to distinguish FTD vs NC, BV vs SV vs PNFA, and BV vs SV vs PNFA vs NC.

Result

In BV, significant differences in atrophy patterns were observed in the frontal lobe, demonstrating an anterior‐posterior gradient compared to SV, PNFA and NC (P<0.01). SV exhibited left side dominant asymmetric atrophy, particularly in the inferior temporal lobe, compared to BV, PNFA, and NC (P<0.01). Additionally, the inferior horn of the lateral ventricle in SV had higher volume than other subtypes, attributable to atrophy of surrounding brain regions. In contrast, the differences in atrophy patterns for PNFA were statistically less significant when compared to other FTD subtypes. Automated brain volumetry software‐based classifications demonstrated high accuracy of FTD vs NC (Accuracy 95% CI = [0.88, 0.89]), BV vs SV vs PNFA ([0.79, 0.81]), and BV vs SV vs PNFA vs NC ([0.82, 0.83]).

Conclusion

Our study demonstrates the effectiveness of automated brain volumetry and machine learning in identifying FTD and differentiating frontotemporal dementia subtypes, contributing to an enhanced understanding of subtypes and improved diagnostic precision in neurodegenerative disorders.
Tau Aggregates in Cerebrospinal Fluid: A Promising Biomarker for Neurodegenerative Diseases
Authors: Islam Md Tohidul , Karikari Thomas K , Blennow Kaj
Published: January 2025

Background

This research introduces a novel method for quantifying aggregated tau in body fluids, specifically cerebrospinal fluid (CSF), aiming to enhance the diagnosis and monitoring of neurodegenerative diseases, with a focus on Alzheimer's disease (AD).

Method

By combining tau protein amplification with a highly sensitive single‐molecule array (Simoa) immunoassay using an anti‐tau antibody CT19.1 in a homogenous manner, the approach enables precise measurements of tau aggregates in CSF.

Result

Preliminary testing involved 40 CSF samples from AD and non‐AD individuals, treated with a recombinant tau amplifier that we innovated in our research facility and subjected to an extended incubation period. Without amplification, the immunoassay showed baseline signals. However, after amplification, the technique not only elevated signals to a detectable range but also differentiated AD CSF from non‐AD samples.

Conclusion

Our methodology integrates tau amplification with a remarkably sensitive immunoassay detection system, allowing for precise quantification of tau aggregates in CSF. The approach is to adapt into the assay for plasma and serum samples. This expansion of the method's applicability has the potential to revolutionize non‐invasive diagnostic tools for neurodegenerative diseases. This innovation opens a possibility to facilitate the tracking of disease progression and the assessment of treatment responses, thereby making significant contributions to the advancement of clinical research and therapeutic trials. Another important aspect of this approach is the use of the assay antibody CT19.1 which is generated in our facility. This antibody binds to the pathologically significant MTBR region, which is considered the core region that facilitates tau aggregation, which indicates a possibility to explore further as therapeutic intervention.
Associations of load and progression of imaging markers of microvascular lesions and neurodegeneration with odor identification decline: a population‐based study
Authors: Oltra Javier , Kalpouzos Grégoria , Ekström Ingrid , Larsson Maria , Qiu Chengxuan , Laukka Erika J
Published: January 2025

Background

Olfactory deficits are predictive of cognitive decline and dementia. Previous studies have linked brain magnetic resonance imaging markers of neurodegeneration to olfactory deficits in aging; however, these studies analyzed cross‐sectional data for markers, olfaction, or both. Furthermore, potential cerebrovascular contributions to understanding why olfactory deficits predict dementia remain unexplored. We aimed to examine whether markers of microvascular lesions and neurodegeneration and their progression are associated with the rate of olfactory decline in community‐dwelling older adults.

Method

Participants were 405 individuals (mean age=70.2 years; 60% females) from the Swedish National study on Aging and Care in Kungsholmen (SNAC‐K) who were free from dementia at baseline. We analyzed microvascular lesions (presence of lacunes, white matter hyperintensities volume, global perivascular spaces [PVS] count) and neurodegeneration (lateral ventricular, hippocampal, and total gray matter volumes) markers, available up to 6 years and an olfactory measure (Sniffin’ Sticks odor identification task), available up to 15 years. Additionally, we assessed summary scores for microvascular lesions and neurodegeneration load (range 0–3), accounting for all markers of each category (1 point for its presence or for being in the worst quartile, as appropriate). Data were analyzed with linear mixed‐effects models.

Result

After adjustment for sociodemographic (age, sex, and education) and extra covariates (smoking status and semantic memory), a higher global PVS count (β =‐0.041; 95% CI, ‐0.077 to ‐0.005) and a high load (≥2 points) of neurodegeneration (β=‐0.112; 95% CI, ‐0.221 to ‐0.002) at baseline were associated with a faster olfactory decline. Longitudinally (n=228), faster accumulation of PVS (β=‐1.812; 95% CI, ‐3.474 to ‐0.150), faster hippocampal atrophy (β=1.348; 95% CI, 0.413 to 2.283), and an increment from low (≤1 point) to high load for microvascular lesions (β=‐0.167; 95% CI, ‐0.327 to ‐0.007) and neurodegeneration (β=‐0.206; 95% CI, ‐0.321 to ‐0.092) were associated with an accelerated olfactory decline.

Conclusion

Both microvascular lesions and neurodegeneration are longitudinally associated with olfactory decline in aging. This relationship supports the notion that olfactory deficits could be valuable as an early marker for dementia. More longitudinal studies are needed to untangle the mechanisms in play between cerebral vascular burden, atrophy, and olfaction.
Urine BMP is lowered in frontotemporal dementia due to progranulin mutations
Authors: Tucker Katie , Swift Imogen J , Goldsmith Sophie E , Esteve Aitana Sogorb , Rohrer Jonathan D.
Published: January 2025

Background

GRN mutations are a common cause of frontotemporal dementia (FTD), with previous studies linking granulin deficiency to reduced bis(monoacylglycerol)phosphate (BMP) levels, which ultimately impairs ganglioside degradation. BMP is involved in the lysosomal functions within cells, as it facilitates the adhesion of hydrolases and activator proteins where the lysosomal membranes meet, therefore a lack of BMP could impact lysosome function and integrity. We hypothesised that urine levels of BMP isoforms will be lower in FTD patients with GRN haploinsufficiency, as a reflection of reduced BMP in neural tissues, when compared to those with FTD caused by C9orf72 expansions and MAPT mutations, or healthy controls. The objective of this study was to investigate changes to urinary phospholipids as potential biomarkers of GRN mutations in FTD.

Method

A panel of 3 different di‐22:6 BMP, and 3 di‐18:1 BMP isoforms, as well as total di‐22:6 and di‐18:1 BMP, were measured in urine collected from the UCL GENFI cohort consisting of 36 controls, 11 symptomatic GRN mutation carriers, 11 symptomatic C9orf72 carriers and 12 symptomatic MAPT mutation carriers. A mass spectrometric method was used to quantitate molecular species of BMPs in urine, with results normalised to creatinine. Data analysis was performed in Stata, using an age and sex‐adjusted bootstrapped regression to compare the different symptomatic groups to the controls, with P<0.05 considered statistically significant.

Result

GRN mutation carriers showed reduced levels of the 2:2 di‐22:6 BMP isoform (mean=11.9 (standard deviation=7.5)) when compared to controls (17.9 (13.5); p=0.015), with a trend for reduced levels of the 2:2 di‐18:1 BMP isoform also (3.5 (2.1)) for GRN mutation carriers compared with (4.6 (4.2)) for controls, consistent with the idea that mutations in GRN lower levels of BMP. Concentrations of the 2:3 and 3:3 isoforms as well as the total amount were not significantly different between control and mutation groups.

Conclusion

Our results indicate that GRN mutations cause a reduction in the levels of certain isoforms of BMP in urine. Future studies will be helpful to see if urinary BMP concentrations increase with treatments that restore progranulin levels.
Potentially inappropriate medication use among older adults with cognitive impairment and dementia attending primary care‐based memory clinics
Authors: Sharma Rishabh , Lee Linda , Chang Feng , Patel Tejal
Published: January 2025

Background

The use of potentially inappropriate medications (PIMs) in older adults with dementia and/or Mild Cognitive Impairment (MCI) has been associated with increased adverse events, drug‐related problems (DRPs), prolonged hospitalization, risk of falls, and increased length of stay. This study aimed to identify which explicit tool, Beers criteria 2023 or Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) 2023, identifies more PIM use among older adults with MCI or dementia.

Methods

A cross‐sectional study was conducted at a Multispecialty Interprofessional Team‐based (MINT) memory clinic. Patients with MCI or dementia were recruited between Jan and August 2023. Patient medical records were reviewed for PIMs using Beers Criteria 2023 and STOPP criteria 2023. Bivariate logistic regression analysis was employed to identify potential factors associated with the use of PIMs.

Results

Overall, 44 participants were enrolled in the study, with a mean age of 80.2± 6.2 years. Among 44 patients, 36.4% (n = 16) patients had MCI, followed by one‐fifth of patients (n = 9) who had mixed dementia and 11.4% (n = 5) with vascular cognitive impairment. At least one PIM was identified in 47.7% (n = 21) and 27.2% (n = 12) of the study participants based on Beers' and STOPP’s criteria, respectively. Using the Beers criteria, 50 PIMs were found, with an average of 0.9 PIMs for each patient, while a total of 31 PIMs were identified using the STOPP criteria, with an average of 0.6 PIMs per patient. There was a significant association between ≥ 9 number of comorbidities and PIMs as per Beers criteria (OR = 8.4, 95% Confidence interval: 1.27‐ 55.39, P = 0.027). However, no statistically significant association was observed with PIMs as per STOPP criteria.

Conclusion

The frequency of PIMs identified using Beers and STOPP criteria highlights the importance of identifying and addressing PIMs in this population. This study adds valuable insights to the progressing comprehension of medication‐related complexities in older adults living with MCI or dementia.
Clinical Profile of AXS‐05 in Treating Alzheimer’s Disease Agitation: Results from the Phase 2/3 Development Program
Authors: Cummings Jeffrey L. , Grossberg George T , Streicher Caroline , Tabuteau Herriot
Published: January 2025

Background

Patients with Alzheimer’s disease (AD) often experience burdensome neuropsychiatric symptoms, including agitation which occurs in both home and long‐term care (LTC) facilities, and is associated with substantial increases in caregiver burden and LTC placements. AXS‐05 (45‐mg dextromethorphan/105‐mg bupropion), a novel, oral NMDA receptor antagonist and sigma‐1 receptor agonist, approved by the FDA for major depressive disorder, is being investigated for treatment of AD agitation (ADA). AXS‐05 has been evaluated in 2 randomized, double‐blind studies: Phase 2 ADVANCE‐1 (NCT03226522); Phase 3 ACCORD (NCT04797715).

Method

ADVANCE‐1/ACCORD enrolled patients (65‐90 y) with a diagnosis of probable AD using 2011 NIA‐AA diagnostic criteria. ADVANCE‐1 evaluated the acute effects of AXS‐05 on improving ADA. Patients were randomized 1:1:1 for 5 weeks (AXS‐05 or bupropion [105‐mg] or matching placebo). Primary endpoint: change from baseline in the Cohen‐Mansfield Agitation Inventory (CMAI) total score. ACCORD evaluated the effects of AXS‐05 in preventing ADA relapse using a randomized discontinuation design; it comprised an open‐label period (OLP; ≤9 weeks) until response was sustained (≥4 consecutive weeks). In the double‐blind period (DBP), patients were randomized 1:1 (AXS‐05/placebo) for up to 26 weeks in the DBP or until relapse. Primary endpoint: time‐to‐relapse.

Result

ADVANCE‐1 comprised 357 patients in the modified intent‐to‐treat population: AXS‐05 (n = 152) bupropion (n = 49), placebo (n = 156) (mean baseline CMAI total scores = 60.7, 66.1, 59.4, respectively). At Week 5, AXS‐05 significantly reduced CMAI total score by 15.4 points vs bupropion (10.0 points; P<.001) and placebo (11.5 points; P = .010). In ADVANCE‐1, common adverse events (AEs; ≥3%) included somnolence (8.2%), dizziness (6.3%), and diarrhea (4.4%). ACCORD comprised 178 patients in the OLP (mean CMAI = 70.9) and 108 patients in the DBP (AXS‐05, n = 53; placebo, n = 55) (mean CMAI = 43.7). AXS‐05 increased time‐to‐relapse vs placebo (hazard ratio = 0.275; P = .014). AXS‐05 was associated with lower relapse rates vs placebo (7.5% vs 25.9%; P<.05). In ACCORD, common AEs (≥3%) included dizziness (9.6%), diarrhea (4.5%), and fall (5.1%). AXS‐05 was not associated with cognitive impairment or sedation in either study.

Conclusion

AXS‐05 demonstrated a substantial, rapid reduction in ADA vs controls after 5 weeks of treatment, increased time‐to‐relapse vs placebo, and was well‐tolerated, supporting its development as a promising treatment option for ADA.
Longitudinal cognitive trajectories in ADAD: The relationship with glucose metabolism [18F]FDG PET
Authors: Zapater‐Fajari Mariola , Luckett Emma S. , Chiotis Konstantinos , Bucci Marco , Wall Anders , Almkvist Ove , Rodriguez‐Vieitez Elena , Graff Caroline , Nordberg Agneta K
Published: January 2025

Background

[18F]FDG PET is essential since it allows us to differentiate between different dementia disorders/types, revealing distinct neurodegenerative patterns in those predisposed to the condition. Individuals with Autosomal Dominant Alzheimer's Disease (ADAD) have a predictable age of onset, enabling the study of cognitive and pathological changes before clinical manifestation. Our objective was to investigate temporal course and regional links between cognition and glucose metabolism as a measure of early synaptic impairment in ADAD.

Method

Forty‐five participants were included in the present study: 26 non‐carriers, and 19 mutation‐carriers (11 APP and 8 PSEN1) who had up to 5 measurements of [18F]FDG PET and neuropsychological testing within a time interval of 7.2±6.4 years. Expected years to symptom onset (EYO) in mutation‐carriers ranged from ‐25.8 to 10.3 years. Nine cognitive tests, emphasizing Episodic Memory (EM: learning and delayed recall of the Rey Auditory Verbal Learning and delayed recall of the Rey‐Ostetriech Complex Figure) and Executive Function/attention (EF/A: Digit Symbol, Rey Copy, Trail Making Test A and B, Digit Span Forward and Backward), were z‐scored using non‐mutation carriers as the reference group. Mixed‐effects models were used to identify the differential effect of mutation status on the longitudinal trajectories of cognition or [18F]FDG. We also assessed whether the interaction of [18F]FDG with mutation status could predict cognitive decline.

Result

Compared to non‐carriers, all cognitive tests significantly declined across EYO in carriers (all p<0.01), except Digit Span Backward (p=0.19). Notably, some EF/A and all EM tests showed decline 15‐10 years before EYO in carriers (Figure 1A‐E). [18F]FDG levels started to decline in Temporal, Parietal and Posterior Cingulate regions around 10‐5 years before EYO, with significantly steeper slopes detected for carriers vs non‐carriers (all p<0.007) (Figure 1F‐H). Steeper [18F]FDG regional decline patterns were found to predict steeper decline over EYO in most cognitive tests in carriers compared to non‐carriers (Table 1).

Conclusion

Our results link cognitive decline to [18F]FDG hypometabolism in several brain regions. Specific tests of EF and EM may detect early synaptic impairment due to their close relationship with [18F]FDG decline. This longitudinal study shed light on early changes in cognitive domains in ADAD individuals, offering insights into AD progression.
Expectation and perspectives of patients and physicians on new treatment for early Alzheimer Disease: Results of a physician survey and patient focus group interview
Authors: Bell Joanne , Kurzman H. Ricky , Borentain Stephane , Paulsen Russ , Holzapfel Andrew , Hampel Harald
Published: January 2025

Background

With the recent approval of disease modifying therapies (DMT) for early Alzheimer’s disease, there is a need for prescribing physicians to accurately communicate expectations of treatment effects to patients and their care partners. To better understand potential challenges and solutions to enhance this communication, physicians were surveyed, after which patients and care partners participated in focus groups.

Method

Step one consisted of an online survey of 100 US‐based neurologists, geriatric medicine specialists and Alzheimer’s disease specialists to ascertain physician perspectives on meaningful benefits associated with anti‐amyloid monoclonal antibody treatment (DMT) over currently available symptomatic treatments. Informed by the physician survey findings, six focus groups collected qualitative narratives from patients and their care partner(s). The objectives were to explore patient and care partner treatment goals, their experience with symptomatic treatment and their expectations for new therapies.

Results

Physicians reported that the main concerns for patients and their care partner are memory loss (84%) behavioral and mood changes (51%) and ability to complete daily activities (51%). Most physicians expected a DMT to be effective in slowing the disease progression, and 66% expected to see cumulative benefit over time with continued treatment. Physicians reported that being able to perform activities of daily living (84%), maintaining quality of life (79%) and remaining independent (77%) are the most meaningful treatment outcomes for patients. Physician expectations were largely similar between symptomatic treatment and DMT. During the focus groups, patients and care partners noted the impact on financial status, social interaction, and loss of independence to be the three major areas of concern associated with their diagnosis. Focus group participants noted that maintaining their current state longer is a meaningful treatment outcome and prioritized three domains: effective communication, thinking clearly and less fear while performing daily activities.

Conclusion

This research suggests the need for a better physician/patients‐care partner communication on appropriate treatment expectations and for the development of tools to facilitate this communication. Findings from this research need to be confirmed by a large survey of a nationally representative sample of US patients.
Spatial and sex‐specific hippocampal proteomic analysis of an early Alzheimer’s disease mouse model using MALDI‐imaging
Authors: Contreras Ana , Jimenez‐Herrera Raquel , Djebari Souhail , Mulero‐Franco Jaime , Navarro‐López Juan D. , Jimenez‐Diaz Lydia
Published: January 2025

Background

A key neuropathological feature in the early stages of Alzheimer's disease (AD) involves hippocampal dysfunction arising from the accumulation of amyloid‐β (Aβ). Previously, our laboratory identified a shift in the synaptic plasticity long term potentiation (LTP)/long term depression (LTD) induction threshold, leading to memory deficits in a non‐transgenic murine model of early AD generated by intracerebroventricular (icv.) injections Aβ1‐42 oligomers (oAβ1‐42), one of the most predominant pathogenetic factors in initial stages of the disease. However, the specific alterations in proteins within hippocampal subfields remain uninvestigated. Here, we hypothesized that there might be unique protein changes in the hippocampus induced by oAβ1‐42 and potentially influenced by sex‐dependent factors.

Method

To do so, we evaluated hippocampal‐dependent memory using a Barnes maze and the Object location memory test (OLM) in the non‐transgenic model of early AD. Both memory encoding and retrieval deficits were shown 1 hour post‐icv. injection, although no significant sex differences were found. Then, an innovative spatial proteomic study was performed to assess the hippocampal proteome using matrix‐assisted laser desorption/ionization (MALDI) imaging mass spectrometry that allows peptide detection with spatial resolution directly on tissue sections.

Result

Results from sixteen brains from C57BL/6 adult male and female mice 1 hour post‐icv. injected with oAβ1‐42 or vehicle were analyzed. MALDI imaging was performed using a RapifleXTM MALDI TissuetyperTM TOF/TOF mass spectrometer followed by protein identification by traditional MS/MS directly on the tissue. To precisely delineate anatomical hippocampal region and subfields, a Nissl staining was performed at adjacent tissue sections. More than 600 peptides were detected, and several of them showed significant differences in expression levels due to treatment or sex. To further analyze the data, the protein‐protein interaction (PPI) between the identified changed proteins was analyzed using the STRING database.

Conclusion

The specific hippocampal subfields changes in the proteome caused by early amyloidosis provide new insight in the pathogenesis of AD and valuable potential biomarkers for early diagnosis and potential therapies.

Acknowledgements: Grants PID2020‐115823‐GB100/ MCIN/AEI/10.13039/501100011033 and SBPLY/21/180501/000150/ JCCM and “ERDF A way of making Europe” both to LJ‐D and JDN‐L. Margarita Salas Postdoctoral Research Fellow to AC funded by European Union NextGenerationEU/PRTR.
Implementation of Digital Cognitive Assessment for Early Detection of Cognitive Impairment: A Davos Alzheimer’s Collaborative Flagship Site
Authors: Kowa Hisatomo , Morimoto Kohei
Published: January 2025

Background

In Japan, the number of patients with dementia is increasing and there is a shortage of human resources who can conduct detailed psychological examinations, and the development and implementation of new tools is essential for improving dementia care. Japan is one of seven sites across the globe focusing on healthcare system preparedness as part of the Davos Alzheimer’s Collaborative Early Detection flagship program. As part of this program, Japan implemented new tools including a digital cognitive assessment (DCA) and blood‐based biomarker (BBM) to increase rates of early detection of cognitive impairment.

Methods

Patients 60+ years old were given a Mini‐Mental State Examination (MMSE), a common pen‐and‐paper test of cognitive function, and based on the score, primary care providers recorded a pre‐referral diagnosis. Patients who scored abnormal or borderline on the MMSE were then referred to a specialist center and completed a full work‐up including a clinical and psychological examination, a DCA (Cogstate Cognigram), blood test for reversible causes, imaging (i.e., MRI, perfusion SPECT), and a BBM (C2N PrecivityAD). Based on the results from the full clinical work‐up, the specialist provided a post‐referral diagnosis.

Results

In the early detection program, the MMSE detected 46 total patients with cognitive impairment (MMSE scores ≥10 and <28), with 33 (72%) cognitively abnormal and 13 (28%) borderline scores. The number and type of pre‐referral diagnostic assessment made based on the MMSE scores and from the post‐referral diagnosis following the full clinical work‐up are provided in Table 1. There was good agreement between the initial and final diagnosis, with 8 total changes in diagnosis. The most notable changes came in the Alzheimer Disease diagnosis category where there was a net increase in 4 diagnoses of AD (2 were reversed and 6 new diagnoses of AD were added).

Conclusion

Comprehensive assessments, including implementing new tools like a DCA and BBM, along with traditional clinical examination are necessary to make an accurate diagnosis. Initial findings from the Japan flagship site contribute to the global learnings to help speed and scale future innovations and developments in order to reach the right patients at the right time.
Presymptomatic Detection and Monitoring of Alzheimer’s Disease Using a Multi‐Disease Diagnostic Platform Employing Autoantibodies as Blood‐based Biomarkers
Authors: DeMarshall Cassandra , Viviano Jeffrey , Sahin Mert , Nagele Robert ,   the Parkinson’s Study Group (PSG), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2025

Background

It is well known that Alzheimer’s disease (AD)‐related pathological changes can begin up to a decade before patients experience telltale symptoms, yet presymptomatic detection remains an unmet goal. In the present study, we demonstrate the utility of a panel of autoantibodies capable of detecting AD‐related pathological processes at the earliest points along the AD continuum, including presymptomatic AD (up to 10 years before onset of symptoms) and prodromal AD (mild cognitive impairment, MCI).

Method

Utilizing Duritect‐ADTM, a blood‐based test employing a customized panel of autoantibody biomarkers and Luminex xMAP® technology, sera from ADNI subjects with confirmed presymptomatic or prodromal AD (MCI) were screened to detect the presence of AD‐related pathology. Autoantibodies in this panel showing consistently increased titers in MCI and presymptomatic AD relative to controls were evaluated using Random Forest and Receiver Operating Characteristic curves for their ability to distinguish diseased subjects from age‐ and sex‐matched controls, as well as from individuals with other neurodegenerative and non‐neurodegenerative diseases.

Result

Here, we present results from analytical validation of the Duritect‐ADTM Test. Previous published results showed that a panel composed of eight autoantibody biomarkers differentiated ADNI participants with confirmed prodromal AD from corresponding age‐ and sex‐matched controls with 96% accuracy, 92% specificity and 100% sensitivity. These same autoantibody biomarkers were also capable of identifying cognitively normal subjects who later converted to MCI or AD, years before the onset of symptoms.

Conclusion

Results demonstrate the utility of the Duritect‐ADTM blood‐based autoantibody test as an accurate, non‐invasive, and inexpensive diagnostic screener, not only for detection of early, AD‐related pathology associated with prodromal AD (MCI), but also at earlier presymptomatic disease stages, several years before the onset of clinical symptoms.
Effect of diagnostic and genetic status on the relationship between rs‐fMRI complexity and tau & amyloid PET in Alzheimer’s disease
Authors: Jann Kay , Cen Steven , Santos Mariella I , Wijesinghe Dilmini , Zhang Ru , Ringman John M , Wang Danny JJ
Published: January 2025

Background

Non‐linear statistical analyses on resting‐state fMRI (rs‐fMRI) using complexity measures have demonstrated progressive decline in complexity from cognitively normal subjects (CN) to patients with Mild Cognitive Impairment (MCI) and patients with Alzheimer’s disease (AD). While complexity has been shown to be negatively associated with tau‐PET, the association with amyloid or effects of genetic characteristics (APOE4) remains unknown.

Method

From the Alzheimer’s Disease Neuroimaging Initiative (ADNI3) we identified participants with tabulated SUVR values for amyloid and tau as well as one resting state fMRI scan for the same visit. The rs‐fMRI complexity was calculated as Multiscale Sample Entropy (MSE) (r=0.5, m=2, scale=6). SUVR values from precuneus, parahippocampal, inferior temporal and entorhinal regions were used in a multivariate generalized linear model to investigate the adjusted independent effects to corresponding rs‐fMRI complexity. Whether such effects were modified by either diagnosis (CN, MCI, AD) or APOE4 status (# alleles) were tested using the interaction terms in the multivariate model. Age and gender were controlled for all models.

Result

The final cohort consisted of 127 subjects (Table 1). We observed statistically significant negative associations between complexity and tau in parahippocampus, inferior temporal gyrus and precuneus (Table 2A). Diagnostic status does not modify these associations, however, APOE4 status showed a statistically significant interaction effect for tau and complexity in precuneus (Table 2C). For amyloid no associations nor interaction effects were found (Table 2B).

Conclusion

Our study confirmed previously reported statistically significant inverse relationship between rs‐fMRI complexity and tau‐PET, which is indicative of disfunction of neuronal signaling in the presence of tauopathy. While diagnostic classification showed no effects, the APOE4 genetic risk had a strong modifying effect leading to a stronger negative relationship between tau‐PET and fMRI‐complexity. The null‐finding for amyloid was expected, since, while the presence of amyloid increases risk for cognitive decline, it is the occurrence of tau that leads to cognitive decline and neurodegeneration. Overall, genetic risk potentially increases the prevalence of amyloid in this cohort and consequentially leads to a cumulative and more pronounced decrease in rs‐fMRI complexity in the presence of tau.
TTR cardiac amyloidosis, polyneuropathy, and dementia at old age – bystander, cause or “smoking gun” guilty by association
Authors: Petrea Rodica Elena , Turk Katherine W. , Knobel Mark D , Charidimou Andreas , Budson Andrew E.
Published: January 2025

Background

Mixed dementia type – Alzheimer’s Disease (AD), cerebral amyloid angiopathy (CAA), and vascular ‐ is vastly recognized as a cause of dementia in older adults. Whereas CAA, primarily leptomeningeal, is a frequent complication in hereditary transthyretin cardiac amyloidosis (TTRCA), it is unusually reported in association with wild‐type TTR, with or without polyneuropathy. The knowledge of mixed dementia and wild‐type TTR association is even scarcer.

Methods

Case Report. 81‐year‐old, Right‐handed man, with a 5‐year history of diagnosed wild‐type TTRCA and polyneuropathy, treated with Tafamidis, vascular risk factors, and remote history of benign head injuries, was seen in our Memory Disorders Clinic for evaluation of moderate dementia. MOCA score was 7/30 on the day of evaluation.

Results

Our patient had 2 brain MRIs over 5‐year follow‐up. The first MRI was performed at initial memory complaints of mild cognitive impairment (MCI) concurrent with the diagnosis of cardiac amyloidosis and polyneuropathy. A second brain MRI was performed during prolonged transient neurological deficit ‐ aphasia with prominent word‐finding difficulties – accompanying delirium following septic knee arthritis surgery. The second MRI revealed foci of susceptibility weighted imaging (swi) artifact in line with superficial cerebral hemosiderosis in the left frontal lobe, and within the bilateral thalami, all new from the first MRI, which only revealed one focus of right periventricular white matter SWI microhemorrhage and moderate confluent white matter hyperintensities, more prominent in the left frontal and parietal lobes, progressed on the second MRI. The cognitive impairment (MCI to moderate dementia) and supporting MRI brain imaging evolved over 5 years and we indicate contributory components of probable CAA, vascular, and AD pathology.

Conclusions

We report a rare association between probable AD, CAA, and vascular dementia, in a patient diagnosed with wild‐type TTRCA and polyneuropathy. We aim to increase awareness of dementia following the cardiac onset of wild TTRCA, possibly similar to the hereditary TTRCA. We inquire about the fortuitous or causative association of mixed dementia type and wild TTRCA, with or without polyneuropathy. We propose to study the intricately mixed etiology of cognitive impairment and its relationship to AD in wild TTRCA through a national registry.
Longitudinal Change in Proper Names from Logical Memory Tasks are Sensitive to Plasma pTau217 Levels
Authors: Basche Kristin E , Langhough Rebecca E. , Jonaitis Erin M. , Du Lianlian , Bruno Davide , Wilson Rachael E , Hermann Bruce P , Johnson Sterling C. , Mueller Kimberly D
Published: January 2025

Background

Previous studies have found connections between recall of proper names (PN) and amyloid positivity in cognitively unimpaired (CU) adults at risk for Alzheimer’s Disease (AD; Mueller et al., 2020). Given the promising prospect of employing plasma‐based biomarkers to determine amyloid burden, we looked at associations between longitudinal change in PN and total score recall from Logical Memory (LM) story recall test and plasma pTau217.

Method

Participants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) study, who were CU at baseline LM visit; had item‐level, longitudinal LM and plasma pTau217 data from a recent blood draw (n=412; EDTA plasma samples analyzed using the ALZpath pTau217 Simoa assay on a Quanterix HD‐X). Linear‐mixed effects models were utilized to examine whether the last available plasma pTau217 measure moderated retrospective age (centered at mean=63) trajectories associated with LM Total Score and PN subscores; pTau217 interactions with quadratic age were removed if they were non‐significant. Models included a person‐level random intercept term, sex, practice effects, and WRAT‐III reading standard scores as covariates.

Results

Sample characteristics overall and by last observed plasma pTau217 category (Ashton et al, 2023 pre‐print) are shown in Table 1. The sample was mostly female (n=278, 67.5%), and white (n=393, 95.4%), with an average age of 58 (sd=6.44) at baseline visit. The interaction term of pTau217 was significant for all of the models for linear age (Table 2, β ranging from ‐0.50 through ‐0.08, p<0.001); the interaction of pTau217 was also significant for quadratic age in the PN delayed subscore (β=‐0.00, p=0.010) and the LM delayed total score (β=‐0.01, p=0.031).

Conclusion

Change in LM total and PN subscores are sensitive to amyloid burden via plasma pTau217. Participants with high levels of pTau217 performed more poorly over time than those with intermediate or low levels (Figure 1). Despite being limited to only nine items on LM tasks, PN subscores continue to demonstrate their strength as a potential indicator of amyloid accumulation as measured by a quick and lower‐burden blood test.
Deep Learning based Automated Segmentation of Hippocampus and Hippocampal Subfields from Postmortem MRI
Authors: Nirmala Anoop Benet , Li Karl , Rashid Tanweer , Honnorat Nicolas , Wang Di , Li Jinqi , Fadaee Elyas , Charisis Sokratis , Walker Jamie M. , Richardson Timothy E. , Wolk David A , Fox Peter T , Bieniek Kevin F. , Seshadri Sudha , Wisse Laura E.M. , Habes Mohamad
Published: January 2025

Background

The hippocampus and its subfields in the human brain play a pivotal role in forming new memories and spatial navigation. The automated assessment of the hippocampus and its subfields are useful tools for the early diagnosis of Alzheimer's disease and other neurodegenerative diseases such as primary age‐related tauopathy, Lewy body dementia, limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), and frontotemporal lobar Dementia. Postmortem brain magnetic resonance imaging plays a crucial role in neuroscience and clinical research, providing valuable insights into the structural and pathological features of the brain after death. Postmortem MRI can be used to validate findings from in vivo imaging studies, link these findings to histopathological data. Deep learning methods such as convolutional neural networks are widely used in image segmentation. However, deep learning methods have not previously been applied to segmenting the hippocampus and its subfields (Head, Body, Tail, and Dentate Gyrus) from postmortem MRI.

Method

Double U‐Net is a convolutional neural network architecture that combines two U‐Net architectures. The U‐Net architecture is widely used for semantic segmentation tasks, particularly in medical image analysis, where it has shown success in functions such as tumor segmentation. We have trained a double U‐Net model on 15 annotated postmortem MRI scans include scans from nine females and six males, with an average age of 78 and a standard deviation of 7, which have been collected at our university brain bank (Figure 1). Before feeding the data to the model, all the data were registered, intensity normalized, and cropped to a size of 64 x 96 x 48. The model is trained with a learning rate of 0.0001s and dice loss as the objective function.

Result

The model's performance is evaluated quantitatively (Table 1) and qualitatively (Figure 2). The qualitative analysis is performed with metrics such as Dice, Precision, and Recall. In whole hippocampus segmentation, the model achieved an overall Dice score of 93.01%, and for subfield segmentation, it reached a Dice score of 87.30%.

Conclusion

Deep learning‐based segmentation of the hippocampus and its subfields can be performed on postmortem brain images and may be helpful in diagnosing Alzheimer's and other neurodegenerative diseases.
Advocate the Voice of People with Dementia ‐ Design of Dementia Care Educational Package for the Practitioners with the 16 Principles of Proper Caring Attitude (DemenTitude®) in Hong Kong
Authors: Chui Kenny Chi Man
Published: January 2025

Listening to the voices of people with dementia and understanding their perception of the surrounding world is one of the keys to providing person‐centred care in daily practice. The care not only focuses on the specific knowledge and skills but also the proper caring attitude towards dementia. Stigma is still severe in Hong Kong, and the implementation of dementia‐inclusive language is not practical due to the lack of education in this aspect. An educational package with 16 principles of proper caring attitude was designed regarding the local context and cultural adaption. Qualitative research with in‐depth interviews and participatory observations was conducted in the community care and residential care homes of Hong Kong. Following the theoretical framework blending interpretivism and the sociocultural perspective on dementia in Hong Kong, the 16 principles of proper caring attitude, called DemenTitude®, were formulated from the findings. The aims are to reduce the stigma of dementia among the caring staff and to raise awareness of dementia‐inclusive language.

The 16 principles were translated from Cantonese to English: (1) Unveiling limitless interpretations; (2) Listening more than criticise; (3) Memories fade, history endures; (4) Communication is all about interaction; (5) Trusting their feeling and perception; (6) The same stays the same; (7) Behavior speaks; (8) Beyond the matter‐of‐fact; (9) Process is the key for assessment; (10) Dignity through equality, treat as adults; (11) Meaningful engagements form life; (12) Mind your words; (13) The power of touch is better than words; (14) Person‐centred Care always as the root; (15) Quality and Quantity, both counts; (16) Care takes priority, “attitude” over “speed”. The evaluation of this educational training and care philosophy showed a significant improvement in the positive perception of dementia among the participants. Further development and promotion of “attitude” training should be needed.
Correlation analysis of ApoB, ApoA1 and ApoB/ApoA1 with cortical morphology in patients with memory complaints
Authors: Wang Jiayu , Chen Lei , Wang Ziqi , Duan Mingjun
Published: January 2025

Background

Apolipoproteins and cortical morphology are closely associated with memory complaints, and both may contribute to the development of Alzheimer’s disease.

Method

A total of 97 patients from the University of Electronic Science and Technology (UESTC) (n=42) and the Fourth People's Hospital of Chengdu (FPHC) (n=55) were grouped based on recruitment location, and underwent neuropsychological tests. ApoB, ApoA1, ApoB/ApoA1, plasma Alzheimer’s biomarker, apolipoprotein E (ApoE) genotyping, 3T magnetic resonance imaging. The CAT12 toolbox (SPM12) was performed for the calculation of each patient's cortical morphology index based on structural MRI data, and the cortical morphology index and apolipoproteins were analyzed by multiple regression analysis.

Result

Significant positive correlations were found between ApoB and sulcal depth in the lateral occipital cortex for the UESTC and total sample groups (p<0.0001). Sulcal depth in the lateral occipital cortex showed negative correlations from the Shape Trails Test Part A and B in the UESTC, the FPHC and total sample groups. In the FPHC group, the delayed recall of Auditory Verbal Learning Test, Animal Fluency Test and Boston Naming Test were positively correlated with the sulcal depth.

Conclusion

ApoB is associated with the sulcal depth in the lateral occipital cortex, potentially relating to speed/executive function in individuals with memory complaints.
Exploring the current approach to reablement for community‐dwelling people living with dementia: preliminary practitioner‐led goals and targets for practice change
Authors: O'Connor Claire , Poulos Christopher , Kurrle Susan , Anstey Kaarin J.
Published: January 2025

People living with dementia have a range of functional, physical, cognitive, and behaviour needs. Reablement (and/or ‘rehabilitation’) is an important multidisciplinary approach, such as using occupational therapy and exercise, to address each person’s needs. People with dementia in Australia are being referred to community aged care teams for everyday living support, and an evidence‐informed reablement handbook is freely available (www.hammond.com.au/reablement). Despite this, evidence‐informed reablement is still not routinely available. This project aims to explore how reablement is currently provided for people with dementia in the community, and to identify practitioner perspectives around potential goals and targets for practice change. The preliminary outcomes from this research (presented here) will feed into a broader project that seeks to understand how to implement evidence‐informed reablement for people with dementia in Australia.

To explore how reablement is currently provided for people with dementia, a retrospective file audit was conducted with two community aged care providers in New South Wales, Australia. At the time of data collection, the providers had not implemented the evidence‐informed reablement handbook into practice. Data from the clinical file notes from each provider were compared against the reablement handbook. Site‐specific outcomes were then presented back to the respective allied health teams from each provider via focus groups; through this process, practitioners identified potential goals and targets for practice change.

Data from 10 clients with cognitive impairment or dementia were included in the audit. There was partial alignment with the handbook in terms of interventions delivered (e.g. personally prescribed multicomponent exercises; provision of compensatory strategies), and some areas where discrepancies existed (e.g. very few written support plans provided to clients). Twelve allied health professionals (occupational therapy, physiotherapy, social work, dietetics) participated in the focus groups. A range of potential targets for practice change were identified, such as better tailored information for clients’ cognitive/physical functioning, and more structured functional cognition assessment.

Although some alignment with the reablement handbook existed, there was room for improvement in provision of reablement for people with dementia. Moving forward, broad consultation with a range of stakeholders is needed to determine the best implementation approach on a national scale.
Novel piperazine‐benzoquinone derivative as a possible lead molecule selectively targeting AChE for the management of dementia in Alzheimer’s disease
Authors: Silakari Pragati , Piplani Poonam , Kumar Amit , Grewal Amarjot Kaur
Published: January 2025

Background

The present study recapitulates the potency of the novel synthesized piperazine‐benzoquinone derivative as a lead molecule selectively targeting AChE along with the antioxidative potential for the management of cognitive decline in Alzheimer’s disease.

Method

Novel piperazine‐benzoquinone derivative was synthesized implementing appropriate synthetic procedures and was characterized by various spectral and elemental techniques. The purity of this synthetic analogue was ascertained by TLC, melting point determination and elemental analyses. Further, the compound was evaluated for its selective in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential at different concentrations using mice brain homogenate as the source of the enzyme. The analogue further evaluated for their antioxidant potential using DPPH radical scavenging and hydrogen peroxide radical scavenging protocols at five different concentrations and further studied against behavioural alterations using step down passive avoidance and escape learning protocol at a dose of 0.5 mg/kg with reference to the standard drug donepezil. Scopolamine at a dose level of 2.0 mg/kg was used as an inducer of dementia in the animal model. The ex vivo acetylcholinesterase (AChE) inhibition using mice brain homogenate as the source of the enzyme were also performed. Biochemical estimation of the markers of oxidative stress (lipid peroxidation, superoxide dismutase, glutathione and catalase) has also been carried out to determine the role of the synthesized molecule on the scopolamine induced oxidative damage.

Result

A synergistic effect of two structural components viz. the benzoquinone moiety and the cyclic secondary amino subunits on the inhibitory activity against AChE has been anticipated. The compound exhibited selective acetylcholinesterase activity (IC50 06.795 µM), appreciable selectivity index value (0.353) and significant antioxidant potential. The ex vivo AChE inhibition assays were also in conformity with the behavioural studies data along with the docking results showing important interactions with AChE protein (Figure 1)

Conclusion

Outcomes depicted the anti‐amnesic effect of the synthesized conjugate on scopolamine‐induced memory impairment probably related to mediation of cholinergic system and their effective antioxidant activity. Results obtained were found to be appreciable and provided promising lead which can be further explored structurally and pharmacologically, presenting a favourable scenario for the development of selective AChE inhibitors.