bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross sectional dopamine transporter imaging and myocardial sympathetic scintigraphy study in patients with dementia with Lewy bodies
Authors: Hirano Shigeki , Tang Zhihui , Koizumi Yume , Izumi Michiko , Kitayama Yoshihisa , Yamagishi Kosuke , Tamura Mitsuyoshi , Ishikawa Ai , Kashiwado Kouichi , Iimori Takashi , Mukai Hiroki , Yokota Hajime , Horikoshi Takuro , Uno Takashi , Kuwabara Satoshi
Published: January 2025

Background

Dopamine transporter (123I‐FP‐CIT) single‐photon emission tomography (SPECT) and 123I‐meta‐iodobenzylguanidine (123I‐MIBG) image play roles as indicative biomarkers in diagnosing patients with dementia with Lewy bodies (DLB). Brain‐ and body‐first subtypes of DLB were hypothesized implying that subset of DLB may have normal 123I‐FP‐CIT or 123I‐MIBG results, respectively. The purpose of this study was to explore the diagnostic sensitivity of two combination imaging modalities (123I‐FP‐CIT SPECT and 123I‐MIBG image) in patients with DLB and examine the clinical difference between brain‐ and body‐first subtype.

Method

Possible DLB patients, defined by the fourth consensus DLB criteria, who underwent both 123I‐FP‐CIT SPECT and 123I‐MIBG image was retrospectively collected. Semi‐automated software and their results were utilized to define abnormality for both scans. Demographic data, cognition, motor, and core features were compared between the brain‐first and body first DLB subgroups.

Result

Of the 114 patients with DLB, 66 underwent both scans. Mean (SD) age was 74.1 (7.1) years, male was predominant (62.1%), min‐mental state examination total score was 21.7 (4.8) and unified Parkinson’s disease rating scale motort subscore was 14.7 (4.8). Thirty‐six (54.5%) patients showed both abnormal scans and four patients (6.1%) were both normal scans. Seventeen patients (25.8%) showed abnormal 123I‐FP‐CIT result with normal 123I‐MIBG result (brain‐first DLB), nine patients (13.6%) showed normal 123I‐FP‐CIT result with abnormal 123I‐MIBG result (body‐first DLB). No clinical differences were observed between brain‐first and body‐first DLB subtypes.

Conclusion

Approximately 40% of DLB patients displayed normal result in either image. Normal results of a single imaging test may not refute the possibility of DLB.

No clinical difference was observed between brain‐ and body‐first DLB subtypes.
Exploring potential of Allopurinol in Dementia of Alzheimer’s type
Authors: Kumar Amit , Sharma Diksha , Silakari Pragati , Grewal Amarjot Kaur
Published: January 2025

Background

Dementia is a mental condition defined by a severe loss of intellectual ability that interferes with one’s occupational or social activities. The rapid increase in the number of patients with dementia and Alzheimer’s disease (AD) will result in tremendous consequences for our society and economy. Hypoxanthine is a purine compound that is implicated in the progression of AD. The conversion of hypoxanthine into uric acid by xanthine oxidase reductase (XOR) leads to the formation of superoxide species that increase oxidative stress. The aim of the present study is to investigate the protective effect of allopurinol on STZ‐induced Alzheimer’s‐type dementia.

Method

A docking study was done to evaluate the interaction of allopurinol with AChE. Once the interaction was confirmed, the study used Swiss albino mice. The test drug was administered to STZ mice for a total of 7 days (16‐22 days). Animals were subjected to the Morris Water Maze (MWM) training trials for 4 days (Days 19‐22). On the 21st and 22nd days, we performed the step‐down passive avoidance test. On the 23rd day, retrieval trials were conducted on MWM and step‐down passive avoidance, and animals were sacrificed and the whole brain extracted for biochemical and histological investigations.

Result

STZ‐induced mice showed decreased performance in MWM, stepdown‐passive avoidance, and altered biochemical and inflammatory cytokines. The histopathological study revealed severe infiltration of neutrophils and amyloid deposition. In the study, allopurinol treatment mitigated STZ‐induced cognitive decline via behavioural, biochemical, and histopathological changes.

Conclusion

The results suggest that the neuroprotective effects of allopurinol in STZ‐induced Alzheimer’s‐type dementia might be attributed to anticholinesterase, antioxidative, and anti‐inflammatory effects.
Clinical performance of the Lumipulse G NfL CSF assay in cases with AD and FTD
Authors: Agüero Pablo , Téllez Raquel , Gonzales Alicia Ruiz , Wagner Sonia , Querejeta Agustín , Mahillo Ignacio , Ruiz Andrea , Sainz María José , Cremades‐Jimeno Lucía , Sanchez‐Juan Pascual , Gómez‐Tortosa Estrella
Published: January 2025

Background

Neurofilament light chain (NfL) is a fluid biomarker of axonal damage reported to be elevated in cases with dementia, and particularly in FTD. In this study we evaluate the performance of a recently developed NfL assay to be analyzed through the Lumipulse chemiluminescent platform, which is frequently available in clinical settings for the study of AD core biomarkers.

Method

We evaluated CSF NfL levels using the Lumipulse G600II platform (Fujirebio, Iberia) in 70 cases, including 33 patients with AD (supported by CSF biomarkers consistent with an A+T+(N)+ classification scheme), 26 with confirmed FTD (typical phenotype and CSF with a A‐T‐ profile), and 11 controls. NfL was also determined in plasma samples of the same cases by single molecule array (SIMOA) with a Quanterix assay. We analyzed the correlation of NfL as measured in these two samples by the two different platforms and their value to discriminate between AD and FTD cases.

Result

NfL in CSF was higher in FTD (mean‐SD= 2417‐2326 pg/mL) than in AD cases (1144‐594, p=0.07) and controls (809‐327, p=0.03), with no differences between AD and controls. The same applied for plasma NfL with more remarkable statistical differences: FTD (mean‐SD= 37‐21) vs AD cases (19‐7, p>0.001) and vs controls (18‐7, p=0.007). There was a significant linear correlation between NfL values in CSF and plasma in all cases (Pearson R=0.84, p<0.001). By groups, the correlation was higher in FTD cases (R=0.83) and controls (R=0.89) than in AD cases (R=0.46). The best discrimination between FTD and AD cases for CSF NfL was obtained at 1671 pg/mL (AUC: 0.675, 59% sensitivity, 90.6% specificity), while levels of 1395 pg/mL obtained the best discrimination between FTD and controls (AUC: 0.777, sensitivity 64%, specificity 100%).

Conclusion

The Lumipulse NfL CSF assay could be useful in clinical settings to improve discrimination among dementia subtypes and controls. Elevated NfL CSF levels are highly specific of FTD and correlate well with plasma levels. Furthermore, NfL levels may support an underlying neurodegenerative process in cases with ambiguous phenotype and an A‐T‐(N)‐ CSF profile.
Predicting Antipsychotic Drug Doses for BPSD: A Transfer Learning Approach Using Neuroimaging Data
Authors: Yue Ling , Hong Bo , Tao Tianli , Li Xia , Xiao Shifu , Zhang Han
Published: January 2025

Background

About 50‐90% people with dementia would develop behavioral disturbances, namely, behavioral and psychological symptoms of dementia (BPSD). Antipsychotic medications are widely used to control severe BPSD symptoms which suffers serious safety risks. It is challenge for individualized precise prediction of antipsychotic drug doses. Neuroimaging, particularly MRI, reveals brain structure associated with aging, cognitive decline, and psychiatric symptoms, making it a potential tool for predicting the drug doses. This study employs transfer learning to predict drug dose and offer neuroanatomical interpretation of BPSD from the perspective of deep learning.

Method

We employed a two‐step process to train our model (Figure 1). Initially, a large dataset from the Chinese Brain Molecular and Functional Mapping (CBMFM) project (n=646, 334 females and 312males, age 18‐82) was used to pretrain the model with a brain age prediction task. Subsequently, the pretrained model was fine‐tuned for drug dose prediction from the Alzheimer's Disease and Related Disorders Center in Shanghai Jiao Tong University (ADRDC) dataset (83 BPSD patients, 27 males and 56 females, age 55‐80). Finally, we utilized gradient‐weighted class activation mapping to generate attention maps and conducted statistical analyses on the attention maps to identify critical brain regions for drug dose prediction. To determine the individual usage of different antipsychotic drugs, the concept of defined daily dose (DDD) was used. The DDD, which individualized control the BPSD, was calculated, ranging from 0 to 1.5 mg/day, serving as the label for fine‐tuning.

Result

Our pretrained Cas‐ResNet exhibited enhanced performance with fewer training epochs, achieving a competitive Pearson correlation of 0.59 between estimated and real DDD (Figure 2). Through feature interpretability analysis, we identified five significant brain regions crucial for BPSD drug dose prediction, mainly located in the temporal lobe, including the parahippocampal area and the striatum (putamen and caudate)(Figure 3). These findings indicate that the antipsychotic dosage to control the BPSD is linked to brain structural alterations, involving both dementia‐related and emotion‐regulating areas.

Conclusion

For the first time, we showed a promising result of using a lightweight deep learning model to predict drug dose prescribed for controlling BPSD. The work promotes the discussion toward appropriate use of antipsychotics in patients with dementia.
YOLOv5‐based Detection and Classification of Early and Late Mild Cognitive Impairment through Corpus Callosum Analysis
Authors: Kancharla Vamshi Krishna , Sinha Neelam
Published: January 2025

Background

Alzheimer’s disease is a progressive neurodegenerative disorder that mainly affects the brain resulting gradual decline in a cognitive function, memory impairment, alterations in behavior, potentially resulting in the inability to engage in a conversation and react to the surroundings. Corpus callosum (CC) is the principal white fabric matter present in the center of the brain that connects the left and right cerebral hemispheres. Neurodegenerative diseases can impact the size and structure of the CC, leading to its atrophy and dysfunction. This study aims to detect the CC in a given Structural MRI and classify Early Mild Cognitive Impairment (EMCI) vs. Late Mild Cognitive Impairment (LMCI). This study introduces the prospect of utilizing a YOLOv5‐based framework for CC detection, aiming to distinguish between individuals with EMCI and LMCI. In addition, we have also interpreted our results using Eigen CAM.

Method

In this study, we proposed a Fine‐tuned Yolov5 based object detection model for detecting CC and classifying EMCI vs LMCI. Unlike previous studies that focused solely on CC (texture analysis) for detecting MCI, our method considers both CC and the surrounding context for better EMCI vs LMCI classification. In our approach, we used MRI slices along with the corpus callosum area, enclosed in a bounding box tightly fitted to the CC coordinates. The YOLOv5 model consists of three parts: the backbone extracts features, the neck combines features at different scales, and the head makes final predictions. In this case, the object of interest for the model is the CC to classify EMCI vs LMCI.

Result

The dataset used in this study was obtained from ADNI and consists of total 100 subjects, evenly distributed between EMCI vs LCMI. The dataset was partitioned into 80% for training and 20% for testing. We achieved 97% accuracy on test dataset.

Conclusion

This study demonstrates YOLOv5’s efficiency in CC detection for EMCI and LMCI classification. The classification results are further interpreted using Eigen CAM. In future Fine‐tunning the model parameters and exploring other CAM varients can improve the results.
Possibilities of Transcatheter Intracerebral Laser Photobiomodulation Therapy in Patients with Dementia in the Treatment of Various Microcirculatory Cerebral Lesions
Authors: Maksimovich Ivan V
Published: January 2025

Background

Most cerebrovascular lesions are aggravated by dementia. This study examines the possibility of reducing dementia by stimulating cerebral angiogenesis and neurogenesis using Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT) in patients with Alzheimer’s disease (AD), distal cerebral atherosclerosis, Binswanger’s disease (BD), and vascular parkinsonism (VP).

Methods

The study included 404 patients with dementia, aged 29‐81 (mean age 78).

Examination: assessment of CDR, TDR, MMSE, cerebral MRI, MRA, CT, MSCTA, scintigraphy (SG), rheoencephalography (REG), cerebral multi‐gated angiography (MUGA).

48 (11.88%) patients suffered from AD. According to dementia severity, patients were divided into: preclinical stage (TDR‐0) ‐ 4, mild stage (TDR‐1) ‐ 16, moderately severe stage (TDR‐2) ‐ 21, severe stage (TDR‐3) ‐ 7 patients.

356 (88.12%) patients suffered from diseases such as distal cerebral atherosclerosis ‐ 302 (84.83%), BD ‐ 17 (4.78%), VP ‐ 37 (10.39%) people. According to dementia severity, patients were divided into: unnoticed dementia ‐ 21, dementia at level (CDR‐1) ‐ 312, (CDR‐2) ‐ 23 people.

All patients underwent Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT).

Results

All 48 (100%) AD patients showed improvement in cerebral microcirculation and 10‐20% increase in cerebral temporal lobes volume, which indicates the development of cerebral angiogenesis and neurogenesis as well as tissue regeneration. The process was accompanied by dementia level decrease and cognitive functions restoration. Consequently, patients were transferred to a milder TDR group. Depending on the initial dementia severity, the resulting positive effect is observed for 2‐12 years.

All patients with distal cerebral atherosclerosis 302 (100%), BD 17 (100%) and VP 27 (100%) after Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT) showed improved cerebral microcirculation, decreased cerebral involutional changes, which indicates the development of angiogenesis, neurogenesis, and tissue regeneration. This led to a long‐term (over 10 years) decrease in dementia level and cognitive functions restoration.

Conclusions

Despite the differences in AD etiology, distal cerebral atherosclerosis, BD and VP, Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT) is an effective method for stimulating angiogenesis and neurogenesis. It leads to improved cerebral blood supply and restoration of tissue structures, dementia decrease, and mental and cognitive functions improvement. The resulting effect lasts for a long time.
Bidirectional association between gait speed and cognition in community‐dwelling non‐demented older adults: A eight‐year longitudinal study
Authors: Su Ying‐Hao , Chen Jen‐Hau , Chen Yen‐Ching , Chiou Jeng‐Min , Shiu Chenghsi
Published: January 2025

Background

Slow gait speed and poor cognitions share numerous risk factors, including age, physical activities, chronic inflammation, education, metabolic abnormality, and the presence of multimorbidity. However, the causal relationship between gait and cognitions remains controversial. This study aimed to explore the reciprocal relationship of gait speed with global and domain‐specific cognition in non‐demented older adults.

Method

This study used data from four waves of Taiwan Initiative for Geriatric Epidemiological Research (TIGER, 2013‐2021) with biennial assessments of casual walking speed and cognitions. Global cognition, memory, executive function, verbal fluency, and attention were assessed using Montreal Cognitive Assessment‐Taiwanese version (MoCA‐T), immediate and delayed recall, trail making test part‐A and part‐B (TMTA and TMTB), categorical naming task, and forward and backward digit span test, respectively. A cross‐lagged panel model (CLPM) and a linear mixed model were both used to investigate the bidirectional association between gait speed and cognitive function. Covariates included baseline age, sex, body mass index physical activities, higher education, physical activities, multimorbidity, smoking, Apolipoprotein E (APOE) ϵ4 status, family income, and marital status.

Result

A total of 459 adults with a mean age of 74.5 (standard deviation 5.2) were included, and 239 participants (52%) were female. After adjustments for potential confounders, faster earlier gait speed was associated with better subsequent global cognition (MoCA‐T: β=.28, 95% confidence interval [CI]=.014‐.55), memory performance (immediate and delayed recall: β=.10, 95% CI=.04‐.17; β=.09, 95% CI=.02‐.17), verbal fluency (β=.09, 95% CI=.007‐.18), and executive function (TMTA: β=.15, 95% CI=.047‐.26). Similarly, better earlier cognitions of MoCA‐T (β=.08, 95% CI=.019‐.15), immediate and delayed recall (β=.09, 95% CI=.00‐.17; β=.11, 95% CI=.033‐.19), verbal fluency (β=.08, 95% CI=.003‐.16), and executive function (TMTA: β=.17, 95% CI=.086‐.26) were associated with faster subsequent gait speed. The results of linear mixed models were consistent with findings from CLPM analyses.

Conclusion

We found reciprocal associations of gait speed with global cognition, memory, executive function, and verbal fluency. Early screening of gait speed and cognitive function helps identify individuals at risk and supports the maintenance of normal cognition and physical performance.
Neuroimaging Biomarkers in Neuropsychiatric Symptom Clusters
Authors: Kapustin Daniel , Rashidi‐Ranjbar Neda , Wang Wei , Binns Malcolm , McLaughlin Paula M , Abrahao Agessandro , Grimes David A. , Lang Anthony E , Marras Connie , Masellis Mario , Orange Joseph B , Rajji Tarek K. , Roberts Angela C , Saposnik Gustavo , Swartz Richard H , Tang‐Wai David F. , Tartaglia Carmela , Troyer Angela , Zinman Lorne , Fischer Corinne E. , Kumar Sanjeev
Published: January 2025

Background

Neuropsychiatric symptoms (NPS) constitute a major challenge for patients with Alzheimer’s disease (AD). We have recently demonstrated that in AD, overall NPS burden is significantly associated with patient function. However, few studies have examined the relationship between specific symptom clusters with neurological biomarkers. Therefore, we identified NPS clusters in AD and explored their association with structural neuroimaging markers.

Method

Participants with AD (N = 111) were included from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). NPS were assessed using the neuropsychiatric inventory questionnaire (NPI‐Q), and symptom clusters were identified through exploratory factor analysis. The Semi‐Automatic Brain Region Extraction (SABRE) pipeline was used to compute regional cortical thickness and subcortical volumes using participant MRI data. We then evaluated correlations between symptom clusters with subcortical volumes and regional cortical thickness.

Result

Factor analysis identified four symptom clusters explaining 62% of the variance. These were labeled as “behavioral” (disinhibition, irritability, motor disturbance, and agitation), “psychotic” (hallucinations, delusions, and euphoria), “neurovegetative” (apathy and appetite), and “affective” (depression, anxiety, nighttime behavior) clusters.

The psychotic cluster was associated with increased cortical thickness in bilateral frontal regions, the left inferior parietal lobe (r=0.23, p=0.02), and with left anterior cingulate volumes (r=0.21, p=0.03). The neurovegetative cluster was associated with reductions in volume among bilateral frontal and right‐sided temporal and parietal regions. The affective cluster was associated with increased left anterior cingulate volume (r=0.21, p=0.03).

Conclusion

NPS symptom clusters in AD separate into behavioral, psychotic, neurovegetative, and affective dimensions. These symptom groups demonstrate unique associations with neuroimaging markers.
Clinician perspectives on successes and challenges in engaging care partners
Authors: Chertkow Howard
Published: January 2025

Involvement of caregivers in dementia research is an admirable goal. Involvement of caregivers in care planning for patients and people living with dementia, is essential to good medicine. However, it is important to assess and realistically consider areas where researchers and caregivers, and physicians and caregivers, may disagree. Several kinds of such disagreement and formulating an approach to these will be discussed. Three examples: Involvement of patients in Alzheimer Disease clinical trials. The researcher must be realistic but optimistic in the possible benefits of clinical trials. At the same time, expectations must be managed. It would be naive to consider that caregivers and people with lived experience participate for purely altruistic reasons. Therefore, when a clinical trial fails to produce obvious benefits (the patient may be in a placebo group, or the drug may have limited efficacy), the caregiver often considers withdrawing from the study. How should a researcher approach such a situation? Is there a way for caregivers and patients to be given autonomy, and yet carry clinical trials to the necessary completion? A second example involves prognostication. particularly when (as in Canada) medical assistance in death is now available for dementia patients. Who determines the narrative to be presented to the patient? If the caregiver wishes for greater pessimism or optimism on the part of the physician, is it ethical to diverge from the “scientific” information to accomodate prognostication to the preference of the caregiver? A third complex area is communication. Some caregivers are now requesting that the word “dementia” not be used, because it brings with it stigma. Other families maintain that the new terminology (such as “major neurocognitive disorder”) is mere obfuscation a lacks the clarity needed for communication. Should the language and terminology used be determined by caregivers? Should this be an area of discussion at the beginning of any medical interaction?

We will discuss these and other scenarios where the complexity of the relationship between caregiver and physician/researcher are notable, and suggest approaches and processes to address these.
Elevated Blood Biomarkers of Neurodegeneration and Blood Brain Barrier Dysfunction Correlate with Lower MRI Regional Brain Volumes Two Years after COVID‐19
Authors: Frontera Jennifer A. , Ge Yulin , Boutajangout Allal , Ahmed Wajiha , Betensky Rebecca A , Debure Ludovic , Jiang Li , Links Jon , Masurkar Arjun V. , Sun Zhe , Thawani Sujata , Vedvyas Alok , Wisniewski Thomas
Published: January 2025

Background

Cognitive impairment is one of the most frequently reported post‐acute sequelae of COVID‐19, yet the pathophysiology underpinning this symptom remains unknown. We aimed to explore the correlation of blood markers of inflammation, BBB disruption and neurodegeneration with MRI volume measurements in COVID‐19 patients with and without cognitive impairment, and among patients with no prior history of COVID‐19.

Method

We conducted a prospective study of COVID‐19 patients (COV+; laboratory verified SARS‐CoV‐2 infection) and non‐COVID‐19 controls (COV‐; no history of SARS‐CoV‐2 infection and negative SARS‐CoV‐2 nucleocapsid antibody). All patients underwent neuropsychological testing using the Uniform Data Set Version 3 Cognitive Battery. Patients were coded as having cognitive impairment (COG+) based on neuropsychological testing (≥1 abnormal test result), and clinician interview with the patient and informant. 3T MRI (3D T1‐MPRAGE) sequences were utilized for regional volume measurements using MRICloud (Johns Hopkins University) segmentation software. The ratios of regional to total intracranial volume (SPM software) were reported to correct for differences in head size. Fasting plasma biomarkers of neurodegeneration, BBB dysfunction, and inflammation were measured concurrent with MRI testing. Bivariate Spearman correlation coefficients were calculated comparing MRI regional volumetric measures with blood biomarkers among COV+ versus COV‐ subjects with and without cognitive impairment (COG+ versus COG‐). Significance was set at P≤0.001 after Bonferroni correction.

Result

A total of 90 subjects were included (N=75 COV+ with median 724 days from index SARS‐CoV‐2 infection, N=15 COV‐; N=39 COG+, N=51 COG‐). Among all COV+ subjects (N=75), neurodegenerative biomarkers (NFL, amyloid‐ß‐40, GFAP, ptau‐181), BBB markers (hepatocyte growth factor) and TNF‐a were significantly negatively correlated with regional MRI volumes, most notably in the limbic and hippocampal regions (Figure 1, bold=P≤0.001); whereas this signature of correlations was not observed in COV‐ subjects (N=15). Among COV+ subjects with cognitive impairment (COV+COG+, N=33), significant negative correlations were observed between neurodegenerative biomarkers (NFL, amyloid‐ß‐40, GFAP, ptau‐181) and MRI volumes (particularly frontal, temporal and limbic), whereas COV+COG‐ subjects (N=42) did not demonstrate this pattern (Figure 2).

Conclusion

Two‐years post‐COVID‐19, signature correlations between neurodegenerative, BBB and cytokine blood biomarkers and MRI regional volumes differ between COVID‐19 subjects versus controls, particularly among those with cognitive impairment.
LSM14A as a potential CSF biomarker for mild cognitive impairment and Alzheimer’s disease
Authors: Ildız Sümeyra , İlhan Nazlıcan , Samancı Bedia , Sordu Pelin , Alaylıoğlu Merve , Hanagasi Hasmet , Gurvit İbrahim Hakan , Bilgiç Başar , Dursun Erdinc , Gezen‐Ak Duygu
Published: January 2025

Background

mRNAs are required to progress cellular processes such as synaptic plasticity and memory formation. Processing bodies (P‐bodies) are storage units for mRNAs located at dendritic translation sites, so these mRNAs can participate in synaptic plasticity immediately when needed. P‐bodies consist of 3 main proteins: DDX6, 4E‐T, and LSM14A. It is thought that LSM14A is the part that binds to the mRNAs within the P‐bodies via its Lsm region, which is the region that recognizes and binds to mRNA. And so, LSM14A plays essential roles in mRNA translation, storage, and degradation. In neurodegenerative disorders, dendritic damage is seen in the early stages. It is unclear how much dendritic substance is released into the extracellular space after cellular damage. Some studies show the presence of exosomes and mRNA in the cerebrospinal fluid (CSF). The finding of mRNAs at dendrites with P‐bodies suggests that mRNAs could pass into the CSF via P‐bodies. In this study, we investigated the presence and the level of LSM14A in the CSF to determine its potential to be an early‐phase biomarker of Alzheimer's disease (AD).

Method

In this study, the level of LSM14A protein was detected by ELISA in CSF of 21 patients with mild cognitive impairment (MCI), 40 patients with AD, and 18 cognitively unimpaired individuals. Raw data was analyzed by GraphPad InStat DTCG 3.06 with a one‐way ANOVA method followed by the Tukey‐Kramer posthoc test.

Result

The level of LSM14A in the MCI group is significantly higher than in the control group, and the level of LSM14A positively correlated with patients' age. In AD patients, LSM14A levels increased in the first two years of the disease. LSM14A was negatively correlated with AD duration.

Conclusion

According to our results, the level of LSM14A in the CSF is high in the MCIs. The disease duration of AD cases that were less than two years also showed elevated levels of LSM14A. Our preliminary results suggest that CSF LSM14A protein might be a CSF biomarker for the early stage of AD.
Rapidly progressive dementia: criteria proposal
Authors: Satyadev Nihal , Tipton Philip W , Dunham S Richard , Brier Matthew R , Morris John C. , Graff‐Radford Neill R , Day Gregory S
Published: January 2025

Background

Rapidly progressive dementia (RPD) is variably defined across published cohorts. A standardized definition is needed to support multicenter studies required to inform the causes of RPD and optimize recognition and management of treatment‐responsive causes. An optimal definition will capture the broad spectrum of causes of RPD, adequately differentiate patients with rapid and typically progressive presentations of neurodegenerative disease, and be reliably implemented across healthcare settings and centers.

Method

The Clinical Dementia Rating® (CDR) is a validated dementia staging tool that is widely used in clinical trials and observational studies. We applied the CDR to diagnose RPD in patients who developed dementia (CDR ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. This definition was prospectively applied to patients with suspected RPD at Mayo Clinic in Florida (MCF: Jacksonville, FL; Jan 2020 – Oct 2023) and Washington University in St. Louis (WU: Saint Louis, MO; Jun 2016 – Dec 2019), and retrospectively applied to individuals within the National Alzheimer’s Coordinating Center (NACC) dataset. Criteria performance was compared across cohorts.

Result

Two‐hundred twenty‐six patients were referred with suspected RPD at MCF‐WU. Of these, 155/226 (68.6%) met our proposed RPD criteria, including patients with Alzheimer disease and related dementias (ADRD; 34/155, 21.9%), Creutzfeldt Jacob disease (CJD; 25/155, 16.1%), autoimmune encephalitis (52/155, 33.5%), vascular pathologies (14/155, 9.0%), toxic/metabolic disruptions (7/155, 4.5%) and primary psychiatric disorders (4/155, 2.6%). A small subset of NACC participants met our proposed RPD criteria (836/20,418; 0.04%), emphasizing the unique nature of RPD. Causes of RPD in NACC included ADRD (676/836, 80.1%), CJD (72/836, 8.6%), and vascular pathologies (24/836, 2.9%). Rates of progression (∆CDR sum‐of‐boxes/year) clearly distinguished patients with RPD from non‐RPD in both cohorts (MCF‐WU, 13.6±5.8 vs 4.7±5.9, p<0.001; NACC, 6.7±3.1 vs. 1.7±1.4, p<0.001).

Conclusion

Our CDR‐based definition of RPD distinguished patients with a broad spectrum of causes of RPD from those with typically progressive dementia across multiple cohorts. Broad application of this criteria would standardize diagnosis of RPD and support the design and implementation of multicenter studies RPD.
Cognitive reserve, microstructural brain lesions, and cognitive function in dementia‐free adults in UK Biobank
Authors: Han Xiaolei , Huang Xin , Du Yifeng , Qiu Chengxuan , wang yongxiang
Published: January 2025

Background

Microstructural brain lesions have been linked to cognitive health. However, their combined effect and the role of the cognitive reserve (CR) remain unclear. We investigated the interplay of microstructural brain lesions and cognitive reserve in cognitive function in middle‐aged and elderly adults.

Method

This study used data from a prospective cohort of 26,490 UK Biobank participants in the MRI substudy. Markers of microstructural brain lesions included fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (ICVF), orientation dispersion (OD) indices, and isotropic volume fraction (ISOVF), which were estimated using diffusion magnetic resonance imaging (dMRI). Processing speed, reasoning, attention, executive function, and memory were assessed with neuropsychological tests, from which composite scores were derived. The composite CR indicator was generated from early‐life education, midlife occupation, physical activity, and social activity and was dichotomized into low and high CR based on mean CR score. We used multivariable linear regression models to examine the relation between markers of microstructural brain lesions and cognitive function while taking into account the potential interaction (interplay) of brain lesions and CR on cognitive function.

Result

Controlling for sociodemographic, vascular, and genetic factors, decreased FA and ICVF and increased MD, as markers of impaired integrity of white matter microstructure, were significantly associated with lower composite z‐score of processing speed, attention, and executive function. Reduced ISOVF was associated with higher z‐score of processing speed [multivariable‐adjusted β‐coefficient=‐0.03. 95% CI ( ‐0.041, ‐0.019), p<0.001]. In the stratified analysis by levels of CR, decreased FA and ICVF were significantly associated with lower z‐scores of reasoning and memory, respectively, only in participants with low CR.

Conclusion

This study suggests that impaired integrity of white matter microstructure is associated with reduced processing speed, attention, and executive function and that high CR could modify the association of microstructural brain lesions with cognitive function (e.g., memory and reasoning).
Comparative study of neuroimaging evaluation between idiopathic normal pressure hydrocephalus and progressive supranuclear palsy
Authors: Inagawa Shoya , Yamamoto Ryo , Inagawa Yuta , Takenoshita Naoto , Shibukawa Shuhei , Yoshimaru Daisuke , Saito Kazuhiro , Shimizu Soichiro
Published: January 2025

Background

Idiopathic normal pressure hydrocephalus (iNPH) and progressive supranuclear palsy (PSP) are considered to be different pathologies, but they have similar clinical features such as cognitive dysfunction and gait disturbance. Therefore, it is difficult to understand between the two diseases in actual clinical practice. The aim of study is whether the indivisual characteristic in MRI is useful to devide into two groups.

Method

15 iNPH patients and 9 PSP patients were enrolled. The subjects were recruited retrospectively from those who had been diagnosed in our department. The MRI device was 3 T MAGNETOM Vida (SIEMENS), and the Evans index and DESH score were measured using T2WI/FLAIR. Furthermore, we used FreeSurfer for 3D‐T1WI to measure the volumes of the brainstem, corpus callosum, and ventricles. Each brain region was adjusted using the whole brain volume, multiple corrections were performed on the final remaining regions, and comparisons were made between the two groups.

Result

There were no significant differences in brain stem volume between the two groups. However, Evans index (iNPH: 0.351 ± 0.0, PSP: 0.286 ± 0.0, p < 0.01), DESH score (iNPH: 6.87 ± 1.2, PSP: 2.44 ± 2.1), p<0.01), corpus callosum volume (iNPH:854.75±369.9 mm^3, PSP:532.16±186.1 mm^3, p<0.05), cerebrospinal fluid volume (iNPH:2220.26±657.5 mm^3, PSP :1544.38±338.1 mm^3, p<0.01), a significant difference was observed.

Conclusion

MRI findings related to the ventricles may be differentiating both diseases.
ATP1A3 as a target for isolating neuron‐specific extracellular vesicles from human brain and biofluids
Authors: Zhang Zhengrong , You Yang , Sultana Nadia , Ericsson Maria , Martens Yuka A , Sun Min , Kanekiyo Takahisa , Ikezu Seiko , Ikezu Tsuneya , Shaffer Scott A
Published: January 2025

Background

Neuron‐derived extracellular vesicles (NDEVs) are a valuable resource for understanding brain conditions and discovering neurodegenerative diseases biomarkers, notably Alzheimer’s disease (AD). Recent interest focuses on capturing neuron‐specific EVs from patient‐derived samples, characterizing their contents as a pathological reflection of the central nervous system (CNS). Our recent study identified ATPase Na+/K+ Transporting Subunit Alpha 3 (ATP1A3) as a prevalent neuron‐specific EV marker specifically expressed in brains. This study systematically analyzes neuronal EVs to assess the specificity of ATP1A3 to NDEVs and its potential as a target for NDEV pulldown from accessible biofluids for disease monitoring. Additionally, ATP1A3 is compared with other proposed NDEV markers.

Method

We applied immunoelectron microscopy to detect ATP1A3, L1 cell adhesion molecule (L1CAM) and neural cell adhesion molecule 1 (NCAM1) in EVs isolated from iPSC‐derived excitatory neurons, brain tissue, cerebrospinal fluid (CSF) and plasma. Neuronal EV enrichment was achieved through immunoaffinity isolation, utilizing anti‐ATP1A3, L1CAM and NCAM1 antibodies separately. Evaluation involved quantitative mass‐spectrometry, immunoblotting and ELISA. To compare the enrichment of neuronal markers, EVs isolated from CSF and plasma samples were analyzed using ExoView and Nanoimager. Additionally, we investigated the potential of ATP1A3+ plasma EVs as AD biomarker by comparing the value of amyloid‐beta peptide (Aβ) in ATP1A3+ plasma EVs measured by Nanoimager and other plasma AD biomarkers as determined by SIMOA.

Result

ATP1A3, identified as a neuron‐specific protein, exhibits substantial enrichment in NDEVs isolated from induced human neurons, brain tissue, CSF, and plasma samples, surpassing NCAM1 or L1CAM. Both single‐ and bulk‐EV analysis consistently demonstrate a higher enrichment of ATP1A3 associated EVs in human samples. Immunoprecipitation of ATP1A3+ EVs from human brain tissues reveals superior neuronal cell‐type specificity over NCAM1+ and L1CAM+ EVs by label‐free mass spectrometry. Increased Aβ levels are observed in ATP1A3+ EVs derived from CSF and plasma of AD cases by SIMOA. Moreover, Aβ+ populations in ATP1A3+ EVs from plasma can distinguish AD from mild cognitive impairment and control cases via Nanoimager compared to the conventional quantification of AD markers.

Conclusion

Our findings demonstrate that ATP1A3 as a promising target for isolating NDEVs from biofluids, offering potential diagnostic advancements in neurological research.
Association of biological age with health outcomes and its modifiable factors
Authors: Yu Jin‐Tai
Published: January 2025

Background

Identifying the clinical implications and modifiable and unmodifiable factors of aging requires the measurement of biological age (BA) and age gap.

Method

Leveraging the biomedical traits involved with physical measures, biochemical assays, genomic data, and cognitive functions from the healthy participants in the UK Biobank, we establish an integrative BA model consisting of multi‐dimensional indicators.

Result

Accelerated aging (age gap >3.2 years) at baseline is associated incident circulatory diseases, related chronic disorders, all‐cause, and cause‐specific mortality. We identify 35 modifiable factors for age gap (p < 4.81 × 10−4), where pulmonary functions, body mass, hand grip strength, basal metabolic rate, estimated glomerular filtration rate, and C‐reactive protein show the most significant associations. Genetic analyses replicate the possible associations between age gap and health‐related outcomes and further identify CST3 as an essential gene for biological aging, which is highly expressed in the brain and is associated with immune and metabolic traits.

Conclusion

Our study profiles the landscape of biological aging and provides insights into the preventive strategies and therapeutic targets for aging.
Drawing the neurodegenerative line: plasma biomarkers and retinal OCTs shed light on pathophysiological and diagnostic similarities between Alzheimer's Disease and Multiple Sclerosis
Authors: Zeldich Dean , Cheng Chia Hsin , Guan Yi , Koo Bang‐Bon
Published: January 2025

Background

Recent evidence suggests extensive myelin dysfunction in Alzheimer’s Disease (AD), lending to investigation of biomarkers previously implicated in both AD and Multiple Sclerosis (MS) to find objective and obtainable diagnostic screening tools. Glial fibrillary acidic protein (GFAP), Chitinase‐3‐like protein 1 (CHI3L1), Chemokine (C‐X‐C motif) ligand 13 (CXCL13), and neurofilament light chain (Nfl) have been known to mark neuronal pathology in both diseases making them attractive markers. Retinal Optical Coherence Tomography (OCT) becomes a popular diagnostic tool in both conditions as an inexpensive and rapid way of obtaining a window into the cerebrum.

Method

AD (n=3952) and MS (n=1988) patients were selected from the UK‐Biobank using ICD10 codes. Past medical history of strokes and brain cancer were used as exclusionary criteria. Case‐control differences were analyzed in cognitive measures, retinal OCT, plasma proteins, and magnetic resonance imaging (MRI) data. AD subjects were further stratified. Correlation and predictability of plasma markers and retinal OCTs with cognitive and MRI measures were investigated with linear regression models, age‐ and sex‐controlled.

Result

Stable AD, MS, and AD converters showed significantly worse cognitive performances compared to controls. GFAP and Nfl were significantly elevated in MS (additionally, CHI3L1), AD patients, and AD converters as early as 5 to 10 years before diagnosis. Retinal OCT markers such as retinal nerve fiber thickness (RNFT) were significantly decreased in MS patients, while less clear patterns were observed for AD and converters. MRI measures obtained 10 years after baseline visit revealed significantly smaller hippocampal volumes and more white matter hyperintensities in both AD and MS patients compared to controls. Overall, retinal OCT measures (i.e., thinner RNFT, smaller optic disc diameter) significantly correlated with worse cognitive outcomes and elevated protein markers for both groups. While certain measures of cognitive decline (e.g., mean reaction time, numeric memory) better correlated with well‐established MRI hallmarks for neurodegeneration.

Conclusion

Inexpensive and non‐invasive biomarkers such as plasma proteins and retinal OCT measures carry significant prognostic potential in AD and MS while allowing for a deeper characterization of the neuronal and glial pathology in both diseases.
Feasibility and Acceptability of Objective Pain Assessment Using Multimodal Sensing Signals in Older Adults with Alzheimer's Disease: Preliminary Results of a Pilot Study
Authors: Andrade Fernanda Souza , Ornelas Julie , Park JuYoung , Engstrom Gabriella , Shih Richard D. , Telkes Ilknur
Published: January 2025

Background

Chronic pain remains mostly untreated in those with Alzheimer’s disease and related dementias (ADRD), mainly due to limited capacity to verbalize pain. Development of reliable objective biomarkers of chronic pain could improve pain assessment and treatment. We explored feasibility and acceptability of using a wearable electroencephalograph (EEG) and a screen‐based eye tracker system to identify neural signatures of chronic pain in this population.

Method

Inclusion criteria were ADRD in an early to moderate stage defined by Mini‐Montreal Cognitive Assessment (Mini‐Moca) and Quick Dementia Rating System (QDRS) scores and chronic pain (3 months or longer). Participants underwent a single‐session test where participant‐reported outcome (PRO) measures were obtained with 32‐channel EEG. Neural signals were recorded at resting and during a cognitive task with visual stimuli. Attention to the stimuli was captured using an eye‐tracking system.

Result

Five of 29 applicants met all criteria and were included. The majority were excluded due to dementia severity or lack of chronic pain. Four subjects (3 females) concluded the study. Participants' ages ranged from 76 to 93 years. They were diagnosed with Alzheimer’s disease, dementia of unspecified type, or dementia related to Parkinson’s disease. Mini‐Moca scores ranged from 2‐8 of 15 and QRDS ranged from 6‐20 of 30. On Visual Analog Scale for pain, three participants rated mild to moderate pain (2 to 5 out of 10) and one rated severe pain (9 out of 10). Three reported that pain significantly affected their ability to walk, relationships with people, and enjoyment of life. All participants reported feeling comfortable with the EEG cap and eye tracker, were satisfied with the study, and would recommend the study to others. In terms of feasibility, the major challenge was to calibrate the eye tracker system and the duration of the cognitive task which was 30 minutes.

Conclusion

While using a table‐top eye tracker was comfortable for all participants, the calibration phase was difficult. In one case, the image‐based task was not feasible which might be related to participant having moderate dementia. Our preliminary work suggests that wearable modalities may work better in people with ADRD and carry the potential to assess pain objectively.
Identification of Balance biomarkers using Inertial sensor for Early Detection of Dementia
Authors: Jamshed Mobeena , Shahzad Ahsan , Kim Kiseon
Published: January 2025

Background

Early‐stage dementia, Mild Cognitive Impairment (MCI), is challenging to diagnose since it is a transient condition distinct from complete cognitive collapse. Recent clinical research studies have identified that balance impairments can be a significant indicator for predicting dementia in older adults. Accordingly, we aimed to identify key balance biomarkers using wearable inertial sensors for early detection of dementia/MCI.

Method

At National Research Center for Dementia (South Korea), 60 participants (30 Cognitively Normal‐CN, 30 Mild Cognitive Impairment‐MCI) were selected based on assessments conducted by medical professionals at Chosun University Hospital / Chonnam National University Hospital (Gwangju). Shimmer‐3 inertial sensor was placed on lower back of participants, with a tri‐axial accelerometer and tri‐axial gyroscope. The data was collected under four different conditions: eyes‐open (EO), eyes‐closed (EC), right‐leg lift (RL), left‐leg lift (LL). A set of 76 postural sway measures were considered with 43 time‐domain and 33 frequency‐domain features.

Feature ranking was executed through the utilization of "Leave‐One‐Subject‐Out (LOSO)" cross‐validation technique for each condition. Filter methods: one‐way‐ANOVA (Analysis of Variance), Mutual Information and Wrapper methods: Random Forest, Support Vector Machine (SVM) were utilized to evaluate feature subsets. The proportional value of each feature was calculated by the number of times it showed in the top feature list. The final score was obtained by combining scores from all the techniques, which indicated the relative weight of characteristics across the various approaches. Further feature analysis was conducted using SHAP (Shapley‐Additive‐exPlanations).

Result

The multi‐step methodology, for feature selection, adopted in our research ensured a rigorous process, combining the strengths of Filter and Wrapper methods. In time‐domain: root‐mean‐square, mean‐distance, 95%‐confidence circle sway‐area, path‐length, mean sway‐velocity were the key features identified. While in frequency‐domain: spectral edge‐frequency, mean‐frequency, peak‐frequency, centroid‐frequency, spectral‐entropy were found to be the principal features of relevance. These features were also included in the top list of features based on SHAP impact value, hence proving the effectiveness of our method in identifying important biomarkers for detection of MCI.

Conclusion

The inertial sensors based postural balance assessment provides useful biomarkers that can facilitate early screening of MCI / dementia in home settings.