Background:Coronavirus disease 2019 (COVID-19) has been associated with central nervous system dysfunction implicating cerebrovascular and neurovascular units, as reflected in lower regional cerebral blood flow among non-hospitalized individuals that experienced post COVID-19 condition (PCC). This study investigates whether PCC is associated with altered regional cerebral blood volume assessed using Dynamic Susceptibility Contrast (DSC) Magnetic Resonance Imaging (MRI). The comparison control group are individuals without PCC who previously experienced cold or flu-like symptoms, or COVID-19. Methods:Fifty-seven participants were recruited: 36 with PCC (mean age: 42.7, standard deviation: 10.4, 26 females) and 21 controls (mean age: 41.6, standard deviation: 14.7, 13 females). T2*-weighted DSC MRI was performed at 3 Tesla to image the first passage of the bolus. A total of 22 regions of interest (ROIs) were considered. Group differences in DSC-derived cerebral blood volume (rCBV) and cerebral blood flow (rCBF) were evaluated using Bayesian regression, providing median group differences, highest density interval (HDI), and the probability of direction (PD) estimates. Results:The two groups (PCC and controls) were matched for age, sex, days from symptom onset, and number of previous vaccines, but had different degrees of self-report illness severity. The rCBV analysis showed median group differences (range: -0.05 to -0.13), with PD > 0.90, indicating a high probability of decreased rCBV in the PCC group, involving the superior frontal gyrus, thalamus, paracentral lobule, cingulate gyrus, postcentral gyrus, middle frontal gyrus, inferior frontal gyrus, and superior temporal gyrus ROIs. By comparison, group differences in rCBF were muted and did not reach PD > 0.90. Discussion:We found group-level differences that were reflected by lower regional rCBV in PCC relative to controls. The imaging findings are suggestive of cerebrovascular alterations several months after the initial illness.

Paper-based tests of cognition (such as the Trail-Making test, or TMT) have long been used in clinical and research settings to evaluate how the healthy or impaired brain supports behavioral performance. Despite widespread use, the neural correlates of such tests are poorly understood, and the tests have sensitivities and specificities that are less than desired. To address these shortcomings, a multi-modal research protocol is proposed that simultaneously combines novel tablet technology, eye tracking, and functional magnetic resonance imaging to explore the relationships between kinematic and visual behavior and neural activity associated with cognitive test performance. Protocol rationale, step-by-step methodology, and results from a representative participant are provided to demonstrate protocol validity and to illustrate the potential of exploring the kinematic, visual, and neural correlates of a representative test of cognition. The current protocol can expand the limits of existing clinical MRI neuroscience research, with implications for the future diagnosis and management of various cognitive disorders.

BackgroundMild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease and related dementias (ADRD), represents a critical window for intervention. Although mitochondrial dysfunction is increasingly implicated in neurodegeneration, most therapies target downstream protein aggregation. Transcranial photobiomodulation (tPBM) delivers near-infrared light to enhance mitochondrial respiration.ObjectiveWe hypothesized that tPBM in MCI would be safe, feasible, and associated with improvements in cognition, mitochondrial function, and default mode network (DMN) functional connectivity (FC).MethodsWe conducted a single-blind, randomized, sham-controlled pilot trial (NCT05563298) in adults ≥50 years with MCI. Twenty participants were randomized 1:1 to active or sham devices. Active devices delivered pulsed 810-nm light for 20 min per session; shams emitted light for 2 seconds. Stimulation targeted DMN hubs and the olfactory bulb. Participants self-administered treatment at home six days per week for six weeks.ResultsAdherence was high (active 96.9%; sham 94.2%). Adverse events (AEs) were reported by 10 of 20 participants (4 active, 6 sham). No serious AEs occurred. Compared with sham, active tPBM produced greater improvement in global cognition (Mini-Mental State Examination; p = 0.03, d = 1.05) and episodic memory (California Verbal Learning Test-II long-delay recognition; p = 0.02, d = 1.09). Serum pyruvate and lactate increased with a reduced lactate-to-pyruvate (L/P) ratio (p = 0.007, d = -1.37). DMN FC increased (p = 0.014, d = 1.25), and plasma IL-6 declined (p = 0.02, r = -0.52).ConclusionsHome-based tPBM was safe, well tolerated, and feasible, with high adherence and mild AEs. Cognitive, metabolic, and network-level findings are consistent with enhanced mitochondrial efficiency and anti-inflammatory effects. These results support larger, double-blind, multicenter trials to evaluate tPBM as a mitochondria-targeted therapy in early ADRD.

Introduction: Peripheral nerve field stimulation (PNFS) for facial pain delivers subcutaneous electrical stimulation to reduce pain. Blood oxygenation level-dependent (BOLD) functional MRI (fMRI) can be used to characterize central effects of neuromodulation techniques such as deep brain stimulation and spinal cord stimulation (SCS). However, the safety and utility of MRI in patients with PNFS have not been established, limiting both clinical MRI use and the application of fMRI in this population. This study evaluated the MRI safety and feasibility of imaging an active SCS implant used for PNFS in patients with facial pain; and defined sequence parameters for concurrent BOLD fMRI acquisition. Methods: An anthropomorphic 3D-printed phantom filled with tissue-mimicking gel and fitted with an SCS implant replicating a patient with PNFS was used for in vitro safety testing. Two phantom experiments evaluated the relationship between (i) head-averaged specific absorption rate (SAR), (ii) time-averaged positive radiofrequency magnetic field component (B1rms+) and maximal temperature rises at critical locations (i.e., distal lead electrodes, cranial coiling, and implantable pulse generator) across clinical and research-based structural and fMRI sequences. For validation, a PNFS patient was scanned using localizer, T1-weighted magnetization-prepared rapid gradient echo, T2-weighted sampling perfection with application-optimized contrasts using different flip angle evolutions, and BOLD fMRI sequences informed by phantom experiments. Results: FMRI during active PNFS is safe under specific conditions, with temperature increases remaining below the 2°C threshold at all monitored locations. Heating had a stronger relationship with head SAR (higher adjusted coefficient of determination [R2] value) than B1rms+, particularly at distal lead electrodes. These in vitro findings informed selection of safe fMRI protocols for in vivo scanning. A patient (n = 1) underwent MRI with no device- or patient-related adverse events. Successful fMRI acquisition was achieved, demonstrating engagement of pain-related regions in the patient. Conclusion: Phantom testing confirmed the safety and feasibility of MRI with an active SCS device configured for facial PNFS. These findings, specific to the tested conditions, underscore the need for context-specific safety evaluations to enable safe MRI in such implantable medical devices.

Electric dipole antennas can be designed in a variety of geometries and applied across a wide range of configurations. Appropriately designed dipole antennas can provide deep tissue penetration and low radiofrequency (RF) power deposition in magnetic resonance imaging (MRI), making them attractive for applications requiring safe and effective RF transmission in deep regions. On clinical 3 T MRI systems, however, conventional dipoles are too large in size for practical imaging of the head. Inspired by telecommunications designs, the present work adapts meandered dipoles (where the conductor is folded to shorten the antenna) with the resonance frequency controlled through trace geometry. Additionally, multi-channel configurations are considered to improve RF power transmission. A straight dipole was progressively transformed into meandered geometries and characterized using benchtop measurements and electromagnetic simulations. Analyses evaluated frequency response, near-field behavior, power-flow directionality, and distributions of local tissue heating and transmitted RF magnetic field in multi-channel arrays. A four-channel parallel-transmit (pTx) prototype was also used to show the feasibility of dipole-based head imaging at 3 T. The present work demonstrates a practical implementation of compact, low-heating dipole arrays for head MRI, with potential for extension to ultra-high-field or multinuclear imaging.

Introduction Psychosis, characterized by hallucinations or delusions, affects up to 50% of patients with Alzheimer’s Disease (AD). It is linked to faster cognitive decline, greater caregiver burden, and shows a higher prevalence in females, highlighting sex-specific differences in disease manifestation. While the APOE4 allele is a well-established genetic risk factor for late-onset AD, the influence on psychosis remains unclear. Estrogen may influence psychosis by modulating dopamine signaling and regulating neuroinflammation, which could explain both sex differences in psychosis risk and inconsistencies across study findings. However, its exact role in AD-related psychosis remains poorly understood. We examined the influence of APOE4 homozygosity, sex, and estrogen hormone therapy (EHT) on the expression of psychosis symptoms in AD, hypothesizing that APOE4 homozygosity increases hallucinations in females, while EHT reduces psychosis prevalence. Methods Data from 29,306 individuals diagnosed with AD were obtained from the NACC Uniform Dataset. Psychosis was defined based on the presence of hallucinations (auditory and/or visual) and delusions, identified by a clinician. Stepwise generalized additive models were run with APOE4 Status, EHT, and CSF biomarkers (Aβ42, t-tau, p-tau - markers of AD pathology) as predictors, while adjusting for age, education, and MMSE. Analyses were stratified by sex to explore potential differences in psychosis outcomes. Results APOE4 homozygosity was positively associated with experiencing delusions in the past month in both males (p < .01, OR = 1.234) and females (p < .01, OR = 1.26). In females only, APOE4 homozygosity was also positively associated with hallucinations (p < .01, OR = 1.29). These effects persisted following the addition of CSF biomarkers and EHT to the model (p < .01, OR = 1.22 - 1.28). Among males, higher p-tau and t-tau levels were positively associated with delusions (p < .05, OR = 1.253 - 1.309), and Aβ42 was negatively associated with visual hallucinations, suggesting reduced Aβ clearance and increased aggregation (p < .05, OR = .513), when adjusting for APOE4 homozygosity. EHT use was linked to reduced odds of experiencing hallucinations in females (p < .05, OR = .403). Conclusions EHT demonstrated a symptom-specific protective effect against hallucinations, highlighting hormonal regulation as a key modifier of certain psychosis features in females. This finding is particularly relevant in the context of sex differences in how APOE4 homozygosity influences AD-related psychosis. In addition, the distinct tau–psychosis relationships in males suggest different neurobiological mechanisms underlying psychosis across sexes. Findings emphasize the need for sex-and hormone-informed approaches over one-size-fits-all models to improve clinical management of neuropsychiatric symptoms in AD.

BACKGROUND:Advanced magnetic resonance imaging (MRI) of the cerebellum remains underutilized to detect early microstructural abnormalities associated with multiple sclerosis (MS) clinical disability. OBJECTIVES:To examine associations between cerebellar magnetization transfer ratio (MTR) and clinical measures in people with radiologically isolated syndrome (RIS), early relapsing-remitting MS (RRMS), and primary progressive MS (PPMS). METHODS:MTR data were acquired at 3.0 T across four sites in 53 RIS, 202 RRMS, 46 PPMS, and 42 control participants, as part of the Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo). Multiple linear regression analyses evaluated associations between cerebellar MTR and clinical measures. RESULTS:Across MS subtypes, lower cerebellar MTR was associated with greater motor disability, most notably with impaired manual dexterity (β = -1.04 to -0.67). After the false discovery rate correction, two associations remained statistically significant (p < 0.01): lower MTR in the inferior cerebellar peduncles was associated with worse cerebellar function in RRMS, and lower MTR in the anterior lobe was associated with worse manual dexterity in PPMS. CONCLUSION:This large, multi-center, hypothesis-generating study identified two statistically significant associations between cerebellar MTR and clinical disability, alongside several exploratory findings. These results suggest that cerebellar MTR may capture clinically relevant microstructural abnormalities in early MS.

Introduction The choroid plexus (CP) increases in volume across the Alzheimer’s disease (AD) continuum, suggesting its potential as a clearance-related biomarker. However, few studies have examined ante-mortem CP volume in relation to post-mortem AD pathology, the gold standard for diagnosis. Methods Participants who had structural magnetic resonance imaging and post-mortem pathology, with an interval of ≤ 5 years between imaging and death, were examined. Normalized CP volume (NCPV) was semi-automatically segmented from the lateral ventricles and analyzed using Bayesian linear regression to estimate associations with cognitive impairment (CI), AD pathology, and relevant clinical/demographic data. Results Intermediate and high levels of AD pathology and CI were associated with larger NCPV, whereas female sex was associated with lower NCPV. Subgroup analyses showed larger NCPV in individuals with greater CI despite comparable levels of AD pathology. Discussion These findings link CP enlargement to neuropathologically confirmed AD burden and CI, supporting further investigation of CP structure and function in AD.

The cerebellum has garnered increasing interest as a promising deep brain stimulation (DBS) target for dyskinetic cerebral palsy and other conditions such as cerebellar ataxia and stroke. Functional MRI of cerebellar stimulation can facilitate a more comprehensive understanding of the mechanisms underlying symptom response; however, evidence regarding its safety and feasibility is lacking. In this report, we first assessed the risk of radiofrequency-induced heating through simulations informed by postoperative CT images from 3 patients with distinct cerebellar DBS hardware orientations. Following heating estimates, and as part of an ongoing trial (NCT06122675), we then collected 3 functional MRI runs in one anesthetized patient with DBS turned ON, turned OFF, and cycled ON/OFF in 30-second intervals. Simulations suggested acceptable heating under our scanner and sequence conditions, with peak temperature increases ranging from 0.6°C-1.5°C. Preliminary stimulation-induced brain activations and functional connectivity changes appeared consistent with the underlying structural anatomy.

PURPOSE:To introduce SelExNet: a self-supervised framework for two-dimensional spatially selective excitation that jointly optimizes radiofrequency (RF) pulses and gradient waveforms, and extends to multi-channel transmission MRI. METHODS:Building on prior RF-only and joint RF-gradient optimization approaches, SelExNet couples neural RF and gradient generators with a differentiable Bloch simulator to enable self-supervised pulse optimization without requiring pre-designed target pulses. The framework jointly designs RF pulses and parameterized variable-density spiral gradient waveforms for both single- and multi-channel transmission, with patient-specific adaptation using measured, previously unseen B 0 and B 1 + maps. RESULTS:Joint optimization of RF and gradients improved excitation fidelity compared to RF-only optimization. In phantom experiments with synthetic field maps, pretrained pulses showed distortions, whereas fine-tuned pulses restored geometry and uniformity. In vivo studies demonstrated anatomically precise excitation, with fine-tuning improving sharpness and reducing off-target signal. CONCLUSION:The proposed framework enables joint RF-gradient design and extends self-supervised pulse optimization to multi-channel transmission MRI. SelExNet achieves high-fidelity, anatomically precise excitation and demonstrates robustness to field inhomogeneities, offering a scalable pathway for ultra-high field imaging.

OBJECTIVE:Psychosis in Alzheimer's disease (AD), including hallucinations and delusions, affects up to 50% of patients and is linked to faster cognitive decline. Delusions can occur across AD, with persecutory delusions early and misidentification delusions late, while hallucinations emerge in advanced stages and predict greater cognitive and functional decline. The APOE4 allele is the strongest genetic risk factor for late-onset AD, although its influence on neuropsychiatric symptoms, including psychosis, remains unclear. This study examined the interaction between APOE4 status, sex, EHT use, and psychosis symptoms in AD using data from participants in the National Alzheimer's Coordinating Center Uniform Data Set. METHODS:Generalized Additive Models assessed nonlinear associations between predictors and psychosis outcomes, including the presence of delusions, hallucinations, and their visual and auditory subtypes. Analyses were stratified by sex (males: n = 13,841, females: n = 15,354). Predictor variables included APOE4 status, current use of estrogen hormone therapy (EHT) in females. Due to limited data availability, CSF biomarkers (Aβ1-42, p-tau181, t-tau) could not be included in the main models and were instead examined in a secondary sub analysis. RESULTS:APOE4 homozygosity was associated with significantly greater odds of delusions in the past month in both males and females, with a stronger effect in females (p<0.05). In females only, APOE4 homozygosity was significantly associated with hallucinations, with no effect in males (p<0.05). EHT was associated with lower risk of hallucinations in females (p<0.05). CONCLUSIONS:These findings underscore sex-specific genetic and biological contributors to psychosis in AD and support sex-stratified approaches to understanding and addressing psychosis symptoms in clinical settings.

BACKGROUND AND PURPOSE:Diffusion MRI measures indicative of white matter integrity have consistently been shown to be altered in the state of the corticospinal tract (CST) and corpus callosum (CC) of patients with amyotrophic lateral sclerosis (ALS). However, diffusion MRI acquisitions are not routinely collected as part of the standard medical imaging of patients with ALS. T1-weighted MRI scans are commonly available in the clinical assessment of most patients with ALS. While visual inspection of these scans reveals little about the cerebral pathology of ALS, analysis of their textural patterns has identified disease-related abnormalities in patients at various stages of the disease. The present study aimed to examine the spatial and temporal profile of CST and CC degeneration in patients with ALS using texture analysis of T1-weighted MRI scans obtained at baseline and at 4- and 8-month follow-ups. MATERIALS AND METHODS:The study involved data from 64 patients with ALS and 83 healthy controls who participated in the multicenter Canadian ALS Neuroimaging Consortium (CALSNIC) project. The texture feature "autocorrelation" (autoc) was quantified along the superior-inferior course of the CST and along the anterior-posterior direction of the CC of participants. RESULTS:Progressive textural changes were observed within the bilateral CST, particularly in the primary motor cortex region, posterior limb of the internal capsule, and the cerebral peduncle. As the disease progressed, significant textural changes developed in the middle and anterior parts of the CC. Autoc values in these regions correlated with the degree of upper motor neuron dysfunction on neurologic examination. CONCLUSIONS:Progressive CST and CC degeneration was characterized in ALS using a novel imaging texture analysis approach, with changes observed over an interval of 4 months.

Background:Motor vehicle accidents remain a leading cause of accidental death worldwide. Death and injury rates are particularly high for both young inexperienced drivers and elderly drivers. Understanding the behavioral changes that are associated with maturation and aging could inform assessments of driving performance and lead to new measures identifying at-risk drivers. To shed further light on such effects, this study aims to characterize simulated driving behavior across and within age groups using a large driving simulation dataset. Methods:The analyzed dataset consisted of 112 participants [47/112 (42%) female] between the ages of 17 and 85 (average ± standard deviation: 54 ± 22 years). Participants performed navigation in scenarios modeled after the standard licensing test of Ontario, Canada, which included a series of turns at intersections with different levels of complexity (e.g., involving oncoming traffic or pedestrians) and levels of distraction (requiring auditory responses to common-knowledge questions). Behavioral metrics were defined and investigated not only for the full completion of each task but also based on common subtasks (e.g., braking at an intersection), which were then compared across and within age groups (young, middle-aged, old). Results:Overall, young adults behaved similarly to middle-aged adults for basic tasks but showed differences during traffic navigation subtasks when distracted, such as starting to decelerate significantly later when approaching intersections. Old drivers, on the other hand, drove at lower average speed, stopped earlier at intersections, and left increased distances to pedestrians, but required significantly more time to complete the driving tasks. Conclusion:With rich detail arising from intra-task quantification, the results were consistent with and additive to previous literature showcasing that compared to middle-aged adults, young adults showed performance suggestive of riskier driving behavior, and old adults showed performance suggestive of caution consequent to declining driving ability. In particular, the intra-task quantification revealed that the driving of young adults was more impacted by the presence of distraction (e.g., delayed decelerating), whereas old adults prioritized safe driving (e.g., correctly braking at intersections) over responding to distractions. The study may be used as motivation for future studies of driving safety and accident prevention, and informed assessment of governmental regulations.

Mild Cognitive Impairment (MCI) is a frequent precursor to Alzheimer’s dementia (AD). Mitochondrial dysfunction, marked by reduced cytochrome c oxidase (CCO) activity and lower ATP production, is linked to these neurodegenerative diseases. This study evaluates transcranial photobiomodulation (tPBM), a non-invasive technique using near-infrared light to stimulate mitochondrial CCO, potentially enhancing neuronal energy and cognitive function in individuals with MCI. Twenty patients with mild cognitive impairment (MCI) were randomly assigned to an active treatment group (n = 10) or a sham control group (n = 10) using visually identical devices to maintain blinding. Participants completed daily home-based tPBM sessions for 6 weeks. Pre- and post-treatment assessments included cognitive tests (MMSE, TMT-A & B, CVLT-II) and biomarker evaluations (blood samples via ELISA). Neuroimaging included proton magnetic resonance spectroscopy (¹H-MRS) of the posterior cingulate cortex (PCC) and whole-brain structural and resting-state functional MRI. Change scores were calculated by subtracting baseline from post-treatment values. Compliance exceeded 98% in both groups, and tPBM was well-tolerated. The active tPBM group showed significantly greater post-treatment improvements from baseline (p < 0.05) compared to the sham group, including: (1) better recognition memory (higher long-delay hits, fewer false positives on the CVLT-II); (2) improved cognition (higher MMSE); (3) faster processing speed (shorter TMT-B times); (4) decreased plasma IL-6 levels; (5) higher choline/creatine ratio and a trend toward increased myoinositol/creatine in the PCC; (6) increased left nucleus-accumbens volume; and (7) enhanced functional connectivity within the DMN and between the caudate and DMN, along with decreased FC within the limbic network. Daily, home-based tPBM is a well-tolerated and feasible intervention that led to significant improvements in both cognitive function and biological markers in individuals with MCI. The active tPBM group demonstrated enhanced cognition, recognition memory, and processing speed, alongside reductions in inflammation and structural and functional brain changes, including increased neuroplasticity and alterations in brain connectivity. These findings suggest that tPBM may promote neuronal function and brain network modifications, particularly within the default mode network and limbic regions, providing evidence for its potential as a therapeutic approach in the early stages of Alzheimer's disease.

Oxidative stress (OS) has been implicated in age-related neurodegeneration and may be important in prodromal states such as vascular mild cognitive impairment (vMCI). Higher peripheral OS is reported in vMCI patients; however, the role of central antioxidant defenses in vMCI and their correlation to cognition is unclear. Glutathione (GSH) is a major brain antioxidant, and the current study assessed brain GSH in possible vMCI vs. controls. Possible vMCI patients (1 standard deviation (SD) below population norms in verbal memory, executive function (EF), processing speed, or working memory, age 55-85, and currently enrolled in a 6-month exercise rehabilitation program due to having 2 or more vascular risk factors or previous vascular event) and cognitively-normal (CN) controls were recruited. All participants received 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy) to quantify brain GSH at baseline in the anterior cingulate (AC) and occipital lobe (OL). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b). In 43 participants (mVCI n = 22, CN n = 21), AC-GSH (I.U. ± SD) was higher in mVCI (1.96 ± 0.29) compared to CN (1.64 ± 0.48) (F (1,29.7) = 6.9, p = .01); this difference remained after correcting for cerebrospinal fluid (CSF) volume (F (1,28.4) = 6.5, p = .02), and controlling for age and sex (B [SE] = 0.33 [0.11], p = .007). There was no difference in OL-GSH before or after correcting for CSF volume. Higher AC-GSH, but not OL-GSH, was correlated with poorer global cognition (Montreal Cognitive Assessment -Full score, B [SE] = 2.15, p = .03), and poorer EF performance (B [SE] = -0.67 [0.25], p < .001). These relationships remained significant after correcting for CSF volume. The current study suggests an upregulation of AC glutathione in vMCI, which may reflect a compensatory increase in antioxidants as a response to oxidative stress challenges reported in these patients. Higher brain GSH in the AC region is correlated with poorer global cognition and executive function performance, suggesting a link between local brain antioxidant response and disease-relevant cognitive domains.

Neuropsychiatric Symptoms (NPS) in Alzheimer's Disease (AD) can exacerbate symptom burden and impair quality of life in patients. It is imperative to gain a better understanding of factors that contribute to NPS manifestation. This study explores the association between NPS scores and blood-based biomarkers implicated in AD including Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light Chain (NFL), Amyloid Beta 40 (AB40), Amyloid Beta 42 (AB42), and Phosphorylated Tau at Threonine 181 (pTAU181). Individuals with a diagnosis of Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI) were included based on data from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) database. From 126 participants, 107 had completed the Neuropsychiatric Inventory Questionnaire (NPI-Q) and provided blood samples for measurement of GFAP, NFL, AB40, AB42, and pTAU181 plasma levels. To assess the association between NPS severity scores and blood-based biomarkers, a partial Spearman correlation was conducted; adjusting for age, sex, and education level. A False Discovery Rate (FDR) threshold of 0.05 was applied to all p -values to control for multiple comparisons. We found significant correlations between several NPS domains and blood-based biomarkers. Apathy scores had a significant positive correlation with pTAU181 ( Rs  = 0.27, p  =  0.04) and NFL plasma levels ( Rs =0.30, p  =  0.02); Anxiety scores showed a significant positive correlation with GFAP ( Rs  = 0.28, p  =  0.03) and NFL plasma levels ( Rs  = 0.33, p  =  0.006); Euphoria scores were positively correlated with NFL plasma levels ( Rs  = 0.27, p  =  0.05); Appetite, Motor function, and Total NPI severity scores had a significant positive correlation with GFAP plasma levels ( Rs  = 0.31, p  =  0.01; Rs = 0.31, p  =  0.01; Rs = 0.29, p  =  0.03). No significant findings were observed for AB40 and 42 with any NPS domain. Our findings suggest that certain blood-based biomarkers—pTAU181, NFL, and GFAP— are associated with the development of NPS in Alzheimer's Disease. These biomarkers may help shed light on underlying mechanisms and monitor NPS severity. However, further research in larger cohorts and longitudinal studies is needed to confirm these findings and explore causal relationships.

Neuropsychiatric symptoms (NPS) are prevalent in individuals with Alzheimer's disease (AD), impacting disease progression and patient quality of life. AD pathology (amyloid and tau) and related TDP-43 neuropathology may contribute to NPS. The National Alzheimer's Coordinating Center (NACC) database was used to explore the relationship between NPS and AD, TDP-43 neuropathology and clinical diagnosis. A total of 1391 participants from the NACC database were included in the analysis, with data available on NPS (NPI-Q domains), clinical diagnosis (normal cognition, impaired-not-MCI, MCI, and dementia) and neuropathology. Logistic and linear regression models assessed associations between NPS presence or absence, severity and interactions involving clinical diagnosis and AD and TDP-43 neuropathology, including their co-occurrence. Age, sex, education, cognitive scores, and APOE e4 status were adjusted for in all models. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to quantify the effects. The regression models for several NPS domains were statistically significant with clinical diagnosis being the most consistent across domains (Table 1). The clinical diagnosis and neuropathology were significantly associated with apathy (OR = 2.80, 95% CI [2.13, 3.66], p < .001; OR = 1.74, 95% CI [1.09, 2.80], p = .021, respectively) and delusions (OR = 2.71, 95% CI [1.44, 5.09], p = .002; OR = 3.12, 95% CI [1.14, 8.54], p = .026, respectively). Interaction effects were also observed for apathy (OR = 0.88, 95% CI [0.77, 1.00], p = .049) and delusions (OR = 0.75, 95% CI [0.58, 0.98], p = .038). Clinical diagnosis also influenced NPS severity in nighttime behaviors (β = 1.14, 95% CI [0.02, 0.26], p = .018) and apathy (β = 0.16, 95% CI [0.01, 0.32], p = .039). Age, sex, education, cognitive scores, and APOE e4 status had domain-specific effects. The findings highlight the role of clinical diagnosis on NPS across domains, with AD and TDP-43 neuropathology and demographic factors exerting domain-specific effects, most notably in delusions and apathy. Interaction effects between neuropathology and clinical diagnosis were only seen in apathy, suggesting that pathology and clinical diagnosis may have independent effects on NPS. Future research is warranted to examine these effects longitudinally.