Brain Structure and Function

Syntax processing impairment is a defining feature of primary progressive aphasia (PPA), particularly in the nonfluent/agrammatic variant. However, current models are derived largely from Indo-European languages, and it remains unclear whether the cognitive and neuroanatomical mechanisms of syntax processing generalize to Chinese, an analytic, pro-drop language that encodes grammatical relationships primarily through word order and function words rather than inflectional morphology. Participants were recruited from the international Chinese Language Assessment in PPA cohort and included 64 individuals with PPA (19 logopenic, 15 nonfluent/agrammatic, 15 semantic, and 15 unclassifiable/mixed) and 60 cognitively healthy controls. Participants completed sentence comprehension and production tasks with systematically manipulated syntactic features. Item-level linguistic determinants were examined using ridge regression, diagnostic performance using receiver operating characteristic analyses, and neuroanatomical correlates using voxel-based morphometry of structural MRI. Performance on sentence comprehension and production was influenced by grammatical and lexical features. Subject-relative clauses, passive constructions, a higher proportion of function words, longer character length, and greater lexical content were associated with poorer performance among participants with PPA. Sentence comprehension was impaired in the logopenic, nonfluent/agrammatic, and semantic variants, even when isolated to the syntactic component of the sentence comprehension task. Similarly, sentence production was impaired across all PPA variants (all P < 0.01 versus controls). No significant differences were observed among PPA variants. Adjusted receiver operating characteristic analyses demonstrated high discrimination between each PPA variant and controls, with areas under the curve ranging from 0.87 to 0.97 for sentence comprehension-syntax and from 0.91 to 0.97 for sentence production. However, pairwise comparisons showed no significant differences in discriminative performance among PPA variants after correction for multiple comparisons. Both sentence comprehension-syntax and sentence production showed associations with semantic and repetition measures in addition to motor speech measures. Voxel-based morphometry showed that higher sentence comprehension-syntax scores were associated with greater grey matter volume in left frontotemporal and cingulate regions, whereas higher sentence production scores were additionally associated with greater gray matter volume in frontostriatal structures, including the caudate, putamen, and thalamus. Syntactic processing impairment in Chinese-speaking individuals with PPA extends beyond the nonfluent/agrammatic variant and is associated with distributed frontotemporal and frontostriatal regions, as well as lexical-semantic and auditory verbal short term memory mechanisms. These findings suggest that the cognitive and neural manifestations of syntactic impairment may be shaped by language-specific typological properties, underscoring the need for linguistically informed approaches to the assessment and interpretation of PPA.

Chinese is one of the living languages with the highest homophone densities, making homophone processing a critical component of language comprehension and orthographic decoding, as well as an ideal model for examining its cognitive mechanisms. This study assessed mono- and bi-character homophone selection function in 129 Mandarin- and Cantonese-speaking participants, including 66 cognitively healthy individuals, 17 with semantic variant (sv) primary progressive aphasia (PPA), 23 with the nonfluent/agrammatic variant (nfv) PPA, and 23 with the logopenic variant (lv) PPA. All PPA variants showed impairment in homophone selection, with most significant deficits in svPPA and lvPPA. ROC analyses demonstrated its strong diagnostic utility for distinguishing PPA from controls. Voxel-based morphometry revealed that homophone performance correlated with gray-matter volume in left anterior and inferior temporal regions, with variant-specific patterns observed. These findings described the potential role of homophone selection in diagnosing PPA syndrome in Chinese speakers, illuminate crosslinguistic influences on language impairment in PPA, and provide novel insights into the cognitive processing of homophones.

INTRODUCTION: The basal forebrain (BF) provides the principal cholinergic innervation to the cortex and the hippocampus and is among the earliest regions affected by neurodegenerative processes. Yet, whether its subnuclei differ in how their structural integrity changes with age and in their vulnerability to neurological and psychiatric disorders is unresolved. METHODS: Here, in 81,870 UK Biobank participants aged 45-87 years, we built age- and sex-specific normative models of grey-matter volume in the nucleus basalis of Meynert (Ch4) and the septal/diagonal-band (Ch1-3) compartments of the BF and derived individual deviation from these norms. We then tested the selectivity of their normative deviation profile across cross-sectional and longitudinal ageing, manifest neurological and psychiatric disorders, pre-diagnostic neurodegeneration, prospective disease incidence, and neuropsychiatric polygenic liability. RESULTS: The two compartments followed distinguishable age-related profiles across mid-to-late adulthood, which persisted when examined using longitudinal data. Deviation from norms was generally concentrated in Ch4 across neurological diseases and, in almost no condition, greater in the Ch1-3. The Ch4 deficit was further detectable years before diagnosis, was not substantially explained by common inherited genetic risk, and was linked with incident dementia and Parkinson's disease, whereas Ch1-3 carried no independent prospective structural vulnerability. DISCUSSION: These findings identify an anatomically specific age-related profile of the human BF, with structural vulnerability manifest and pre-diagnostic neurological disorders, which is not substantially explained by common inherited risk.

Background: Cervical spinal cord (CSC) compression and myelopathy are frequent, severe complications in mucopolysaccharidosis (MPS) types I and VI. Early detection is critical to prevent irreversible neurological deficits and preserve quality of life. This prospective study aimed to identify quantitative neuroimaging biomarkers of structural CSC damage and myelopathy in MPS I and VI. Methods: Structural and diffusion magnetic resonance imaging (MRI) of the CSC was analyzed in 17 MPS I patients, 3 MPS VI patients (19{+/-}7 years), and 19 case-matched healthy controls (20{+/-}7 years). CSC macrostructure (cross-sectional area, diameters) and microstructure (fractional anisotropy [FA], radial [RD], mean, axial diffusivities) were evaluated within and beyond the maximal compression areas. Results: MPS patients demonstrated reduced CSC cross-sectional area and anterior-posterior diameter at upper cervical levels, alongside widespread microstructural alterations (lower FA, higher RD) throughout the CSC versus controls (pFDR<0.05). Restricted foramen magnum space was associated with microstructural damage at lower cervical levels without overt macrostructural compression. Morphological and microstructural metrics were sensitive to CSC compression and myelopathy severity (pFDR<0.05). Lower CSC integrity correlated with more advanced growth retardation (p<0.001). Among patients receiving hematopoietic stem cell transplantation, earlier treatment correlated with preserved upper CSC morphology (p<0.05). Distinct neuroimaging phenotypes were observed across MPS genotypes (pFDR<0.05). Conclusions: CSC MRI provides candidate neuroimaging biomarkers for early detection and characterization of myelopathy in MPS I and VI. Structural damage extends beyond primary maximal compression areas, highlighting these markers for clinical monitoring and future therapeutic trials.

Purpose: To evaluate whether visually assessed high-quality prostate MRI, as defined by the Prostate Imaging Quality (PI-QUAL) scoring system, is sufficient to ensure consistent AI model performance, or whether hidden acquisition-related technical effects introduce variability that cannot be detected through visual inspection. Methods: This retrospective study included 568 bpMRI scans from seven institutions, classified using PI-QUAL v2 into high-quality (scores 2-3) and low-quality (score 1) groups. Quantitative image quality features were extracted using MRQy from T2w and ADC sequences. Three experiments were conducted on high-quality scans: (1) unsupervised clustering to identify hidden technical batch effects; (2) V-Net models (M) for prostate capsule segmentation on T2w using single-cluster and balanced multi-cluster training strategies; and (3) VoxelMorph-based deformable registration (M2) to align ADC maps to T2w images. Performance metrics included DSC, precision, recall, volume ratio, HD95, ASSD, and TRE. Kruskal-Wallis tests assessed cross-cluster variability, Two One-Sided Tests (TOST) evaluated performance equivalence, and bootstrap resampling quantified training efficiency. Results: Clustering identified four clusters among 277 high-quality bpMRI scans. Single-cluster models showed variable performance (DSC=0.41-0.85) with significant batch effects (p<0.001), even with 140 training samples. The balanced multi-cluster model (n=60) eliminated batch effects (p=0.075), achieved equivalent performance (p<0.001), and demonstrated 2.23-fold greater training efficiency despite using 2.3-fold fewer samples. Registration performance also varied significantly across clusters (TRE=0.86-5.47 mm, p<0.001). Conclusion: Acquisition-related batch effects significantly impact AI generalizability in prostate MRI, even among high-quality scans. Quantitative clustering enables detection of technical variations and supports diversity-aware training strategies that achieve equivalent performance with 2.3-fold fewer samples while eliminating batch effects.

Lesion network mapping (LNM) has provided a compelling framework in clinical neuroscience, linking focal brain damage at heterogeneous anatomical locations to shared functional networks across behavioural syndromes. Recently, the methodological specificity of LNM has come under discussion following observations that derived network maps tend to converge onto the normative connectome's generic degree distribution. While current efforts largely treat this convergence as a statistical inference challenge addressable via post-hoc spatial null models or individual-level analyses, we identify a foundational upstream measurement artifact operating within individual patients: the lesion "bystander effect". Because pathological lesions follow biological constraints rather than functional brain parcellations, a typical lesion encapsulates both a symptom-driving critical node and surrounding asymptomatic bystander tissue. By averaging connectivity profiles across the entire lesion mask, LNM mechanically dilutes focal clinical signals. Across empirical clinical cohorts, individual-level machine learning classifiers, synthetic within-cohort lesion unions, and whole-brain spherical simulations, we demonstrate that increasing lesion extent deterministically drives network maps toward the connectome degree vector following a mathematical power law. Fulfilling the clinical promise of LNM will therefore require computational strategies that isolate the causal functional core from surrounding bystander tissue prior to network projection.

Background: Dopamine replacement reshapes subthalamic activity in Parkinson's disease, but whether this response reflects anatomically organized network reconfiguration remains unclear. Objectives: To determine whether levodopa preferentially reorganizes dorsal subthalamic spectral activity and cortico-subthalamic directionality. Methods: Twelve participants undergoing bilateral subthalamic deep brain stimulation contributed 30 contacts (14 dorsal, 16 ventral). Recordings obtained OFF and ON medication underwent spectral parameterization and multiband state-space analysis. Simultaneous electroencephalography in six participants enabled assessment of directional cortico-subthalamic coupling using the phase slope index. Results: Levodopa suppressed beta power more strongly dorsally than ventrally (-2.473 versus -0.120 dB; p=0.0438). Dorsal theta power increased, with a trend toward an increase after baseline normalization (p=0.07). Dorsal contacts exhibited greater theta-beta (+5.904 versus +1.610 dB; p=0.006) and gamma-beta (+2.516 versus +0.384 dB; p=0.0188) state-space shifts, principally driven by beta suppression. Gamma changes did not differ regionally. Concurrently, dorsal low-beta and beta interactions shifted toward cortical leading at selected electrodes, whereas ventral responses were less consistent. Conclusions: Levodopa produces a topographically organized subthalamic response, combining preferential dorsal beta suppression with altered cortico-subthalamic directionality. These findings position contact anatomy as a key consideration in characterizing dopaminergic network responses and motivate clinical validation of spatially informed multiband biomarkers for adaptive stimulation.

Background: Ultra-low field (ULF) magnetic resonance imaging (MRI) offers accessible point-of-care neuroimaging, yet its capability to support multivariate network analyses remains understudied. Methods: We systematically evaluated the feasibility and reliability of Morphometric Similarity Networks (MSN) and Morphometric Inverse Divergence (MIND) networks derived from paired high-field (HF, 3T/1.5T) and ULF (64mT) scans in a primary cohort(N=23) and an independent replication cohort (N=19). We tested the impact of super-resolution processing, cortical parcellation granularity (Desikan-Killiany vs. Destrieux), and mesh resolution (fsnative vs. fsaverage5) on edge-level cross-scanner agreement (Lin's concordance correlation coefficient, CCC) and subject-level identifiability. Results: MIND networks demonstrated higher edge-level HF-ULF agreement (mean CCC = 0.95) and ULF reproducibility (mean CCC = 0.98) compared to MSNs (mean CCC = 0.86-0.87 and 0.91-0.94, respectively). In contrast, MSNs yielded higher subject-level differential identifiability across field strengths due to a broader distinction between within- and between-subject similarity. Reconstructing MIND networks on native high-resolution meshes (fsnative) maximised cross-scanner agreement, whereas coarser meshes and finer cortical parcellations enhanced individual network identifiability. Conclusions: Structural similarity networks can be reliably constructed from ULF MRI data. Optimal analytic choices depend on study objectives: MIND on native meshes maximises cross-scanner stability, whereas MSNs excel at preserving individual uniqueness, paving the way for globally scalable connectomic research.

Background: Quantitative susceptibility mapping (QSM) exhibits phase cancellation between paramagnetic (e.g. iron) and diamagnetic (e.g. myelin/protein) sources, obscuring microstructural lesion heterogeneity in multiple sclerosis (MS). We evaluated whether biophysical {chi}-separation identifies clinically meaningful lesion phenotypes and whether reduced echo sampling preserves microstructural sensitivity. Methods: In this cross-sectional study of 183 people with multiple sclerosis (PwMS), we analyzed 3327 quality-controlled white matter lesions using 3T MRI with a five-echo gradient-recalled echo sequence (GRE5) and a subsampled two-echo dataset (GRE2). A hybrid framework combining unsupervised clustering on whole-lesion paramagnetic ({chi}para) and diamagnetic ({chi}dia) features with rule-based compartmental edge-core gradient assignment resolved MS lesion phenotypes. Intralesional microstructural properties were evaluated using linear mixed-effects models. Multivariable linear regressions assessed associations with physical disability (Expanded Disability Status Scale, EDSS; n = 158), cognitive processing speed (Symbol Digit Modalities Test, SDMT; n = 79), and disease duration (DD; n = 161), with sensitivity models adjusting for total lesion volume, count, or DD. Results: The framework identified four reproducible lesion phenotypes (Adjusted Rand Index = 0.924): Type 1 (22.7%; preserved {chi}dia), Type 2 (32.9%; high {chi}para without positive edge-core gradient), Type 3 (35.8%; attenuated {chi}dia), and Type 4 (8.6%; high {chi}para with a positive edge-core paramagnetic gradient). Higher EDSS was selectively associated with more negative signed {chi}dia within Type 4 lesions (whole: {beta} = -0.37, q = 0.020; core: {beta} = -0.37, q = 0.006; edge: {beta} = -0.34, q = 0.030) and Type 2 edge ({beta} = -0.33, q = 0.044). Type 4 core associations remained robust across sensitivity models adjusting for total lesion volume ({beta} = -0.35, q = 0.004), total lesion count ({beta} = -0.37, q = 0.008), and DD ({beta} = -0.32, q = 0.033). Abbreviated GRE2 attenuated Type 4 compartmental associations to non-significance (all q greater than 0.05; core: {beta} = -0.20, q = 0.215). Conclusions: Quantitative {chi}-separation identified four internally stable susceptibility-defined MS lesion phenotypes, revealing disability-associated tissue heterogeneity beyond total lesion burden. Higher EDSS was associated with more negative diamagnetic measures within Type 4 cores after adjustment for lesion burden, pointing toward complex intralesional non-myelin tissue remodeling or reactive astrogliosis. Two-echo subsampling may influence compartment-specific clinical associations. By uncoupling susceptibility sources, {chi}-separation provides a quantitative framework for characterizing disability-associated lesion heterogeneity.

Structural variants (SVs) are larger genetic rearrangements such as deletions, duplications, and insertions and other forms of structural alterations. Given their large size, they can have an outsized effect on phenotype, however, the contribution of SVs to the genetic architecture of orofacial clefts (OFCs) is not well understood. In this study, we sought to better understand the contribution SVs to OFC risk by characterizing de novo SVs (dnSVs) in 1,549 probands with an OFC. Overall, we called 375 dnSVs in 307 probands (0.242 dnSVs per genome). The dnSV rate per genome was highest among individuals with cleft lip (CL, 0.29), followed by cleft lip and palate (CLP, 0.25) and cleft palate only (CP, 0.20), though differences across subtypes were not statistically significant. There were also no differences between sex or syndromic status, but we did identify a significant difference in the rate of duplications across OFC subtypes (p=0.005). Compared to CP (0.028), duplication rates were significantly higher for both CL (0.121; p = 0.003) and CLP (0.096; p = 0.002), suggesting a potential etiologic mechanism for CL/P. We systematically curated each dnSV to classify its potential for influencing OFC risk by examining the genes and regulatory elements disrupted by the SV and evidence for their role in craniofacial development or OFCs. We identified 22 dnSVs in regions associated with recurrent genomic disorders, including seven deletions and one duplication of the well-established OFC risk locus 22q11.2. Additionally, we identified 12 large (>1Mb) SVs, with eight meeting criteria for a likely pathogenic classification based on total gene involvement, and seven dnSVs disrupting well-known genes associated with autosomal dominant forms of OFC. The most notable was SATB2, for which we found four dnSVs, all in individuals with CP. Next, by combining evidence from recurrent dnSVs and de novo single nucleotide variants with Hi-C contact maps and predicted chromatin states from developing craniofacial tissues, we found new candidate genes for OFC risk including FHAD1, NBEA, NR3C2, and SPHKAP. Overall, dnSVs classified as likely pathogenic accounted for putative molecular diagnoses in approximately 1.67% of the cohort, with an additional 0.96% having variants of unknown significance with plausible risk for OFCs. Our results support dnSVs as an important component of OFC etiology and suggest their inclusion in analyses may improve diagnostic yield for affected individuals.

Introduction: Cognitive intraindividual variability (IIV), a measure of fluctuation in performance across time or tasks, is an emerging marker of cognitive decline. However, little is known about within-domain IIV in Latino adults. To address this gap, we examined memory IIV and hippocampal integrity in older Latino individuals. Methods: Sixty-seven participants from the Boston Latino Aging Study underwent cognitive testing and MRI. Linear regressions assessed whether memory IIV was associated with hippocampal volume and hippocampus-cingulum tract fractional anisotropy. Additional analyses evaluated associations using mean memory performance as the outcome. Results: Higher mean performance was associated with greater hippocampal volume (=0.24, p=.03), while memory IIV was not (=0.028, p=.84). Higher memory IIV was associated with lower fractional anisotropy in the hippocampus-cingulum tract (=-0.34, p<.01), while mean performance was not (=-0.07, p=.52). Discussion: Memory IIV may be more closely linked to hippocampal white matter, while mean memory performance may better reflect hippocampal volume.

Introduction: Neuroinflammation is a known pathophysiologic mechanism in multiple sclerosis and a proposed mechanism in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Positron Emission Tomography (PET) imaging of the translocator protein (TSPO) has been widely used to measure neuroinflammation, though second-generation ligands are highly sensitive to a single nucleotide polymorphism, rs6971, resulting in high, mixed, and low affinity binders. It is unknown whether this polymorphism is associated with neuroinflammatory disorders. Materials and Methods: Eighty-six total participant genotypes for TSPO binding affinity were identified through Sanger sequencing (30 fibromyalgia, 21 ME/CFS, 11 multiple sclerosis, and 24 healthy controls). Associations between patient group and genotype were assessed with Fishers Exact test. Associations between genotype and symptom severity from self-report questionnaires were assessed with Kruskal-Wallis tests. Results: In the present study individuals with fibromyalgia, (ME/CFS), or multiple sclerosis were more likely to have a mixed- or low-affinity genotypes compared to healthy controls. Presence of the low or mixed genotypes were also associated with greater self-reported fatigue severity and depressive symptoms. Discussion: These findings should be confirmed in larger samples but suggest functional consequences of rs6971 polymorphism that may be related to the pathophysiology of pain and fatigue illnesses.

INTRODUCTION: Whether APOE e4 modifies relationships between subclinical cardiac phenotypes and brain structure is unknown. METHODS: In Framingham Heart Study Offspring participants, we related antecedent echocardiographic remodeling (Examinations 4-6) to repeated brain MRI, and cardiac magnetic resonance phenotypes to regional cortical morphometry, testing cardiac x APOE e4 interactions with false-discovery-rate (FDR) correction and permutation testing of the regional screen. RESULTS: APOE e4 modified the association between antecedent left atrial (LA) remodeling and subsequent lateral ventricular expansion (beta=-0.00858, P=1.45 x 10^-4, q=0.0023; N=1,305; 3,787 MRI observations), the only FDR-significant result of 16 longitudinal tests, including with participant-specific MRI-time slopes (q=0.034); it weakened when intracranial volume x MRI time was modeled. Four regional ventricular cardiac x APOE e4 interactions met within-family FDR criteria, but their number was consistent with chance (permutation P=0.70). Maximum LA volume index showed an APOE e4-dependent association with left middle-occipital cortical-thickness variability (whole-brain q=0.017; permutation P=0.041) that persisted after ventricular adjustment. Cardiac phenotypes and trajectories showed no FDR-significant APOE e4-dependent associations with plasma Abeta42/40, p-tau181, GFAP, or NfL, and adjustment for these biomarkers changed the regional interactions by at most 3.2%. Allen Human Brain Atlas data showed cholesterol-biosynthesis enrichment in the right superior frontal cortex, implicated by the LV end-systolic volume interaction, but without convergent pathway evidence. DISCUSSION: APOE e4 modified atrial-brain relationships, with the strongest evidence linking antecedent atrial remodeling to later ventricular expansion. Replication with prespecified models is needed.

BACKGROUND: White matter hyperintensities (WMHs), the principal imaging manifestation of cerebral small vessel disease, lack an animal model that produces pathology of sufficient magnitude to validate potential therapeutics. We characterized white matter (WM) degeneration in a renovascular hypertension (RVH) rat model, interrogated its mechanism, and tested its relevance in patients. METHODS: RVH was induced by two-kidney, two-clip surgery and assessed by T2-weighted and diffusion MRI, myelin and axonal histology, and blood-brain barrier (BBB) leakage markers. The influence of angiotensin II (Ang II) on barrier function in brain endothelial cells was examined using transendothelial electrical resistance and reactive oxygen species (ROS) assays. Losartan was infused intracerebroventricularly to block brain AT1R (Ang II type 1 receptor) without systemic blood pressure reduction. WMH burden was compared between patients with and without renal artery stenosis, and WMH progression across antihypertensive classes was assessed in the CHALLENGE (Korea), MSS2 (UK), LBC1936 (UK), and SPRINT-MIND-MRI (US) cohorts. RESULTS: Approximately two-thirds of RVH rats developed WMHs that expanded between 7 and 9 weeks, accompanied by reduced fractional anisotropy, demyelination, axonal and mature oligodendrocyte loss, and glial activation. IgG, albumin, and fibrinogen leakage was confined to affected WM. Ang II impaired endothelial barrier function and generated ROS through AT1R. Intracerebroventricular losartan attenuated WM pathology and improved behavior while blood pressure remained comparably elevated. Patients with renal artery stenosis had higher WMH volumes (10.52 versus 6.52 mL; P = 0.035). Angiotensin receptor blocker use was associated with the slowest tertile of annual WMH progression in the Korean cohort (OR, 2.57 [95% CI, 1.20-5.61]) and among White participants in SPRINT-MIND-MRI (OR, 3.52 [95% CI, 1.05-12.29]). CONCLUSIONS: RVH produces prominent ischemic WM degeneration driven by AT1R signaling, identifying a blood pressure-independent therapeutic target with corroborating clinical evidence.

Magnetic Resonance guided High Intensity Focused Ultrasound (MRgHIFU) has been demonstrated to be a safe and effective minimally invasive therapy for essential tremor (ET). However, it is not clear whether older adults ([&ge;]70 years old) or individuals with comorbidities exhibit similar safety and efficacy. This IRB approved project collected EPIC EMR data on patients that underwent MRgHIFU at Parkview Regional Medical Center from January 2023 to November 2025. 68 patients were assessed for tremor severity using Clinical Rating Scale for Tremor (CRST), quality of life using Quality of life in ET Questionnaire (QUEST), and safety profile via reported post-procedure side effects. CRST and QUEST scores improved up to 1 year from baseline in our patient cohort and efficacies in older ([&ge;]70 years of age) and younger (<70 years of age) patients up to 3 months post MRgHIFU were not statistically different. Effects of comorbidities on CRST or QUEST scores improvements were all transient or did not affect endpoints. Older patients showed fewer total side effects at 3 months (1.17 (95% CI: 0.47-1.87) vs 0.21 (95% CI: -0.09-0.51), p=0.017) as did patients with pulmonary disease at 1 month (1.9 (95% CI: 1.6-2.2) vs 1.1 (95% CI: 0.9-1.3), p=0.036) while patients with family history of tremor showed more side effects at day 1 (1.5 (95% CI: 0.8-2.2) vs 2.5 (95% CI: 2.1-2.9), p=0.025). Age and comorbidities were not detected to adversely affect safety or efficacy following MRgHIFU in ET patients.

Background: Peripheral inflammation has been implicated in the pathophysiology of Parkinson's disease (PD), but its relationship with autonomic dysfunction remains unclear. Objectives: To explore the association between peripheral inflammation, assessed by the neutrophil-to-lymphocyte ratio (NLR), and autonomic function in patients with PD. Methods: We retrospectively analyzed 97 patients with PD who underwent 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy and differential blood cell counts. Associations of NLR with early and delayed heart-to-mediastinum (H/M) ratios, washout ratio, and the coefficient of variation of R-R intervals (CVRR) were assessed using Spearman's rank correlation and multivariable linear regression adjusted for age, sex, and disease duration. Results: No significant univariable correlations were observed between NLR and the autonomic measures. In multivariable analysis, higher NLR was associated with a lower early H/M ratio (B = -0.802, 95% CI -1.598 to -0.005, P = 0.049), whereas no significant associations were observed with the delayed H/M ratio, washout ratio, or CVRR. Sensitivity analyses showed a generally consistent direction of association, although the effect estimate was attenuated after exclusion of two influential observations and statistical significance was not consistently retained. Conclusions: Higher NLR was associated with lower early cardiac MIBG uptake after adjustment for age, sex, and disease duration in patients with PD. This exploratory finding raises the possibility of an association between systemic inflammation and sympathetic dysfunction in PD and requires confirmation in larger prospective studies.

Introduction: This study aimed to characterize the neurochemical profile of Alzheimer s disease (AD) continuum stages using proton magnetic resonance spectroscopy (1H-MRS) data for brain metabolites and macromolecules. We used Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) to classify diagnostic groups and assess feature importance. Methods: Our dataset consisted of 7 T short-echo time 1H-MRS spectra of the posterior cingulate cortex/precuneus of individuals diagnosed with AD (n = 27) or Mild Cognitive Impairment (MCI, n = 27) and Healthy Controls (HC, n = 31). Classification used 100-round Monte Carlo cross-validation based on metabolite concentrations and macromolecular peak intensities. Variable importance in projection (VIP) was assessed across classification models to identify the most relevant neurochemical features. The resulting metabolite rankings were compared with previous literature to evaluate their biological plausibility. Results: Classification was strongest for AD versus HC (AUC=0.88) and lower for comparisons involving MCI. Metabolites contributing most strongly to classification included myo-inositol, ascorbate, and choline-containing compounds, consistent with previous studies on AD-related neurochemical alterations. In addition, specific macromolecular components were identified as relevant features, suggesting a potential contribution of MM signals to the characterization of AD-related neurochemistry. Discussion: These findings support the use of short-echo-time 1H-MRS as a complementary tool for characterizing neurochemical changes in the AD continuum, with potential applications in disease characterization and monitoring, warranting validation in larger cohorts.

Background and Objectives Transient ischemic attack (TIA) diagnosis is challenging because it relies mainly on clinical assessment and exclusion of common differential. Functional MRI (fMRI) may provide a diagnostic biomarker by detecting transient brain dysfunction not visible on conventional imaging. This pilot study aimed to characterize acute motor-task BOLD activation in patients with suspected DWI-negative TIA and compare functional patterns between confirmed TIA and alternative diagnoses. Secondary objectives were to assess longitudinal changes in activation and connectivity at 3 months. Methods In this prospective single-center study, adults presenting within 24 h of transient anterior-circulation neurological symptoms underwent conventional MRI and additional motor-task fMRI. Patients with acute DWI lesions were excluded. Final diagnosis was established after 3-month follow-up. Whole-brain analyses, individualized motor cortex region-of-interest (ROI) analyses, and generalized psychophysiological interaction (gPPI) connectivity analyses were performed during the acute phase and at 3 months. Results Eight patients were enrolled; six had complete longitudinal imaging data and were included in the final analyses. Final diagnoses were TIA (n=2), migraine aura (n=2), functional neurological disorder (n=1), and hypoglycemia (n=1). Whole-brain and ROI analyses showed reduced bilateral motor-related BOLD responses during the acute phase in both TIA patients and in the patient with hypoglycemia. In contrast, patients with migraine and functional neurological disorder exhibited less marked longitudinal changes. In TIA patients, motor cortex activation increased at 3 months, tending to normalize toward values observed in non-TIA participants. Connectivity analyses revealed heterogeneous patterns, but the 2 TIA patients demonstrated increased longitudinal connectivity between the motor cortex contralateral to symptoms and other sensorimotor regions, including supplementary motor, premotor, parietal, and postcentral cortices. Discussion These preliminary findings suggest that TIA may be associated with transient bilateral reductions in motor-network activity. Functional abnormalities appeared to improve over time, supporting the hypothesis of reversible network dysfunction. Although limited by the very small sample size, this study provides the first longitudinal assessment of emergency task-based fMRI in rigorously defined TIA and supports further investigation of acute functional MRI as a potential biomarker of transient cerebral dysfunction.

Purpose: Posterior pharyngeal wall (PPW) thickening is a common structural manifestation of treatment-related internal lymphedema in patients with head and neck cancer and can be evaluated using lateral videofluoroscopic images acquired during modified barium swallow (MBS) studies. However, no standardized method currently exists for quantitative measurement. Methods: This two-phase methodological study first conducted a scoping review to characterize existing approaches to PPW thickness measurement and identify the principal factors contributing to variation in PPW thickness measurement. Eight studies were identified with variation observed across these measurement factors. An empirical reliability study was then performed using 107 MBS studies from 93 Head and Neck Cancer patients. Two independent raters annotated 10 anatomical landmarks on pre-swallow and post-swallow resting frames, and a computer-assisted algorithm quantitatively generated seven candidate PPW thickness measurements based on different vertebral reference points and measurement directions. Reliability was assessed intraclass correlation coefficients (ICCs). Results: Inter-rater reliability was highest for the measurement originating from the midpoint of C3 and extending perpendicular to the anterior C3 surface (ICC, 0.78; 95% CI, 0.72-0.83). Among the normalization references, C2-C4 vertebral length demonstrated greater reliability than C3 vertebral length, with an ICC of 0.88 (95% CI, 0.85-0.91). No significant differences were observed between pre-swallow and post-swallow PPW thickness measurements across the evaluated approaches. Conclusions: These findings provide a methodological foundation for more standardized and reliable quantification of PPW thickness, with potential to expand the role of MBS from the functional evaluation of swallowing to include quantitative characterization of pharyngeal structural abnormalities.

Background and Objectives Interictal spikes on intraoperative electrocorticography have been used to localize the epileptogenic zone but have limited specificity. We hypothesized that identifying spatially distributed, spike-associated very high-frequency activity (vHFA; 500-2,000 Hz) would improve the ability of spikes to localize the epileptogenic zone. We aimed to characterize spike-associated vHFA and to determine whether a seizure outcome prediction model incorporating vHFA could be externally validated across independent centers. Methods This retrospective two-center cohort study included patients with drug-resistant focal epilepsy who underwent electrocorticography and subsequent resection between January 2016 and May 2025. Spikes occurring across contacts within 50 ms were classified as co-occurring; all others were classified as isolated. We determined whether vHFA was associated with co-occurring spikes. We then assessed whether contacts enriched in vHFA-positive co-occurring spikes were more likely to be located within the resected region among seizure-free patients. Finally, we determined whether the rate of such spikes remaining outside the resection predicted seizure outcomes across the two centers. Results Among 56 patients (mean age: 21.2 years; 26 females), we identified 132,359 spikes, of which 1,925 were vHFA-positive. The vHFA peak preceded the associated spike peak by 8.0 ms (95%CI: 5.0-16.0). vHFA-positive spikes were more likely to be classified as co-occurring, even after adjustment for anatomy and inter-electrode distance (OR: 3.43; 95%CI: 2.82-4.17). Among the 35 seizure-free patients, contacts with higher rates of vHFA-positive co-occurring spikes were more likely to be resected (OR: 11.92 per occurrence/min; 95%CI: 5.62-25.32). This association was stronger than that observed for all spikes (OR: 1.09 per occurrence/min; 95%CI: 1.06-1.11). Twenty patients experienced postoperative seizure recurrence; a higher proportion of vHFA-positive co-occurring spikes in preserved areas was associated with recurrence (OR: 3.22 per 0.01 increase in proportion; 95%CI: 1.14-9.12). In bidirectional cross-center validation, models incorporating vHFA-positive co-occurring spikes yielded areas under the receiver operating characteristic curves of 0.80 and 0.69, with better performance when the model was developed using the larger sample. Discussion Spike-associated vHFA may identify a biologically meaningful subset of interictal spikes involved in propagation across the epileptogenic zone. vHFA-positive co-occurring spikes may represent a generalizable intraoperative biomarker of the epileptogenic zone.