Citations

Background/Objectives: Mild cognitive impairment (MCI) affects multiple functional and cognitive domains, rendering it challenging to diagnose. Brief mental status exams are insensitive while detailed neuropsychological testing is time-consuming and presents accessibility issues. By contrast, the Oculo-Cognitive Addition Test (OCAT) is a rapid, objective tool that measures oculometric features during mental addition tasks under one minute. This study aims to develop artificial intelligence (AI)-derived predictive models using OCAT eye movement and time-based features for the early detection of those at risk for MCI, requiring more thorough assessment. Methods: The OCAT with integrated eye tracking was completed by 250 patients at the Mayo Clinic Arizona Department of Neurology. Raw gaze data analysis yielded time-related and eye movement features. Random Forest and univariate decision trees were the feature selection methods used to identify predictors of Dementia Rating Scale (DRS) outcomes. Logistic regression (LR) and K-nearest neighbors (KNN) supervised models were trained to classify PMCI using three feature sets: time-only, eye-only, and combined. Results: LR models achieved the highest performance using the combined time and eye movement features, with an accuracy of 0.97, recall of 0.91, and an AUPRC of 0.95. The eye-only and time-only LR models also performed well (accuracy = 0.93), though with slightly lower F1-scores (0.87 and 0.86, respectively). Overall, models leveraging both time and eye movement features consistently outperformed those using individual feature sets. Conclusions: Machine learning models trained on OCAT-derived features can reliably predict DRS outcomes (PASS/FAIL), offering a promising approach for early MCI identification. With further refinement, OCAT has the potential to serve as a practical and scalable cognitive screening tool, suitable for use in clinics, at the bedside, or in remote and resource-limited settings.

ABSTRACT Lymphocytic colitis (LC) is a subtype of microscopic colitis, often associated with chronic watery diarrhea and characterized by an increase in intraepithelial lymphocytes. Although various medications are implicated in drug-induced LC, its incidence as a treatment-related adverse effect of rearrangement during transfection-selective tyrosine kinase inhibitors is not known. We report a case of pralsetinib-induced LC in a patient with stage 3c nonsmall cell lung cancer. This case highlights pralsetinib-induced LC as a cause of persistent diarrhea that is refractory to standard antidiarrheal treatments and prompts gastrointestinal evaluation and histopathological examination to facilitate early diagnosis and management.

Background/Objectives: To evaluate risk factors for postoperative neurological deficits following cervical endoscopic unilateral laminotomy for bilateral decompression (CE-ULBD) and to determine whether intraoperative neurophysiological monitoring (IONM) can predict neurological compromise. Methods: A multicenter retrospective review was performed on 42 CE-ULBD procedures conducted between 2016 and 2024; 33 cases met the inclusion criteria with available imaging and electromyography data. Demographic, operative, and neurophysiological variables were analyzed. Preoperative stenosis severity was graded using the Kang MRI system. Intraoperative IONM data, including electromyography firing and motor evoked potential (MEP) changes, were correlated with new postoperative weakness. Results: The cohort (69.1% male, mean age 70.2 ± 1.7 years, mean BMI 29.6 ± 1.1) included 56 decompressed levels. The most common operative levels were C3-4 (37%) and C4-5 (24%). Postoperative weakness occurred in four patients (12.1%), all of whom had severe (Grade 3) preoperative stenosis. Among these, 50% exhibited preoperative weakness. Neuromonitoring changes correlated significantly with postoperative weakness (Fisher’s Exact, p < 0.001); 100% of patients with new post-operative weakness had sustained MEP decrease at the time of closure. Conclusions: Patients with severe cervical stenosis and preoperative weakness are at heightened risk of postoperative neurological deficits following CE-ULBD. Elevated epidural pressure from continuous irrigation in a constricted canal may exacerbate cord compression, particularly in those with preexisting myelopathy. IONM changes strongly correlate with new deficits and may exacerbate cord compression, particularly in those with preexisting myelopathy, and may serve as an early warning system for impending neurological injury. Surgeons should exercise caution and maintain low irrigation pressures in patients with severe stenosis undergoing endoscopic cervical decompression.

Purpose: These consensus guidelines by the American Clinical Neurophysiology Society (ACNS) describe best practices for performing intraoperative Electrocorticography (ioECoG) using subdural or depth electrodes for adult and pediatric population. Methods: A group of ACNS members was convened to develop technical standards for performing ioECoG. PubMed searches were performed to identify pertinent peer-reviewed literature. Sections were assigned to individual authors based on expertise. Consensus was achieved during subsequent group discussions to develop evidence-based recommendations to the extent possible. Recommendations: Communication between the neurosurgical and the neurophysiology teams is essential in verifying and documenting the location of the contacts. Most authors recommend ioECoG recordings of at least 5 and up to 30 minutes in duration to allow for sufficient observation of interictal activity. The anesthesia should be adjusted to allow continuous EEG activity and to minimize the effect on the ioECoG recording during general anesthesia or awake surgery. The surgical procedure and technical report should separate ioECoG recordings to define the irritative zone from ioECoG findings during functional mapping. The neurophysiology physician’s physical presence in the operating room is required in the definition of the services. Conclusion: These consensus guidelines by the ACNS describe best practices for performing intraoperative ECoG based on published literature and expert consensus.

Abstract Background African Americans (AA) are twice as likely to develop dementia than non‐Hispanic Whites but remain underrepresented in Alzheimer's Disease (AD) research. Recent studies have identified AA specific risk factors for AD. Therefore, targeted biomarkers and/or therapies may be needed to effectively treat AD in AA. In this study, we aimed to determine if genetic variants that show association with AD‐risk, plasma transcript or protein levels in AA, may serve as accurate and accessible AD biomarkers. Method In 189 clinically diagnosed AA AD cases and 183 AA cognitively unimpaired (CU) controls, we performed targeted DNA sequencing of 10 AD‐associated loci. Genetic variants at these loci were tested for association with corresponding plasma transcripts and total tau protein levels previously measured in this cohort using a custom nanoString panel and Simoa assays, respectively. Utilizing phased haplotypes (SHAPEIT4) from target sequencing, we inferred local ancestry (RFMix v2) using five superpopulations from the 1000 Genomes Project as anchors. Subsequently, we tested the association of each ancestry specific allelic dosages with endophenotypes using Tractor. In receiver operating characteristic (ROC) analyses, the most significant e/pQTLs were added sequentially to a base model that included age and sex to identify e/pQTLs that improved the accuracy to correctly classify AD cases and CU controls. Result Of the 5,112 variants that were tested, 70 were nominally associated with AD‐risk and with plasma transcript or protein levels. Seven of these 70 variants also showed nominally significant associations of AD‐risk and transcript levels with either African or East Asian local ancestry. ROC analysis of age, sex, 33 e/pQTLs in APOE , SORL1 , TLR4 , EPHA1 , ABCA7 , CLU , and CR1 , and plasma levels of APP, ABCA7, AKAP9, CD14, CLU, and APOE ‐ɛ4 dosage achieved 88.2% area under the curve to discriminate AD vs. CU, a 30.4% improvement over the base model that only included age and sex. Conclusion Plasma transcript levels and e/pQTLs are promising diagnostic biomarkers for AD that may improve accessibility and reduce costs for a more accurate diagnosis of AD.

Abstract Background Sensitive, accessible biomarkers of the pathologies underlying Alzheimer's disease and related dementias (ADRD) are critical for accurate diagnosis, deeper understanding of disease mechanisms, and development of new therapies with validated target engagement. The retina is connected to the brain via the optic nerve, which may facilitate the transmission and spread of amyloid beta (Aβ) and tau species. In postmortem studies, retinal Aβ deposits have been associated with neuritic Aβ‐plaque and neurofibrillary tangle burden, particularly in the entorhinal and temporal cortices. The goal of the current study was to evaluate associations between retinal perivascular amyloid and cognition, as well as to explore effect modification by hippocampal volumetry. Method Participants, aged ≥40 years, underwent retinal imaging, brain MRI, FDG‐PET, and a comprehensive neuropsychological assessment. Retinal amyloid imaging was conducted following curcumin ingestion and pupil dilation using a confocal scanning laser ophthalmoscope. Perivascular Aβ plaque counts were quantified in the superotemporal peripheral region following manual identification and tracking of retinal arteries and veins. Associations between retinal perivascular Aβ plaque counts with cognitive domains were evaluated using linear regression models adjusted for age, sex, and estimated premorbid functioning. Where significant associations were detected ( p ‐value<0.05), effect modification by hippocampal volumetry was examined with additional adjustment for intracranial volume. Result The sample included 26 participants (mean age 65±7 years, 50% female). Higher amyloid plaque counts in the perivascular secondary small and tertiary branches and in the periarteriolar tertiary branch were associated with poorer verbal and visual memory (Table 1). Significant interactions were observed between amyloid plaque count in the perivascular secondary small branch (β(95% Confidence Interval) = 0.397(0.037‐0.756), p = 0.033) and periarteriolar tertiary branch (β(95% Confidence Interval) = 0.756(0.165–1.346), p = 0.017) with hippocampal volumetry for visual memory. Conclusion Our pilot study provides preliminary evidence that perivascular Aβ accumulation in smaller vessels of the superotemporal retina may be a marker of memory impairment that may interact synergistically with hippocampal atrophy. Longitudinal studies consisting of multimodal ophthalmic assessments, brain imaging, ADRD biofluid markers, and cognitive testing will be necessary to capture the temporal sequence of retinal pathological changes and their associations with those in the brain.

Abstract Background Monoclonal antibodies targeting amyloid‐β (Aβ), including aducanumab, have been tested to treat Alzheimer's disease (AD). However, limited data exist on neuropathology following treatment and the effects of amyloid‐related imaging abnormalities (ARIA). We report on such data from five aducanumab‐treated study participants with AD of whom two experienced ARIA. Methods Aducanumab‐treated study participants who came to autopsy ( n = 5) were matched to AD controls ( n = 12) based on the presence/type of autosomal dominant AD mutation, APOE genotype, age at cognitive symptom onset, and sex. We assessed cognitive measures, 18 F‐florbetapir PET centiloid, ARIA risk factors, and AD neuropathologic change. Using multiplex immunofluorescence, brain regions affected along Thal Aβ phases were stained for Aβ isoforms and phosphorylated tau, as well as for ARIA‐associated markers, including Perls’ Prussian blue to detect ferric iron, fibrinogen‐α for blood brain barrier integrity, membrane attack complex (C5b‐C9) for complement activation, and activated microglia (IBA1, CD68). Results Study participants included four males and one female, all carrying at least one APOE ε4 allele. Two participants carried a PSEN1 NM_000021.4:c.817G>A , p.Glu273Lys mutation. Cumulative aducanumab dosage ranged between 5–241 mg/kg, with death occurring 5–41 months after the last infusion. Amyloid burden on PET declined in all participants (range 15‐100 centiloids). Two participants experienced ARIA. Compared to AD controls, Aβ aa1‐8 and Aβ 42 were selectively reduced in cortical layer I of aducanumab‐treated study participants ( p <0.05) but not in the total cortex, as shown for the middle frontal cortex in Figure 1. No differences were observed in phosphorylated tau burden. Prussian blue‐stained hemosiderin was present in both treated and untreated AD cases. However, in participants with ARIA, hemosiderin accumulated in superficial cortical layers near CAA‐laden meningeal and penetrating vessels, which also exhibited extensive complement and microglial activation (Figure 2). Conclusions Aβ clearance and ARIA‐related findings were localized predominantly in superficial cortical layers, suggesting that aducanumab biodistribution is more pronounced in these regions rather than deeper cortical layers.

Background This study examines the geographic representativeness of people who smoke, among newly registered users of a free digital tobacco cessation program (‘EX’). Methods User-provided ZIP codes from EX® Program registrants were mapped to Rural Urban Continuum Codes (RUCC). Reach Ratios (ReRas) and 95% confidence intervals were used to determine the extent to which geographic representation in EX was proportionate to their representation in the national population of individuals who smoke, as obtained from the United States National Survey of Drug Use and Health (2018-2020). Under- and overrepresentation was demonstrated by ReRas <1 or >1, respectively. Joinpoint regression analyses were used to determine significant changes in trend for ReRas from 2013 to 2020. Results Individuals who reported smoking residing in nonmetro rural areas were significantly overrepresented in 2018 [ReRa = 1.18 (95% CI: 1.15, 1.23)], 2019 [ReRa = 1.10 (95% CI: 1.07, 1.13)], and 2020 [ReRa = 1.10 (95% CI: 1.06, 1.13)]. Individuals who reported smoking from small metro areas were also overrepresented from 2018 to 2020 [ReRas = 1.09 (95% CI: 1.06, 1.11); 1.06 (95% CI: 1.04, 1.08), and 1.05 (95% CI: 1.03, 1.08), respectively] and individuals who reported smoking from large metro areas were underrepresented during the same time frame [ReRas = 0.87 (95% CI: 0.85, 0.89); 0.92 (95% CI: 0.91, 0.94), and 0.93 (95% CI: 0.91, 0.94), respectively]. ReRas for large metro areas decreased from 2013 to 2018 (annual percentage change, APC = −3.26; 95% CI: −6.69, −1.91). ReRas for non-metro areas increased from 2013 to 2017 (APC = 7.35; 95% CI: 4.10, 17.63). Conclusions Results suggest that individuals that smoke residing in nonmetro rural areas and small metro areas are proportionally reached by a digital tobacco cessation program. However, there continues to be an underrepresentation of individuals who smoke from large metro areas, which warrants further study.

Abstract Background Some cases of Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) feature the mislocalization of the normally nuclear TAR DNA binding protein (TDP‐43) to the cytoplasm where it is incorporated into inclusions in affected brain regions. TDP‐43 plays a crucial role in the suppression of cryptic exons in the mature RNA of many targets in both AD and FTD. One such target, Stathmin‐2 (STMN2), is misspliced in the absence of TDP‐43 leading to a reduction of STMN2 RNA and protein while the levels of the cryptic splice variant is increased. Cryptic exons are not conserved across species, meaning previous Tdp‐43 models did not capture Stmn2 processing defects and Stmn2 loss of function (LOF). We hypothesize that STMN2 LOF contributes to cognitive phenotypes observed in AD and FTD. Method We have generated a novel mouse that more accurately models human disease mechanisms by expressing short‐hairpin (shRNA) via adeno associated virus in the central nervous system of a recently described humanized Stmn2 mouse model in which Stmn2 splicing is dependent on Tdp‐43. In this mouse we will simultaneously model Tdp‐43 loss of function and aberrant Stmn2 splicing. Result Our preliminary experiments demonstrate that humanized Stmn2 mice expressing shRNA against Tardbp have a reduction of Tardbp RNA and TDP‐43 protein compared to mice expressing a non‐targeting shRNA. Tdp‐43 knock‐down is accompanied by cryptic splicing of endogenous mouse targets, Sortilin 1 and Translin . As anticipated, we also detected cryptic Stmn2 splicing, suggesting that correct Stmn2 splicing is dependent on Tdp‐43 in this model. We will further characterize motor and cognitive functions in addition to neurodegeneration and gliosis in these animals. Conclusion We anticipate this novel model, and our subsequent studies will identify relevant disease mechanisms and provide an invaluable tool with which to investigate therapies for AD and FTD.

Abstract Background The National Institute on Aging Alzheimer's Disease Family Based Study (NIA‐ AD FBS) is a multi‐site, longitudinal study aimed to be a data and bio sample resource for investigators worldwide. Since its inception in 2002 the FBS goal has been to promote greater cooperation and sharing of clinical and biological resources among researchers. Methods The focus of the Family Based Study (FBS) has been the recruitment of families with at least two affected individuals and a third first degree relative with or without dementia and willing to participate. Participants are from different ethnic backgrounds including Caucasian, African American and Hispanics. The FBS study is actively recruiting both late onset (LOAD) and early onset Alzheimer's Disease (EOAD) families as well as conducting follow up evaluations every two years, approximately. Uniform assessments are completed across all sites and include DNA, Plasma, PaXgene and PBMC samples collection and brain autopsies whenever possible. We conduct both in person and remote evaluations and use the services of a mobile phlebotomy company to collect bio samples. In addition, we’ve created a protocol for genetic testing on the proband for EOAD families where an additional sample is sent to a CLIA approved lab and after genetic counseling, the presence or not of AD related mutations is disclosed to the families. Results To date, this cohort has recruited 1,756 families and acquired data from 9,682 family members. Families are from Caucasian, African Americans and Hispanics ethnic groups. The cohort has longitudinal clinical data, cognitive assessment, family history and bio samples available for sharing. Genotype data includes APOE, GWAS, WES, WGS, brain methylation, RNA sequencing and biomarkers data. Conclusion The NIA‐LOAD FBS study is the largest collection of familial Alzheimer's Disease worldwide and many genetic studies of Alzheimer's disease (AD) have included cases and controls from this dataset. Over 140 publications have used data and/or samples from FBS to address the genetics of Alzheimer's Disease. The enriched resources provided by this cohort are invaluable to the scientific community.