Gordon Center for Medical Imaging

BackgroundThe Digital Clock Test (DCT) is a novel, computerized version of the clock drawing test (CDT). It has been shown to discriminate well between mild cognitive impairment and Alzheimer's disease (AD) dementia and has been associated with AD biomarkers (i.e., amyloid, tau), similar to widely used screening batteries such as the Preclinical Alzheimer's Cognitive Composite (PACC5) and Mini Mental Status Exam (MMSE). As mood symptoms (e.g., anxiety, depression) are common in older adults and can impact cognition, it is important to determine whether such symptoms impact scores on the DCT relative to other measures/batteries. We sought to examine whether mood symptoms are associated with lower DCT scores and/or impaired performance and compare relationships to the MMSE and PACC5.MethodAll participants were older adults (n = 241, mean age=77.60, 80.10% cognitively normal) enrolled in the Harvard Aging Brain Study. Participants completed neuropsychological assessments (i.e., DCT, PACC5, MMSE; lower scores=worse performance) alongside self‐report questionnaires: the 30‐item Geriatric Depression Scale (GDS) and the 20‐item Geriatric Anxiety Inventory (GAI) (higher scores = greater symptoms for both measures). Separate cross‐sectional linear regression models assessed whether GDS/GAI score predicted DCT, MMSE, and PACC5 scores. Separate ordinal regression models were used to determine whether GDS/GAI score predicted impaired DCT (<75), MMSE (<27), and PACC5 (<‐1.5) scores. Analyses controlled for age, sex, and education.ResultHigher GDS scores, but not GAI scores, were associated with lower scores on all cognitive measures (Figure 1). Higher GDS scores were also associated with increased odds of having impaired MMSE and PACC5 scores, but not impaired DCT scores (Table 1). Additionally, higher GAI scores were significantly associated with increased odds of an impaired PACC5 score, but not impaired MMSE or DCT scores (Table 2).ConclusionIn older adults, greater depressive symptoms were associated with worse performance on both the DCT and standard cognitive screens (MMSE, PACC5). In contrast, both depressive and anxiety symptoms were associated with “impaired” scores on PACC5 and/or MMSE, but not on the DCT. This could suggest that the DCT is a sensitive cognitive screen for AD and related dementias in clinical settings where patients present with co‐occurring mood disturbances.

BackgroundThe brainstem noradrenergic locus coeruleus (LC) is among the earliest regions to accumulate Alzheimer’s disease (AD)‐related hyperphosphorylated tau. Lower novelty‐related LC activity in older cognitively healthy individuals has been related to greater entorhinal (EC) tau deposition and steeper memory decline. Furthermore, rat models accumulating LC pretangle human tau receiving novelty‐like, phasic optogenetic activation of the LC exhibited resilience against tau’s downstream effects on cognition. Using novel modeling approaches to identify phasic‐like activity from BOLD data, we associated in‐vivo phasic‐like, spontaneous LC activity with cortical tau accumulation and cognitive decline in asymptomatic older adults.MethodNinety‐two participants (56 Female, mean age at baseline=75±9.0 years; Table 1) from the Harvard Aging Brain Study underwent FTP(tau)‐PET and 3T resting‐state BOLD‐fMRI imaging (TR/TE=800/37ms, voxel=2mm3) at baseline and longitudinal cognitive testing (mean follow‐up=5.37±1.88 years). Seventy‐three participants also had longitudinal FTP‐PET data (mean follow‐up=4.26±1.78 years). Phasic‐like LC activity events were defined at BOLD‐fMRI signal peaks, maximizing activity integration within the EC, using an in‐house‐developed minimum entropy‐based event‐detection algorithm. The proportion of LC activity explained by the detected events was quantified using the R2‐coefficient. Vertex‐wise robust regressions associated LC activity with cortical tau deposition, adjusted for age and sex. Mixed‐effects models associated LC activity and EC tau accumulation, as well as LC activity and cognitive decline (PACC5, Table 1), adjusted for age, sex, and education (for cognition models).ResultLower phasic LC activity was associated with greater baseline EC tau deposition (Figure 2A‐B) and faster medial temporal lobe tau accumulation (Figure 2C‐D). Lower phasic LC activity was associated with steeper cognitive decline, with larger effect sizes for the memory‐related subtests of PACC5 (Figure 3A‐B). Furthermore, the effect of LC phasic activity on cognitive decline was more pronounced at elevated levels of inferior‐temporal tau (Figure 3C).ConclusionIn line with previous animal and in‐vivo imaging studies, our results suggest that higher phasic LC activity may be protective against the accumulation of tau in early AD‐related cortical regions and its adverse effects on cognition. The findings in this work could inform the design of early targeted interventions to support optimal LC phasic activity to delay cognitive decline.

BackgroundAlzheimer’s disease (AD) cases often present with TDP‐43 inclusions at autopsy, suggesting comorbid Limbic‐predominant Age‐related TDP‐43 Encephalopathy (LATE). These patients show smaller hippocampal volume and more severe cognitive decline than ‘pure’ AD patients. Distinguishing the contributions of both pathologies to neurodegeneration is crucial for treatment development; but is challenging as both pathologies affect the medial temporal lobe (MTL), share similar clinical symptoms and there is no in‐vivo biomarker for TDP‐43. We aimed to disentangle the relative contribution of tau and TDP‐43 pathologies to the atrophy of MTL substructures in AD patients.MethodsWe conduced antemortem cross‐sectional and longitudinal MRI analyses in participants with neuropathological data obtained at post‐mortem. Participants were selected from the ADNI database (N = 85) and grouped according to Braak stages (Low tau [0‐III] or High Tau [IV‐VI]) and the presence of TDP‐43 in the MTL. Statistical analyses included cross‐sectional correlations, group analyses, and liner‐mixed models predicting volume changes before death. All models were adjusted for MRI‐death‐interval, age, sex and intracranial‐volume.ResultsTDP‐43 was mostly associated with the volume of the hippocampal head (R = ‐0.47; P < 0.01, Figure 1) while NFTs were associated with the thickness of the parahippocampal gryrus (PHG; R = ‐0.41; P < 0.01, Figure 1). Consistently, among individuals with low levels of tau, TDP‐43‐positivity was associated with atrophy in all MTL structures except the parahippocampal cortex (PHC, Figure 2). In contrast, in TDP‐43‐negative individuals, high tau was associated with atrophy in the hippocampal body (β = ‐137mm3, P < 0.05), entorhinal cortex (β = ‐0.49mm, P < 0.01) and PHC (β = ‐0.28mm, P < 0.01, Figure 2). Longitudinal analysis showed that the hippocampal head volume reduction over time was faster in the presence of TDP‐43 in the MTL (β = ‐6.71mm3/year, P < 0.001, Figure 3) while the PHG thickness reduction over time was faster with higher Braak stages (β = ‐0.02mm/year, P < 0.05, Figure 3).ConclusionWe observed an anterior‐posterior effect of TDP‐43 and tau on the MTL with TDP‐43 affecting anterior MTL volumes and tau posterior MTL volumes. Hippocampal head atrophy could help distinguish between AD patients with/without comorbid LATE.

BackgroundThe therapeutic potential of non-invasive transcranial electric stimulation (tES) is growing, but challenges in tailoring treatments to individual patients persist. We demonstrated that personalized montages, informed by biophysical modeling, can reduce dose variability and improve target engagement. However, traditional setups are prone to electrode placement errors, leading to inconsistent dosage, localization and potential off-target engagement.MethodsWe developed a pipeline for creating patient-specific 3D-printed caps based on individual MRI scans to allow custom placement of up to 34 electrodes. Hybrid brush electrodes were incorporated to facilitate the use on with-hair regions of the head. The patient-specific caps are integrated within a Neurostimulator/EEG device, enabling precise electrode placement for recording of neural activity and optimized, personalised tES therapies based on individual biophysical brain models.ResultsA proof-of-concept in-silico study highlighted the importance of positional accuracy in electrode placement, particularly in minimizing off-target stimulation in case of the personalized montage configuration. To mitigate positional displacement, we introduced the pipeline for generating patient-specific 3D-printed caps, ensuring precise anatomical fit. The flexible design of these caps supports high-density electrode arrays tailored to various therapeutic montages. Integrated brush electrodes function in both dry and wet modes and are powered by electronics embedded in a neckpiece, enabling multi-step tES and EEG recording with minimal setup for at-home use. Electrical and mechanical evaluations confirmed the system’s feasibility, and a clinical trial with eight healthy subjects showed improved comfort and increased willingness for home use.ConclusionThis customized cap-electrode system provides a practical solution for self-administered, repeatable personalized tES and EEG session at home.Trial registration: The study is registered on the Swiss National Clinical Trials Portal (SNCTP), (SNCTP000005598) and Clinicaltrials.gov (NCT05999916). The study was approved by the Independent Competent Ethics Committee (Ethikkommission Nordwest-und Zentralschweiz (EKNZ)) at the 14 August 2023 and the Competent Regulatory Authority Swissmedic at the 20 December 2023.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12984-025-01769-8.

People with HIV (PWH) experience higher cardiovascular disease event rates not fully explained by traditional risk factors. Clonal hematopoiesis of indeterminate potential (CHIP), an emerging risk factor for cardiovascular disease in the general population, has been reported to be more prevalent in PWH. Using high-coverage targeted CHIP sequencing in the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) cardiovascular disease prevention trial, we investigated whether CHIP increases the risk of major adverse cardiovascular events (MACE) among PWH, as well as whether HIV-associated factors were associated with greater CHIP prevalence among PWH. We analyzed whole-exome and targeted sequencing from 4490 PWH without known cardiovascular disease; 1653 (36.8%) were female, and 2039 (45.4%) were Black. MACE was defined by including cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral artery disease, revascularization, or death from an undetermined cause. A total of 837 (18.6%) had CHIP driver mutations, with 385 (8.6%) at variant allele fraction ≥2% and 61 (1.4%) at variant allele fraction ≥10%. Although overall CHIP was not associated with MACE, the presence of large CHIP (variant allele fraction ≥10%) was associated with increased odds for the first occurrence of myocardial infarction or cardiac catheterization, or revascularization, despite low overall event rates. Adjustments for pitavastatin treatment did not attenuate this association. Furthermore, a larger CHIP clone size was associated with lower CD4 nadir and with increased risk of MACE. In PWH in the REPRIEVE trial who were low-to-moderate risk for incident cardiovascular disease, CHIP was not associated with increased prospective risk of MACE. However, a large CHIP was associated with increased risk of myocardial infarction and revascularization. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02344290.

Fluorescence imaging is a promising intraoperative technique for gastric cancer surgery, enabling clear visualization of surgical margins and detection of occult lesions. However, the lack of near-infrared (NIR) fluorescent probes specifically targeting gastric tumors and normal tissues remains a limitation. To address this, we developed a dual-channel imaging strategy using IR-780 (800 nm) for tumor detection and ESS65-Cl (700 nm) for normal gastric tissue identification. We evaluated their specificity in human gastric epithelial (GES-1) and cancer (SGC-7901) cells, confirming selective uptake: ESS65-Cl in normal gastric cells and IR-780 in tumor cells. In subcutaneous and orthotopic xenograft models, dual-channel imaging allowed simultaneous visualization of tumors and surrounding tissues in distinct colors. Pharmacokinetic analysis revealed that ESS65-Cl achieved a stomach signal-to-background ratio of 3.3 by 48 h, while IR-780 exhibited a tumor-to-background ratio of 4.0, demonstrating high targetability. Moreover, biodistribution studies confirmed efficient clearance of both agents. When combined, these fluorophores enabled precise intraoperative differentiation between gastric tissues and tumors. This approach holds substantial potential for improving surgical accuracy in gastric cancer resection, particularly in defining proximal esophageal margins and gastrectomy boundaries. By enhancing real-time tissue discrimination, dual-channel NIR imaging may increase surgical success rates and improve patient outcomes.

This study aimed to elucidate the molecular and genetic factors contributing to negative 68Ga-DOTATATE PET imaging in neuroendocrine tumors (NETs). By integrating whole exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq), we sought to unravel the interplay between negative results of 68Ga-DOTATATE PET and genetic mutations in NETs. A total of 18 patients with lung, ileal, or pancreatic NETs who underwent 68Ga-DOTATATE and 18F-FDG PET/CT scans as part of their initial diagnostic workup were retrospectively reviewed. WES analysis was conducted to investigate the genetic profile of circulating tumor cells of patients with negative 68Ga-DOTATATE scans. Leveraging scRNA-seq and single-cell somatic variant calling analysis, we compared the mutation burden and genetic hallmarks of NET cells with high /positive SSTR2 expression to those with negative/low SSTR2 expression. Our analysis identified an association between negative 68Ga-DOTATATE scans and reduced survival rates, regardless of tumor grade. WES highlighted a predominance of missense mutations, including CREBBP mutation, particularly in patients with negative PET results (incidence of %67 vs. %0). We observed a deleterious mutation in the SSTR2, likely accounting for the observed negative PET scans (incidence of %33). Single-cell single nucleotide variant (SNV) analysis showed that the total unique mutation burden in cells with negative/low SSTR2 expression was significantly higher compared to cells with positive/high expression; and notably, the CREBBP mutation was observed in more than 50% of patients and approximately 35% of NET cells. These results indicate that the frequency of CREBBP mutations is nearly as high as other well-known NET mutations such as MEN1, PTEN, and RB1. Additionally, CREBBP mutations are significantly more frequent in tumors with negative/low SSTR2 expression. This study suggests that CREBBP mutations in NETs may potentially alter SSTR2 expression, indicating that patients with the mutated CREBBP genotype may not be suitable candidates for SSTR2-targeted PET imaging and radionuclide therapy.