Developing Topics.

Background: Longitudinal studies of Alzheimer's and related dementias (ADRD) are crucial to understanding disease progression. Retention among study participants is vital to successful longitudinal research, as dropout can skew the subject population in ways that significantly compromise study outcomes (e.g.

Developing Topics.

Background: Alzheimer's disease (AD) is a devastating form of dementia, and its prevalence is rising as human lifespan increases. Our lab created the AD-BXD mouse model, which expresses AD mutations across a genetically diverse reference panel (BXD), to identify factors that confer resilience to cognitive decline in AD. This model mimics key characteristics of human AD including variation in age of onset and severity of cognitive decline.

Developing Topics.

Background: Anti-amyloid monoclonal antibody therapies for AD have documented plaque removal on amyloid PET scans. We evaluate the findings for amyloid PET, tau PET, FDG PET and volumetric MRI over the course the open label extension (OLE) for the DIAN-TU gantenerumab treatment, compared to the last imaging obtained prior to the OLE (to evaluate for potential rebound effects) and in comparison to longitudinal imaging in the DIAN Observational study.

Method: This double-blind, phase 2/3 trial (2012-2019), followed by open-label extension (OLE), investigated varying gantenerumab doses up to 1500 mg SQ q2 weeks [NCT NCT01760005].

Developing Topics.

Background: The recently developed construct of mild behavioral impairment (MBI) provides a diagnostic framework for early signs of behavioral dysfunction that may appear even before other symptoms of cognitive decline and dementia in older adults. However, the links between MBI, brain function, and Alzheimer's disease (AD) biomarkers are unclear.

Method: Using data from 128 participants with diagnosis of amnestic mild cognitive impairment or mild dementia of the Alzheimer's type, we test a novel model assessing direct relationships between AD biomarker status (amyloid and tau PET) and MBI symptoms, as well as mediated effects through the functional segregation of the salience, default-mode, and frontoparietal control networks from the other high-level, association networks.

Developing Topics.

Background: Previous studies have documented age-related changes in behavior and cognitive functions and investigated the molecular changes in aging brain using inbred mouse strains such as C57BL/6, BALB/c etc. In this study using a genetically heterogenous mouse population (UM-HET3) we investigated age-related changes in motor and memory functions and their association with blood cell measures.

Method: Both male and female UM-HET3 mice at age of 11 months (middle-aged) and 25 months (old) were used in this study.

Developing Topics.

Background: Sleep dysfunctions are highly comorbid with Alzheimer's disease (AD), though often associated with later stages of AD, sleep disruptions have been noted to appear decades before the onset of cognitive symptoms. Here, we provide the first evidence that genetic factors interact with AD mutations to influence sleep behavior even before the onset of cognitive symptoms.

Method: To identify novel genetic factors underlying disordered sleep that precede cognitive decline in our AD-BXD mouse genetic reference panel (n = 179 mice across 25 strains, 7-months-old), we first used sleep phenotypes measured in the PiezoSleep chambers and performed quantitative trait loci (QTL) mapping and discovered Kirrel3 as the novel gene candidate associated with disordered sleep.

Developing Topics.

Background: Symptoms of Alzheimer's disease and related dementias (ADRD), including memory problems, are often stressful for people living with dementia (PLWD) and family caregivers. However, we know little about daily perceptions of ADRD symptoms and links to physiological stress reactivity within care dyads. We evaluated how daily ADRD symptom stress (i.

Developing Topics.

Background: The SuperAging Research Initiative (SRI) seeks to identify factors that promote cognitive healthspan. SuperAgers are defined as individuals aged 80 and older with episodic memory performance that is at least average for people who are two to three decades younger. A goal of the SRI is to identify the genomic contributors to SuperAging and herein we describe the interim results of DNA- and plasma protein-based analyses.

Developing Topics.

Background: Existing work suggests that Alzheimer's disease (AD) pathology can affect the direction and intensity of information signaling in functional brain regions. This study aims to explore how mild cognitive impairment (MCI) can affect the brain effective connectivity.

Method: We used an event-related functional magnetic resonance imaging (fMRI) paradigm to compare patients with aMCI and healthy controls with normal cognition (NC) as they encoded 90 ecologically-relevant object-location associations (OLAs).

Developing Topics.

Background: Neural flexibility (NF) during tasks was associated with cognitive aging, while that during rest was not associated with aging and cognition in a healthy aging population. However, NF has not been studied in AD. We aim to evaluate whether AD is associated with alterations in NF and probe its predictive utility for AD conversion.

Incidence of surgical infection in cefazolin 3 g versus 2 g for colorectal surgery in obese patients.

Objective: To compare the incidence of surgical site infection (SSI) between cefazolin 3 g and 2 g surgical prophylaxis in patients weighing ≥120 kg that undergo elective colorectal surgery.

Methods: A multicenter, retrospective cohort study was performed utilizing a validated database of elective colorectal surgeries in Michigan acute care hospitals. Adults weighing ≥120 kg who received cefazolin and metronidazole for surgical prophylaxis between 7/2012 and 6/2021 were included.

Developing Topics.

Background: Wisconsin Card Sorting Test (WCST) and Trail Making Test-Part B (Trails B) are commonly used neuropsychological measures of executive functioning. Previously, Trails B was found to be more sensitive than the WCST in predicting executive dysfunction. The Emory WCST (eWCST) was adapted to remove cards with multiple sort options and duplicate cards, creating a more direct measure of executive function.

Developing Topics.

Background: A typical paper/pencil neuropsychological evaluation to assess for mild cognitive impairment (MCI) and dementia is lengthy. There is a need for a brief, digitally administered/scored neuropsychological protocol that can differentiate patients who are cognitively normal versus MCI and dementia. This need is particularly acute with the advent of disease-modifying medications to treat MCI and early Alzheimer's disease (AD).

Alzheimer's Imaging Consortium.

Background: The timing of tau-PET accumulation and cognitive decline in sporadic early-onset Alzheimer's disease (eoAD, age-at-onset<65) has not been established and is needed to optimize tau-PET as an outcome measure in clinical trials. Here we leverage large-sample, longitudinal data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) to model tau-PET accumulation in three regions relative to cognitive decline.

Method: Longitudinal [18F]Flortaucipir-PET (FTP) and CDR-SB scores were acquired in 195 amyloid-PET-positive, sporadic eoAD patients with MCI or mild dementia due to AD at baseline (Table 1).

Alzheimer's Imaging Consortium.

Background: White Matter Hyperintensities (WMH) appear on T2-weighted Fluid-Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI) and are an important biomarker of cerebral small vessel disease (CSVD), cognitive decline, and stroke. However, manual delineation is laborious and bias-prone, while automated segmentation has proven challenging. With the recent conclusion of the MICCAI-Society WMH segmentation challenge, and our large clinical trials, "Risk Reduction for Alzheimer's Disease" (rrAD) and "Hypertension, Intracranial Pulsatility and Brain Amyloid-beta Clearance in older adults" (HIPAC), we investigated the differences in the total WMH volume segmented by various algorithms to ensure the extraction of accurate and meaningful image-derived phenotypes.

Design, Development, and Evaluation of a 3D-Printed Buccal Myomucosal Flap Simulator.

Objective: Buccal myomucosal flap procedures have become a critical tool in the armamentarium of the cleft surgeon. Mastering this technique is complex and providing sufficient training opportunities presents significant challenges. Our study details the design, development, and evaluation of a low-cost, high-fidelity buccal myomucosal flap surgical simulator.

Alzheimer's Imaging Consortium.

Background: Diffusion magnetic resonance imaging (dMRI) permits characterizing differences in white matter microstructure associated with amnestic mild cognitive impairment (aMCI) and Alzheimer's dementia (AD). However, most dMRI measures aggregate signals across multiple axonal fiber populations with varying spatial orientations, which limits the sensitivity and specificity of clinical diagnosis. To overcome this shortcoming, we estimated fiber density (FD) measures, independently from crossing fiber populations, and extracellular cerebral spinal fluid (CSF).

Alzheimer's Imaging Consortium.

Background: Large-scale studies comparing sporadic early-onset AD (EOAD, age<65) and late-onset AD (LOAD, age = 65) are lacking. We compared amyloid-PET outcomes (positivity rate and amyloid burden) between patients clinically diagnosed with sporadic EOAD vs LOAD, leveraging data from the Longitudinal Early-Onset AD Study (LEADS) and the Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3).

Method: 731 patients meeting the 2011 NIA-AA criteria for AD dementia or MCI were included (505 early-onset from LEADS, 226 late-onset from ADNI3, Table 1).

Alzheimer's Imaging Consortium.

Background: The cerebellum is frequently used as the reference region for amyloid PET analysis. However, this reference region has been shown to demonstrate longitudinal variability, particularly with [18F]florbetapir (FBP) PET (Landau, JNM 2015). For investigations in individuals with Down syndrome (DS), cerebellar atrophy and rapid disease progression may increase these longitudinal variabilities.

Alzheimer's Imaging Consortium.

Background: Diagnosing sporadic early-onset AD (EOAD, age-at-onset<65) is challenging: in the multi-center Longitudinal Early-onset Alzheimer's Disease Study, ∼25% of patients with clinically diagnosed EOAD are amyloid-PET-negative. Here we used FDG-PET to characterize the heterogeneity of hypometabolic profiles in these patients and better identify underlying etiologies.

Method: Seventy-four amyloid-PET-negative patients with clinical diagnosis of sporadic EOAD (MCI or mild dementia stage) underwent FDG-PET.

Alzheimer's Imaging Consortium.

Background: Globose neurofibrillary tangles (NFTs) are found in subcortical areas of post-mortem brain from individuals with the second most common primary tauopathy, progressive supranuclear palsy (PSP). The degree of cognitive impairment in secondary tauopathies such as Alzheimer's disease (AD) correlates with the presence of NFTs, which originally appear in the entorhinal cortex before spreading throughout the hippocampus. In contrast, the degree of hippocampal tau pathology in PSP is thought to be limited, consistent with the view that cognitive impairment in PSP is predominantly subcortical.

KRASG12D drives immunosuppression in lung adenocarcinoma through paracrine signaling.

Lung cancer is the leading cause of cancer deaths in the United States. New targeted therapies against the once-deemed undruggable oncogenic KRAS are changing current therapeutic paradigms. However, resistance to targeted KRAS inhibitors almost inevitably occurs; resistance can be driven by tumor cell-intrinsic changes or by changes in the microenvironment.

The CLCA1/TMEM16A/Cl- current axis associates with H2S deficiency in diabetic kidney injury.

The role played by anionic channels in diabetic kidney disease (DKD) is not known. Chloride channel accessory 1 (CLCA1) facilitates the activity of TMEM16A (Anoctamin-1), a Ca2+-dependent Cl- channel. We examined if CLCA1/TMEM16A had a role in DKD.

Drug Development.

Background: Availability of amyloid modifying therapies will dramatically increase the need for disclosure of Alzheimer's disease (AD) related genetic and/or biomarker test results. The 21st Century Cares Act requires the immediate return of most medical test results, including AD biomarkers. A shortage of genetic counselors and dementia specialists already exists, thus driving the need for scalable methods to responsibly communicate test results.

Drug Development.

Background: Prodromal Alzheimer's disease (AD) clinical trials of candidate treatments enroll individuals with mild cognitive impairment (MCI) and biomarker evidence of AD. These trials require co-enrollment with a study partner and complex decision-making, weighing potential risks and benefits of participation. Some patients with MCI lack capacity to provide trial informed consent.