Gonzales, Mitzi M.

ABSTRACT Background The brain–heart axis is central to vascular health, yet no imaging biomarkers capture integrated dysfunction across neural and coronary microvascular networks. Although coronary microvascular dysfunction links to cognitive decline, neural correlates connecting cerebral efficiency with coronary physiology remain unclear. Objectives To determine whether the Unified Structural and Functional Connectivity (USFC)—a multimodal magnetic resonance imaging (MRI) “traffic map” of brain network efficiency—predicts coronary endothelial function and cognition in women with ischemia and no obstructive coronary artery disease (INOCA). Methods Thirty‐three women with suspected INOCA from the Women's Ischemia Syndrome Evaluation (WISE) study (NCT03876223) underwent invasive coronary function testing, cardiac MRI, cognitive evaluation, and multimodal brain MRI. USFC, structural connectivity (SC), and functional connectivity (FC) were computed for predefined 10 backbone pathways. Support vector regression and logistic classification assessed predictive performance. Results USFC explained 16%–20% more variance in coronary endothelial function, myocardial perfusion reserve, and cognition than SC or FC alone ( p < 0.05). Connectivity between the left caudate–superior medial orbital gyrus and right calcarine–inferior occipital gyrus emerged as robust predictors of crystallized cognition ( r = –0.78, p FDR < 0.05) and coronary endothelial function ( r = 0.70, p FDR < 0.05), respectively. USFC also best discriminated low versus high coronary blood flow (area under the ROC curve [AUC]: USFC 0.622 vs. SC 0.349 and FC 0.425; p < 0.05). Conclusions USFC identifies neuro–cardiac pathways linking cerebral efficiency with coronary endothelial function. These results introduce a sensitive biomarker of systemic vulnerability, highlighting occipital and frontostriatal pathways as shared substrates of dysfunction. USFC offers a mechanistic framework for detecting vascular risk across metabolically demanding tissues. Trial Registration ClinicalTrials.gov identifier: NCT03876223

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.

AbstractINTRODUCTIONGiven the close interactions between the retina and the brain, retinal amyloid imaging may serve as a diagnostic and prognostic tool for Alzheimer's disease and related dementias. This retrospective study investigated multivariable associations between retinal perivascular amyloid and cognitive domains.METHODSIntegrated analysis of retinal perivascular amyloid imaging, neuropsychological assessment, and brain magnetic resonance imaging in adults with and without cognitive impairment (N = 26; mean age: 65 ± 7 years; 50% female). Correlations between perivascular amyloid plaque burden and cognitive domains were evaluated with linear regression and interactions with hippocampal volumetry were explored.RESULTSHigher perivascular and periarteriolar amyloid plaque count in the secondary small and tertiary branches were associated with poorer verbal and visual memory in this cohort (p = 0.005–0.009). Higher perivascular amyloid burden interacted with hippocampal atrophy to worsen visual memory (p = 0.033).DISCUSSIONRetinal perivascular amyloid may serve as a non‐invasive marker for cognitive impairment and may shed insight into pathological changes in the brain.Highlights In vivo retinal perivascular amyloid plaque counts are associated with poorer memory. Retinal perivascular amyloid interacted with hippocampal atrophy to worsen memory. Retinal amyloid imaging is a potential biomarker for neurodegenerative diseases.

AbstractBackgroundThe Uniform Data Set (UDS) neuropsychological battery, administered across Alzheimer’s Disease Centers (ADC), includes memory tests but lacks a list‐learning paradigm. ADCs often supplement the UDS with their own preferred list‐learning task. Given the importance of list‐learning for characterizing memory, we aimed to develop a harmonized memory score that incorporates UDS memory tests while allowing centers to contribute differing list‐learning tasks.MethodWe applied item‐banking confirmatory factor analysis to develop a composite memory score in 5,287 participants (mean age 67.1; SD = 12.2) recruited through 18 ADCs and four consortia (DiverseVCID, MarkVCID, ALLFTD, LEADS) who completed UDS memory tasks (used as linking‐items) and one of five list‐learning tasks. All analyses used linear regression. We tested whether memory scores were affected by which list‐learning task was administered. To assess construct validity, we tested associations of memory scores with demographics, disease severity (CDR Box Score), an independent memory task (TabCAT Favorites, n = 675), and hippocampal volume (n = 811). We compared performances between cognitively unimpaired (n = 279), AD‐biomarker+ MCI (n = 26), and AD‐biomarker+ dementia (n = 98). In a subsample with amyloid‐ and tau‐PET (n = 49), we compared memory scores from participants with positive vs negative scans determined using established quantitative cutoffs.ResultModel fit indices were excellent (e.g., CFI = 0.998) and factor loadings were strong (0.43‐0.93). Differences in list‐learning task had a negligible effect on scores (average Cohen’s d = 0.11). Higher memory scores were significantly (p’s<.001) correlated with younger age (β = ‐0.18), lower CDR Box Scores (β = ‐0.63), female sex (β = 0.12), higher education (β = 0.19), larger hippocampal volume (β = 0.42), and an independent memory task (β = 0.71, p<0.001). The memory composite declined in a stepwise fashion by diagnosis (cognitively unimpaired>MCI>AD dementia, p<0.001). On average, amyloid‐PET positivity was associated with lower composite scores, but was not statistically significant (β = ‐0.34; p = 0.25; d = 0.40). Tau‐PET positivity was associated with worse performance, demonstrating a large effect size (β = ‐0.75; p<0.002; d = 0.91).ConclusionThe harmonized memory score developed in a large national sample was stable regardless of contributing list‐learning task and its validity for cross‐cohort ADRD research is supported by expected associations with demographics, clinical measures, and Alzheimer’s biomarkers. A processing script will be made available to enhance cross‐cohort ADRD research.

AbstractINTRODUCTIONWhile Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics, and care.METHODSIn 2023, the Alzheimer's Association hosted its eighth satellite symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm.RESULTSSignificant initiatives in the region, including intracountry support, showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; researchers conducting emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care, and use affordable biomarkers in the region was highlighted.DISCUSSIONThe myriad of topics discussed at the 2023 AAIC satellite symposium highlighted the growing research efforts in LatAm, providing valuable insights into dementia biology, genetics, epidemiology, treatment, and care.

Abstract Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer’s disease (AD). Clinical trials evaluating senolytics, drugs that clear senescent cells, are underway, but lack standardized outcome measures. Our team recently published data from the first open-label trial to evaluate senolytics (dasatinib plus quercetin) in AD. After 12-weeks of intermittent treatment, we reported brain exposure to dasatinib, favorable safety and tolerability, and modest post-treatment changes in cerebrospinal fluid (CSF) inflammatory and AD biomarkers using commercially available assays. Herein, we present more comprehensive exploratory analyses of senolytic associated changes in AD relevant proteins, metabolites, lipids, and transcripts measured across blood, CSF, and urine. These analyses included mass spectrometry for precise quantification of amyloid beta (Aß) and tau in CSF; immunoassays to assess senescence associated secretory factors in plasma, CSF, and urine; mass spectrometry analysis of urinary metabolites and lipids in blood and CSF; and transcriptomic analyses relevant to chronic stress measured in peripheral blood cells. Levels of Aß and tau species remained stable. Targeted cytokine and chemokine analyses revealed treatment-associated increases in inflammatory plasma fractalkine and MMP-7 and CSF IL-6. Urinary metabolites remained unchanged. Modest treatment-associated lipid profile changes suggestive of decreased inflammation were observed both peripherally and centrally. Blood transcriptomic analysis indicated downregulation of inflammatory genes including FOS, FOSB, IL1β, IL8, JUN, JUNB, PTGS2. These data provide a foundation for developing standardized outcome measures across senolytic studies and indicate distinct biofluid-specific signatures that will require validation in future studies. ClinicalTrials.gov: NCT04063124.

Abstract Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy. Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. The treatment increased D and Q levels in the blood of all participants ranging from 12.7 to 73.5 ng/ml for D and 3.29-26.30 ng/ml for Q. D levels were detected in the CSF of four participants ranging from 0.281 to 0.536 ng/ml (t(4)=3.123, p=0.035); Q was not detected. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study. Cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment. CNS levels of IL-6 and GFAP increased from baseline to post-treatment (t(4)=3.913, p=008 and t(4)=3.354, p=0.028, respectively) concomitant with decreased levels of several cytokines and chemokines associated with senescence, and a trend toward higher levels of Aβ42 (t(4)=-2.338, p=0.079). Collectively the data indicate the CNS penetrance of D and provide preliminary support for the safety, tolerability, and feasibility of the intervention and suggest that astrocytes and Aβ may be particularly responsive to the treatment. While early results are promising, fully powered, placebo-controlled studies are needed to evaluate the potential of AD modification with the novel approach of targeting cellular senescence.

AbstractThe Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID‐19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish‐speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health‐care services and to aid caregivers of Latinos living with AD.

AbstractFor many years, it was believed that the aging process was inevitable and that age‐related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age‐related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof‐of‐concept studies, as well as early‐stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.