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Neuroinflammation commences decades before Alzheimer's disease (AD) clinical onset and represents one of the earliest pathomechanistic alterations throughout the AD continuum. Large-scale genome-wide association studies point out several genetic variants- , and -potentially linked to neuroinflammation. Most of these genes are involved in proinflammatory intracellular signaling, cytokines/interleukins/cell turnover, synaptic activity, lipid metabolism, and vesicle trafficking. Proteomic studies indicate that a plethora of interconnected aberrant molecular pathways, set off and perpetuated by TNF-α, TGF-β, IL-1β, and the receptor protein TREM2, are involved in neuroinflammation. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. Under physiological conditions, they are important for neurotransmission and synaptic homeostasis. In AD, there is a turning point throughout its pathophysiological evolution where glial cells sustain an overexpressed inflammatory response that synergizes with amyloid-β and tau accumulation, and drives synaptotoxicity and neurodegeneration in a self-reinforcing manner. Despite a strong therapeutic rationale, previous clinical trials investigating compounds with anti-inflammatory properties, including non-steroidal anti-inflammatory drugs (NSAIDs), did not achieve primary efficacy endpoints. It is conceivable that study design issues, including the lack of diagnostic accuracy and biomarkers for target population identification and proof of mechanism, may partially explain the negative outcomes. However, a recent meta-analysis indicates a potential biological effect of NSAIDs. In this regard, candidate fluid biomarkers of neuroinflammation are under analytical/clinical validation, i.e., TREM2, IL-1β, MCP-1, IL-6, TNF-α receptor complexes, TGF-β, and YKL-40. PET radio-ligands are investigated to accomplish and longitudinal regional exploration of neuroinflammation. Biomarkers tracking different molecular pathways (body fluid matrixes) along with brain neuroinflammatory endophenotypes (neuroimaging markers), can untangle temporal-spatial dynamics between neuroinflammation and other AD pathophysiological mechanisms. Robust biomarker-drug codevelopment pipelines are expected to enrich large-scale clinical trials testing new-generation compounds active, directly or indirectly, on neuroinflammatory targets and displaying putative disease-modifying effects: novel NSAIDs, AL002 (anti-TREM2 antibody), anti-Aβ protofibrils (BAN2401), and AL003 (anti-CD33 antibody). As a next step, taking advantage of breakthrough and multimodal techniques coupled with a systems biology approach is the path to pursue for developing individualized therapeutic strategies targeting neuroinflammation under the framework of precision medicine.

The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer’s disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative and topographic assessment of retinal perivascular amyloid plaque (AP) distribution in individuals with both normal and impaired cognition. Using a retrospective dataset of scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects with varying cognitive states, we developed a novel image processing method to examine retinal peri-arteriolar and peri-venular curcumin-positive AP burden. We further correlated retinal perivascular amyloidosis with neuroimaging measures and neurocognitive scores. Our study unveiled that peri-arteriolar AP counts surpassed peri-venular counts throughout the entire cohort ( P  < 0.0001), irrespective of the primary, secondary, or tertiary vascular branch location, with a notable increase among cognitively impaired individuals. Moreover, secondary branch peri-venular AP count was elevated in the cognitively impaired ( P  < 0.01). Significantly, peri-venular AP count, particularly in secondary and tertiary venules, exhibited a strong correlation with clinical dementia rating, Montreal cognitive assessment score, hippocampal volume, and white matter hyperintensity count. In conclusion, our exploratory analysis detected greater peri-arteriolar versus peri-venular amyloidosis and a marked elevation of amyloid deposition in secondary branch peri-venular regions among cognitively impaired subjects. These findings underscore the potential feasibility of retinal perivascular amyloid imaging in predicting cognitive decline and AD progression. Larger longitudinal studies encompassing diverse populations and AD-biomarker confirmation are warranted to delineate the temporal-spatial dynamics of retinal perivascular amyloid deposition in cognitive impairment and the AD continuum.

Background Multidomain lifestyle interventions have been shown to improve cognition and functional status in adults at elevated risk of developing dementia. The delivery of lifestyle interventions has primarily occurred during face‐to‐face clinical encounters. Unfortunately, this limits patients who live in rural and underserved areas, as well as patients who have mobility issues and transportation difficulties. Method A lifestyle curriculum was developed and delivered using telehealth. The study enrolled patients who met the criteria of a Mini‐Mental State Examination score >18 and could participate in the study through telehealth. Referrals primarily came from neurology and primary care clinics. An electronic medical record system was utilized to document progress and improvement. All participants shared their wearable technology data. A BrainHealth Educator (BHE) delivered personalized digital content to participants, focusing on exercise, nutrition, and sleep. The content was tailored to each participant’s risk factors, APoE genotype, and communication preferences. Result The study included 30 participants, with 23 females and 7 males ranging in age from 40 to over 70 years old. The enrollment and completion rates for exercise programs was 83%, for sleep programs was 83%, for nutrition programs was 58%, with an updated module currently being tested. The average duration of BHE telehealth visits was 30 minutes. There was high acceptance and satisfaction with communicating APOE test results via telehealth. 75% of participants actively used the app and 25% used the phone. 50% of patients logged in once per week. The study covered 9 geographic divisions across the US, achieving engagement across diverse practices, clinicians, and socioeconomic backgrounds, including neurologists, primary care physicians, and geriatricians. 75% of patients provided wearable data, with continuous wearable data submissions. The attrition rate was <10%. Conclusion This study successfully demonstrates that lifestyle intervention delivered via telehealth by a BHE resulted in high patient engagement and satisfaction at nationwide scale. As cognitive health assessment and management rapidly develops, there is a need for lifestyle intervention programs that are structured to support patients at all stages and eliminate health disparities.

Introduction APOE (apolipoprotein E) genotyping determines an individual’s risk of developing Alzheimer’s disease and unique pathological characteristics vital to treatment consideration. The presence of the ε4 allele is considered a dose‐dependent risk factor for late‐onset Alzheimer’s disease, with each additional copy of the allele adding to the risk. Genetic counseling and education are essential as disclosure can lead to psychosocial issues, employment issues, and family stress. Traditionally, genetic counseling for Alzheimer’s disease has occurred during face‐to‐face encounters, thereby marginalizing patients who live in rural and underserved areas with high social determinants of health. In this study, we evaluated the application of telehealth services for APOE‐specific genetic counseling with an emphasis on solutions‐based education promoting health literacy and equity. Methods Participants were enrolled into the program from an electronic referral process from a primary care or neurology outpatient practice. A HIPAA‐secure and encrypted electronic health system was used to conduct the telehealth visits. Consent was collected from all patients. A BrainHealth Educator (BHE), typically an RN, was trained on best practices and protocols on APOE testing from resources such as AGREEDementia.org. BHEs conducted pre‐ and post‐test education and counseling. In addition, BHEs coordinated logistics of at‐home buccal swab self‐collection and sample transportation to lab. Results A total of 29 patients enrolled in the genotyping program with 22 females and 7 males. Each patient had a 30‐minute pre‐test education that reviewed Mendelian inhertiance, APOE polymorphism combinations, and evidence based risk stratification for developing Alzheimer’s disease. All possible genotypes were represented amongst the study subjects (n = 29): E2/E2 (1), E2/E3 (3), E2/E4 (2), E3/E3 (12), E3/E4 (7), E4/E4 (1), pending (3). Conclusions Advancements in cognitive care are rapidly growing and there is a need for genetic risk assessment and stratification. Ordering genetic testing requires adequate pre‐test counseling to ensure appropriate timing and utilization. The interpretation and dissemination of genetic information requires structured support from a trained healthcare professional skilled with providing solutions‐based guidance. Under these circumstances, individuals can receive APOE‐specific genetic health information in a manner that enhances cognitive care planning, prevention, and treatment with targeted monoclonal antibody treatments.

Background Scanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina: vascular changes and amyloid plaque (AP) deposition. The relationship between retinal arteriolar versus venular changes and perivascular amyloid deposition across the continuum of neurodegeneration is imperfectly understood. We investigate the retinal perivascular AP distribution in relationship to cognitive and neuroimaging measures in a cohort of cognitively normal and impaired individuals. Method 34 subjects with normal or impaired cognition underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal peri‐arteriolar and peri‐venular curcumin positive AP were quantified in the supero‐temporal retinal quadrant, in the first, second and third‐order retinal vascular branches. The peri‐venular and peri‐arteriolar AP count were compared between patients with normal and impaired cognition, and their correlation with brain volumes, white matter hyperintensities and cognitive Z‐scores was determined. Result We analyzed retinal para‐venous and para‐arteriolar amyloid count in 28 subjects, mean (SD) age 65 (7.3), 50% female, 19 (52.6%) with impaired cognition. Para‐arteriolar plaque count was higher than peri‐venular plaque in the entire cohort (p<0.0001). Secondary branch peri‐venular amyloid plaque count was higher in patients with MOCA ≤26. Tertiary branch perivascular AP count significantly and negatively correlated with hippocampal volume and positively correlated white matter hyperintensity lesion count. Conclusion Retinal AP deposit peri‐arteriolarly overall and peri‐venularly in the secondary branches in cognitively impaired. Perivascular amyloid burden in small retinal branches correlates with hippocampal volume and white matter hyperintensities.

The vascular contribution to Alzheimer's disease (AD) is tightly connected to cognitive performance across the AD continuum. We topographically describe retinal perivascular amyloid plaque (AP) burden in subjects with normal or impaired cognition. Using scanning laser ophthalmoscopy, we quantified retinal peri-arteriolar and peri-venular curcumin-positive APs in the first, secondary and tertiary branches in twenty-eight subjects. Perivascular AP burden among cognitive states was correlated with neuroimaging and cognitive measures. Peri-arteriolar exceeded peri-venular AP count (p<0.0001). Secondary branch AP count was significantly higher in cognitively impaired (p<0.01). Secondary small and tertiary peri-venular AP count strongly correlated with clinical dementia rating, hippocampal volumes, and white matter hyperintensity count. Our topographic analysis indicates greater retinal amyloid accumulation in the retinal peri-arteriolar regions overall, and distal peri-venular regions in cognitively impaired individuals. Larger longitudinal studies are warranted to understand the temporal-spatial relationship between vascular dysfunction and perivascular amyloid deposition in AD. Retinal peri-arteriolar region exhibits more amyloid compared with peri-venular regions.Secondary retinal vascular branches have significantly higher perivascular amyloid burden in subjects with impaired cognition, consistent across sexes.Cognitively impaired individuals have significantly greater retinal peri-venular amyloid deposits in the distal small branches, that correlate with CDR and hippocampal volumes.

Ophthalmic Imaging Systems (Nasdaq: OISI; BSE: OIS) announced today the appointment of William Mince to the position of president and chief operating officer and Robert W. Medearis as a member of the board of directors. Mr. Mince succeeds Steve R. Verdooner as president. Mr. Verdooner will continue to serve as chief executive officer and chief financial officer. Mr. Medearis will fill a previously authorized but unfilled seat on the company's board of directors.