Biology subjects

Ringman, J. M.

Publications and source records attributed to Ringman, J. M..

4 recordsLinked to original sources

bioRxiv2026

Midlife nonlinearities across scale in Biondi body amyloid formation in the human choroid plexus

Human choroid plexus epithelial cells (CPECs), which produce cerebrospinal fluid and form the blood-cerebrospinal fluid barrier, accumulate discrete intracellular amyloid inclusions called Biondi bodies (BBs). Using systematic manual and machine learning approaches on the choroid plexus glomus, we determined the percentages of CPECs containing thioflavin S-stained BBs as well as BB load and spatial distributions in whole slide images from 77 cases across the human lifespan. On average, BB prevalence was near zero until age 40, rose steeply in the 5th and 6th decades, and exceeded 50% after age 70. As prevalence plateaued, BB load continued to rise with age. Accelerated BB accumulation was seen in two cases of diabetic ketoacidosis, including a 16-year-old, while an 85-year-old with the relatively rare APOE2/E2 genotype had fewer BBs than expected. BB prevalence in the choroid plexus glomus was not associated with Alzheimer's disease, but was lower in females than males. Notably, spatial clustering of BBs was universal across cases while nearest-neighbor analyses suggested cell-to-cell, prion-like BB spread that can account for the nonlinearities seen at tissue and population scales. The abrupt, nonlinear BB accumulation during midlife coincides with or precedes other common aging-associated neuropathologies of the human brain, consistent with broad BB and choroid plexus contributions to brain aging and disease.

pathology↗

bioRxiv2024

Spectrum of gamma-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes

Autosomal Dominant Alzheimers Disease (ADAD), caused by mutations in Presenilins (PSEN1/2) and Amyloid Precursor Protein (APP) genes, typically manifests before age 65. Age at symptom onset (AAO) is relatively consistent among carriers of the same PSEN1 mutation, but more variable for PSEN2 and APP variants, with these mutations associated with later AAOs than PSEN1. Understanding this clinical variability is crucial for developing predictive models and tailored interventions in ADAD. Biochemical in vitro assessment of {gamma}-secretase function is valuable in evaluating PSEN1 variant pathogenicity, disease onset and progression. Here, we examined A{beta} profiles relationships to AAO across causal genes. Our analysis showed linear correlations between mutation-induced shifts in A{beta} profiles and AAO for PSEN2 and APP mutations. Integration with PSEN1 data revealed parallel but shifted correlations, indicating a common pathogenic mechanism with gene-specific onset timing shifts. Our data support a unified model of ADAD pathogenesis wherein {gamma}-secretase dysfunction and shifts in A{beta} profiles define disease onset. This biochemical analysis of ADAD causality and established quantitative relationships deepen our understanding of ADAD pathogenesis, offering potential for predictive AAO modelling with implications for clinical practice, genetic research and development of therapeutic strategies modulating {gamma}-secretase across ADAD forms and potentially more broadly in AD. SummaryWe examined the relationships between (full) A{beta} peptide profiles and age at symptom onset (AAO) across all Alzheimers disease causal genes. Our findings establish a quantitative framework for mutations pathogenicity assessment and AAO prediction; with implications for clinical practice, genetic counselling, fundamental and translational research.

neuroscience↗

bioRxiv2022

FMRI complexity correlates with tau-PET in Late-Onset and Autosomal Dominant Alzheimer's Disease

Neurofibrillary tangle pathology detected with tau-PET correlates closely with neuronal injury and cognitive symptoms in Alzheimers disease (AD). Complexity of rs-fMRI time-series, measured by entropy values, have recently been reported to decrease with aging, APOE {varepsilon}4 genotype and cognitive decline in AD. Here we hypothesize that the complexity of BOLD signals provides an index for tau-related neuronal injury and cognitive decline in the AD process. Data were obtained from the Alzheimers Disease Neuroimaging Initiative phase 3 (ADNI3) and the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) study, including cognitively normal elderly controls, persons with late onset AD (LOAD) and early onset autosomal dominant AD (ADAD) patients and their relatives. Our cohort consisted of a sample of 147 subjects from ADNI3 and 41 subjects from EEAJ with T1 structural, tau-PET (tracer: 18F-AV1451) and fMRI scans. Correlations between SUVR tau-PET and multi-scale entropy (MSE) were calculated voxelwise as well as for standard automated anatomical labeling (AAL) atlas regions while accounting for age, gender, and regional gray matter volume. Potential pathways relating MSE to cognitive function mediated through tau-PET were assessed by path analysis. We found significant negative correlations between low frequency MSE and tau-PET measures in medial temporal lobe, in both ADNI3 and EEAJ cohorts. Furthermore, low frequency MSE showed significant associations with the Clinical Dementia Rating (CDR) scale and the Mini-Mental State Status Exam (MMSE) scores in both ADNI3 and EEAJ cohorts, which were largely mediated through the tau-PET signal. Correlations of MSE with tau-PET in temporal lobes support our hypothesis that the complexity of rs-fMRI is associated with regional tau protein accumulation. Furthermore, the association of MSE with CDR and MMSE, mediated by tau-PET, in disease relevant areas suggests that a reduction in MSE is indicative of decreased information processing capacity and cognitive decline in AD processes.

neuroscience↗

bioRxiv2020

Alteration of perivascular spaces in early cognitive decline

Vascular contributions to early cognitive decline are increasingly recognized, prompting further investigation into the nature of related changes in perivascular space. Using magnetic resonance imaging, we show that, compared to a cognitively normal sample, individuals with early cognitive dysfunction have altered perivascular space presence and distribution, irrespective of Amyloid-{beta}. Surprisingly, we noted decreased perivascular space presence in the anterosuperior medial temporal lobe, which was associated with neurofibrillary tau tangle deposition in the entorhinal cortex, one of the hallmarks of early Alzheimers disease pathology. Our results suggest that anatomically-specific alteration of the perivascular spaces may provide an early biomarker of cognitive impairment in aging adults.

neuroscience↗