Biology subjects

Mladinov, M.

Publications and source records attributed to Mladinov, M..

4 recordsLinked to original sources

bioRxiv2026

Automated quantification of white matter hyperintensity confluence: A measure of spatial organisation beyond volume and visual rating scales

White matter hyperintensities (WMH) are a highly prevalent finding on FLAIR MRI scans and a prominent feature of white matter pathology across cerebrovascular and neurodegenerative diseases. Currently, WMH are assessed with visual rating scales such as the Fazekas scale or with their volume, as calculated from automatic or manual segmentations. Both methods have limitations: Visual rating scales are rater-dependent and coarse, while WMH volume does not take the confluence of lesions into account and thus disregards their spatial organisation. As an alternative, here we propose a novel automated method for quantifying the confluence of white matter hyperintensities on a continuous standardised scale between 0 and 1. The metric is based on WMH segmentations from routine MRI and quantifies the extent to which individual WMH merge into coherent lesions, independently of total lesion volume. We apply the method to QMIN-MC, a large UK memory clinic cohort, and show associations of the confluence metric with age, cognitive performance across domains, and Fazekas ratings. Participants with vascular and mixed dementia showed higher confluence than other diagnostic groups, whereas cognitively unimpaired participants showed lower confluence. However, confluence did not explain additional cognitive variance after accounting for log-transformed WMH volume. Findings were validated in DELCODE, an independent cohort of individuals with neurodegenerative disorders, replicating our original results. In this validation cohort, periventricular WMH confluence remained associated with cognition after adjustment for WMH volume. These findings introduce WMH confluence as a reproducible, automated, and fine-grained measure of lesion spatial organisation. It provides complementary information about morphological WMH severity beyond volume and is an alternative to visual rating scales. Although related to WMH volume in memory-clinic populations, confluence captures clinically interpretable information and may complement existing WMH measures for improved lesion characterisation in studies of white matter disease, ageing, and cognitive impairment.

neuroscience↗

bioRxiv2024

The wake and sleep-modulating neurons of the lateral hypothalamic area demonstrate a differential pattern of degeneration in Alzheimers disease

BackgroundSleep-wake dysfunction is an early and common event in Alzheimers disease (AD). The lateral hypothalamic area (LHA) regulates the sleep and wake cycle through wake-promoting orexinergic neurons (OrxN) and sleep-promoting melanin-concentrating hormone or MCHergic neurons (MCHN). These neurons share close anatomical proximity with functional reciprocity. This study investigated LHA OrxN and MCHN loss patterns in AD individuals. Understanding the degeneration pattern of these neurons will be instrumental in designing potential therapeutics to slow down the disease progression and remediate the sleep-wake dysfunction in AD. MethodsPostmortem human brain tissue from donors with AD (across progressive stages) and controls were examined using unbiased stereology. Formalin-fixed, celloidin-embedded hypothalamic sections were stained with Orx-A/MCH, p-tau (CP13), and counterstained with gallocyanin. Orx or MCH-positive neurons with or without CP13 inclusions and gallocyanin-stained neurons were considered for stereology counting. Additionally, we extracted RNA from the LHA using conventional techniques. We used customized Neuropathology and Glia nCounter(R) (Nanostring) panels to study gene expression. Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when the p-value was <.05. ResultsWe observed a progressive decline in OrxN alongside a relative preservation of MCHN. OrxN decreased by 58% (p=.03) by Braak stages (BB) 1-2 and further declined to 81% (p=.03) by BB 5-6. Conversely, MCHN demonstrated a non-statistical significant decline (27%, p=.1088) by BB 6. We observed a progressive increase in differentially expressed genes (DEGs), starting with glial profile changes in BB2. While OrxN loss was observed, Orx-related genes showed upregulation in BB 3-4 compared to BB 0-1. GO and KEGG terms related to neuroinflammatory pathways were mainly enriched. ConclusionsTo date, OrxN loss in the LHA represents the first neuronal population to die preceding the loss of LC neurons. Conversely, MCHN shows resilience to AD p-tau accumulation across Braak stages. The initial loss of OrxN correlates with specific neuroinflammation, glial profile changes, and overexpression of HCRT, possibly due to hyperexcitation following compensation mechanisms. Interventions preventing OrxN loss and inhibiting p-tau accumulation in the LHA could prevent neuronal loss in AD and, perhaps, the progression of the disease.

neuroscience↗

bioRxiv2024

Spatially conserved pathoprotein profiling in the human suprachiasmatic nucleus in progressive Alzheimer disease stages

Individuals with Alzheimers Disease (AD) experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus (SCN), which is a tiny hypothalamic nucleus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression. We examined postmortem brains of 12 controls without AD neuropathological changes (Braak stage 0) and 36 subjects at progressive Braak stages (I, II, and VI). To investigate potential AD-specific changes, we measured the neuronal counts of arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) positive neurons, along with the Braak stages in the SCN. We investigated in adjacent hypothalamic nuclei which are also composed of AVP+ neurons but show more resilience to AD: paraventricular nucleus (PVN) and supraoptic nucleus (SON). To understand the dysregulated proteins associated to AD progression, we performed in-situ proteomics, investigating 57 proteins, including commonly dysregulated in AD, using GeoMx Digital Spatial Profiling (DSP) in the three nuclei (total of 703 area of interests). Neurofibrillary tangles (NFTs) and tau fibrils were found selectively in SCN. We failed to detect NFTs in SON, only a mild dysregulation of p-tau at Braak VI in PVN and SON. Amyloid plaque was absent in the SCN and SON. Additionally, the SCN showed increased glial proteins already at Braak stage I, whereas the level of these proteins sustained in the other nuclei. The SCN is exclusively vulnerable to AD-tau pathology and show immune dysregulation even at Braak I but is protected against amyloid plaque. This finding revealed selectively in amnestic AD, showing more resilience in AD variant. This tau-related molecular dysregulation in the SCN contributes to circadian rhythm disturbances in AD, a phenomenon observed before the onset of cognitive disorder.

neuroscience↗

bioRxiv2021

Emergence of distinct and heterogeneous strains of amyloid beta as Alzheimer s disease progresses in Down syndrome

0.Amyloid beta (A{beta}) is thought to play a critical role in the pathogenesis of Alzheimers disease (AD). Prion-like A{beta} polymorphs, or "strains", can have varying pathogenicity and may underlie the phenotypic heterogeneity of the disease. In order to develop effective AD therapies, it is critical to identify the strains of A{beta} that might arise prior to the onset of clinical symptoms and understand how they may change with progressing disease. Down syndrome (DS), as the most common genetic cause of AD, presents promising opportunities to compare such features between early and advanced AD. In this work, we evaluate the neuropathology and A{beta} strain profile in the post-mortem brain tissues of 210 DS, AD, and control individuals. We assayed the levels of various A{beta} and tau species and used conformation-sensitive fluorescent probes to detect differences in A{beta} strains among individuals and populations. We found that these cohorts have some common but also some distinct strains from one another, with the most heterogeneous populations of A{beta} emerging in subjects with high levels of AD pathology. The emergence of distinct strains in DS at these later stages of disease suggests that the confluence of aging, pathology, and other DS-linked factors may favor conditions that generate strains that are unique from sAD.

pathology↗