Zaw Myo Hein

Mitochondria are critical for bioenergetics, calcium and redox homeostasis, and apoptosis in neurons. Neurons are especially susceptible to mitochondrial malfunction since they are terminally differentiated and have extraordinary energy requirements. Mechanisms such as defective oxidative phosphorylation, altered fission-fusion dynamics, defective mitophagy, impaired axonal transport and excessive reactive oxygen species (ROS) generation are increasingly appreciated as important mechanisms in major neurodegenerative diseases (NDDs) like Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). The review discusses the structure and function of mitochondria with emphasis on oxidative phosphorylation, ROS and reactive nitrogen species (RNS) signalling, calcium-mediated excitotoxicity, lipid metabolism, and apoptotic and non-apoptotic cell-death mechanisms including necroptosis, ferroptosis, pyroptosis and parthanatos. In particular, disease-specific processes are highlighted, such as impaired mitophagy by amyloid β/tau in AD, PTEN-induced kinase 1 (PINK1)/Parkin dysfunction and complex I inhibition in PD, Superoxide Dismutase 1 (SOD1)/C9orf72-associated mitochondrial defects in ALS, and bioenergetic dysfunction by mutant huntingtin in HD. Therapeutic approaches include mitochondria-targeted antioxidants, fusion and biogenesis enhancers, fission inhibitors, inflammasome modulators, Mitochondrial Permeability Transition Pore (mPTP) inhibitors and gene therapy. Also highlighted are recent advancements such as Ubiquitin-Specific Peptidase 30 (USP30) inhibition, intercellular mitochondrial transfer and regulatory approval of a mitochondria-targeted peptide, together with evidence supporting causality and hurdles underpinning clinical translation. Graded against human-genetic, patient-tissue and model-based evidence, mitochondrial dysfunction is best supported as a primary driver in PD and genetic ALS, and as an early amplifier of proteinopathic or mutant-huntingtin toxicity in sporadic AD and HD.

Alzheimer’s disease (AD) is the leading cause of dementia worldwide and a progressive neurodegenerative disorder characterized by extracellular β-amyloid (Aβ) plaque deposition, intracellular hyper...

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and a leading cause of dementia worldwide, yet effective disease-modifying therapies remain elusive. Rodent models have been indispensable for elucidating key pathological mechanisms, including amyloid-beta (Aβ) deposition, tau pathology, neuroinflammation, and synaptic dysfunction. However, despite decades of preclinical success, the translation of therapeutic findings from rodent studies to clinical efficacy in humans has been largely unsuccessful, highlighting critical limitations in current modelling approaches. This narrative review provides a comprehensive and critical evaluation of rodent models of AD, encompassing transgenic, chemically induced, metabolic, inflammatory, and lesion-based paradigms. Rather than presenting these models in isolation, we propose a systems-level framework that categorizes them based on their ability to recapitulate distinct domains of AD pathology, including genetic, environmental, and systemic contributors. By synthesising existing research, highlighting critical gaps, and proposing a tiered minimum-criteria framework for the development of next-generation models, we offer a definitive operational roadmap instead of merely a list of deficiencies. We highlight that most existing models predominantly reflect familial and reductionist aspects of the disease, while failing to capture the complexity of sporadic AD, aging processes, vascular dysfunction, and whole-body interactions. Importantly, we emphasize emerging dimensions that are underrepresented in current rodent models, including glymphatic dysfunction, cerebral small vessel disease, and the microbiota–gut–brain axis, all of which play crucial roles in AD pathogenesis. We further discuss how integrating these factors into next-generation models may improve translational relevance and therapeutic predictability. By synthesizing current evidence and identifying key gaps, we provide a strategic roadmap for the development of more physiologically relevant and translationally robust rodent models. Advancing toward integrative, systems-based approaches will be essential for bridging the persistent gap between preclinical discoveries and clinical success in AD.

Cerebral small vessel disease (CSVD) is a leading cause of vascular cognitive impairment, yet its earliest stages remain clinically silent and poorly detected. Although white matter hyperintensities (WMHs) are widely used neuroimaging markers, conventional cardiovascular risk scores and cognitive testing lack sensitivity to subclinical cerebrovascular injury. This study investigated whether circulating microparticles (MPs) and fractal analysis of the Circle of Willis (CoW), reflecting cerebrovascular network–hemodynamic complexity, could provide an early, mechanistically informative marker of silent CSVD. Sixty asymptomatic adults with low‐to‐moderate cardio‐cerebrovascular risk (QRISK3) underwent 3 T MRI, cognitive testing, and circulating MPs profiling. Cerebrovascular fractal dimension of the CoW (Df [W]) was computed from 3D time‐of‐flight magnetic resonance angiography. Multivariable regression, mediation analysis (10,000 bootstraps), and ROC analyses were performed. Reduced D _f (W) was strongly associated with greater WMHs burden ( p < 0.001) and significantly outperformed QRISK3 and MPs in discriminating WMHs (AUC = 0.928 vs. ~0.75). Leukocyte‐derived (CD62L ⁺ ) and platelet‐derived (CD62P ⁺ ) MPs were elevated in participants with WMHs and correlated with both WMHs burden and D _f (W), but lost independent significance after adjustment for WMHs, indicating upstream systemic vascular injury. Mediation analysis confirmed that MPs influenced WMHs' burden primarily through their effect on cerebrovascular D _f (W). A combined biological–imaging model integrating MPs and D _f (W) achieved near‐perfect diagnostic accuracy (AUC = 0.952). Despite marked vascular and microstructural abnormalities, neurocognitive performance was preserved, with only a weak association between processing speed and D _f (W), consistent with network reserve in early CSVD. Thus, cerebrovascular fractal complexity may capture the structural imprint of cumulative vascular injury and enable biologically grounded detection of preclinical CSVD.

Background: Mental health disorders such as depression, anxiety, and stress are increasingly prevalent among university students and contribute to long-term cardio-cerebrovascular disease (CCVD) risk. However, limited research has examined the interplay between mental health, CCVD risk factors, and religiosity/spirituality within Southeast Asia’s multicultural context. Methods: This cross-sectional study investigated these relationships among 484 undergraduate students enrolled in medical and health sciences programs across Peninsular Malaysia. Mental health status was assessed using the Depression, Anxiety, and Stress Scale (DASS-21). Self-reported clinical indicators associated with early CCVD vulnerability were also assessed. Religiosity and spirituality were measured using the Duke University Religion Index (DUREL), Brief Religious Coping (RCOPE), Spirituality Scale (SS), and Spiritual Coping Questionnaire (SCQ). Results: High prevalence rates of severe anxiety (50.4%), depression (29.3%), and stress (21.1%) were observed, with significant associations across ethnicity, religion, and academic programs. Higher religiosity and spirituality were generally associated with better mental health outcomes. However, coping style emerged as a key modifier of the relationship between religiosity/spirituality and mental health outcomes, with negative religious coping associated with greater psychological distress, whereas positive coping demonstrated mixed associations and partial mediating effects. Students with poorer mental health also exhibited higher CCVD risk burden. Conclusions: These findings highlight the importance of culturally and spiritually sensitive strategies in promoting student well-being.

Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) leads to neural cell death and inflammation, resulting in white matter injury in premature infants. Here, we show that IVH-induced iron deposition, ferroptosis, myelination failure, and disruption in lipid and oxylipin metabolism are mitigated by iron chelation using deferoxamine. We also identify the specific lipid and oxylipin metabolites and enzymes dysregulated in IVH, which are rescued by deferoxamine treatment. Our findings reveal that IVH causes iron accumulation, ferroptosis, and apoptosis, and leads to gene enrichment that contributes to cell death and oxidative injury in premature rabbits and human infants. IVH activates phospholipases (PLA2) and lysophosphatidylcholine acyltransferase-3 (LPCAT3), elevating levels of polyunsaturated fatty acids, lysophospholipids, and triacylglycerols, which contribute to neural cell injury. Furthermore, IVH upregulates cyclooxygenase, lipoxygenase, and cytochrome-P450 enzymes, which increases oxylipin production, thereby exacerbating inflammation. Importantly, iron chelation using systemic deferoxamine reduces levels of cPLA2, LPCAT3, and oxylipin-generating enzymes, restoring levels of lysophospholipids, triacylglycerols, and oxylipins in kits with IVH. Consistently, deferoxamine treatment alleviates IVH-induced ferroptosis, inflammation, microglial lipid accumulation, myelination failure, and neurological dysfunction. The study identifies that iron-triggered enzymatic dysregulation of lipid and oxylipin metabolism increases the generation of oxylipins and pro-inflammatory lipid metabolites, contributing to white matter injury in IVH survivors. These effects are mitigated by iron chelation.

BACKGROUND The external carotid artery (ECA) supplies major extracranial structures of the head and neck and typically gives rise to 8 branches. Among its ventral branches, the lingual and facial arteries normally arise independently; however, they may occasionally share a common origin, known as the linguofacial trunk (LFT). Recognizing these variants is crucial for surgeons and radiologists to prevent surgical errors and ensure effective treatment. CASE REPORT During a routine cadaveric dissection in the Department of Anatomy, University of Medicine 1, Yangon, Myanmar, we systematically examined the carotid triangle to assess the branching pattern of the ECA. A unilateral LFT was identified on the right side of a male cadaver. The trunk originated approximately 10 mm from the anterior surface of the ECA, just superior to the carotid bifurcation, giving rise to both the lingual and facial arteries. The superior thyroid artery arose independently below this level. On the left side, the ECA branching pattern followed the classical description, with separate lingual and facial arteries. CONCLUSIONS To the best of our knowledge, this is the first published cadaveric case report describing an LFT in a donor from Myanmar, highlighting unilateral LFT as a clinically significant anatomic variation of the ECA. Recognition of this variant is critical in head and neck surgery, selective arterial ligation, and interventional oncology, where failure to identify variant ECA patterns can compromise procedural success and patient safety.