Lipidopathy disrupts peripheral and central amyloid clearance in Alzheimer's disease: Where are our knowledge

IBRO Neuroscience Reports, Journal Year: 2025, Volume and Issue: 18, P. 191 - 199

Published: Jan. 9, 2025

Language: Английский

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Melatonin regulation of phase separation in Neuro-PASC: out-maneuvering Janus-faced amyloids

Exploration of neuroscience, Journal Year: 2025, Volume and Issue: 4

Published: March 24, 2025

The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on global scale. One the main molecular mechanisms responsible for development Neuro-PASC, individuals all ages, is formation inadequate proteolysis/clearance phase-separated amyloid crystalline aggregates—a hallmark feature aging-related neurodegenerative disorders. Amyloidogenesis during viral persistence natural, inevitable, protective defense response exacerbated by SARS-CoV-2. Acting as chemical catalyst, accelerates hydrophobic collapse heterogeneous nucleation amorphous amyloids into stable β-sheet aggregates. clearance aggregates most effective slow wave sleep, when high levels adenosine triphosphate (ATP)—a biphasic modulator biomolecular condensates—and melatonin are available solubilize removal. dysregulation mitochondrial dynamics SARS-CoV-2, particular fusion fission homeostasis, impairs proper distinct subpopulations can remedy challenges created diversion substrates away from oxidative phosphorylation towards glycolysis support replication maintenance. subsequent reduction ATP inhibition synthesis sleep results incomplete brain aggregates, leading commonly associated age-related Exogenous not only prevents dysfunction but also elevates production, effectively augmenting solubilizing effect moiety ensure timely, optimal disaggregation pathogenic prevention attenuation Neuro-PASC.

Language: Английский

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Targeting Soluble Amyloid Oligomers in Alzheimer’s Disease: A Hypothetical Model Study Comparing Intrathecal Pseudodelivery of mAbs Against Intravenous Administration

Diseases, Journal Year: 2025, Volume and Issue: 13(1), P. 17 - 17

Published: Jan. 16, 2025

Neurotoxic soluble amyloid-β (Aβ) oligomers are key drivers of Alzheimer's pathology, with evidence suggesting that early targeting these forms may slow disease progression. Traditional intravenous (IV) monoclonal antibodies (mAbs) face challenges, including limited brain penetration and risks such as amyloid-related imaging abnormalities (ARIA). This hypothetical study aimed to model amyloid dynamics in early-to-moderate (AD) compare the efficacy IV mAn intrathecal pseudodelivery, a novel method confines mAbs subcutaneous reservoir for selective clearance cerebrospinal fluid (CSF) without systemic exposure. A mathematical framework was employed simulate Aβ patients AD. Two therapeutic approaches were compared: mAb pseudodelivery mAb. The incorporated kinetics, affinity, protofibril size, therapy-induced rates evaluate impact both methods on reduction, PET negativity timelines, risk ARIA. Intrathecal significantly accelerated compared administration, achieving scan by month 132, opposed 150 demonstrated no ARIA reduced reaccumulation. By species more effectively, emerged safer efficient strategy AD intervention. offers promising alternative mAbs, overcoming challenges associated blood-brain barrier side effects. Further research should focus optimizing this approach exploring combination therapies enhance clinical outcomes

Language: Английский

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A case of severe ARIA with multiple infarctions and extensive microbleeds following lecanemab administration

Psychogeriatrics, Journal Year: 2024, Volume and Issue: 25(1)

Published: Dec. 18, 2024

Alzheimer's disease (AD), characterised pathologically by the presence of amyloid-beta (Aβ) protein plaques, is leading cause dementia worldwide. Currently, lecanemab, an anti-Aβ antibody, has been approved in many countries for treatment mild cognitive impairment and caused AD. However, it associated with specific adverse events including immune-mediated clearance, which carries risk vasogenic oedema intracerebral haemorrhage, collectively referred to as amyloid-related imaging abnormalities (ARIA). ARIA cases can be subdivided into or effusion (ARIA-E), cerebral microhaemorrhage, macrohaemorrhage, superficial siderosis (ARIA-H). Previous studies have shown that even severe ARIA-H, number microbleeds limited a few dozen.1 In addition, there no prior reports association ARIA-E microinfarctions. Herein, we report patient who developed numerous microbleeds, microinfarctions, after lecanemab administration. The was 57-year-old married woman 16 years education. Her father diagnosed his 60s, her mother 50s. She began experiencing memory symptoms at age 53. first visited clinic our hospital 57 years. not taking any regular medications, antihypertensives antithrombotics. Mini-Mental State Examination (MMSE) score 26/30 on Japanese version Montreal Cognitive Assessment (MoCA) 17/30, indicating disorientation short-term impairment, affecting daily life. Magnetic resonance (MRI) head revealed atrophy left hippocampus parahippocampal gyrus, along two (Fig. 1a). Positron emission tomography using 18F-flutemetamol amyloid plaque deposition frontal, lateral temporal parietal lobes, posterior cingulate praecuneus, striatum 1b). Based these findings, early-onset Japan, genetic testing covered national health insurance; therefore, routinely performed clinical practice. As counselling available hospital, apolipoprotein E (APOE) genotype assessed before receiving lecanemab. met eligibility criteria according guidelines optimal use. expressed wish undergo thereafter started 10 mg/kg twice month. By third dose she fever, but did use antipyretics. About 6 h fourth dose, hemiparesis, confusion, urinary incontinence. 2 days dose. At presentation, included headache, hemiparesis. able walk assistance. On MRI, under same baseline conditions, increased 18, primarily appearing frontal cortices, were more prominent right side. susceptibility-weighted (SWI), this than 100 2b,d,f). Multiple microinfarctions observed occipital lobes cortex, well subcortical white matter 3). Interestingly, despite progression oedema, perivascular spaces had expanded compared 4). subsequently admitted hospital. received intravenous methylprednisolone (1000 mg) 5 days, followed initiation oral steroid therapy. prednisolone (PSL) 1 body weight, tapered weekly; 29th day illness, reduced 20 mg. end treatment, headaches, confusion resolved, follow-up MRI significant improvement 5). 10th MMSE MoCA scores 15/30 10/30, respectively. discharged outpatient when steroids mg PSL. 40th patients' 14/30 11/30, Following development ARIA, discontinued. will continue monitored facility specialising care. current case diagnostic both (fluid-attenuated inversion recovery hyperintensity >10 cm swelling sulcal effacement) ARIA-H (10 new incident microhaemorrhages >2 areas siderosis). This four notable characteristics. First, multiple due ARIA. A PubMed search conducted terms '(Amyloid-Related Imaging Abnormalities) AND (infarction OR stroke)' August 12, 2024, yielded infarctions occurring result noted present similarities angiopathy-related inflammation (CAA-ri).2 It further reported occur one subtypes CAA-ri, angiitis.3 possible showed similar aberrations microvasculature. Our experience indicates thin-slice diffusion-weighted image sequences should suspected. second unique characteristic >100 microbleeds. reviews range typically order dozens, making findings unique.4 Compared detail 7 Tesla-MRI following onset are clearly numerous. Despite absence feature case, may reflect vasculitis local inflammatory responses rather leakage blood components vascular permeability. Third, exhibited changes sufficient midline shift. Most treated asymptomatic, rare fatalities. Although deterioration, shift posed brain herniation necessitating admission intensive care unit. hospitalisation, methylprednisolone, recommended initiated, tendency decrease within headache hemiparesis resolved. patient's function gradually improved. Fourth, ARIA-E-associated swelling, space expansion observed. indicate impaired specifically delayed excretion Aβ regions, potentially burdening glymphatic drainage system removal dissolved treatment.5 thought causes case. unprecedented features, focus mechanisms burden space. These helpful understanding underlying unclear. relatively young. unfortunately, APOE measured, suspect ε4 homozygote. Further research required prevent occurrence patients AD Dr. Mishina, Masahiro, co-author article, Editorial Board member Psychogeriatrics. authors declare conflict interests article. Informed consent obtained from publication report. Data sharing applicable article datasets generated analysed during study.

Language: Английский

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Expansive spatial pattern of Aß deposition in patients with cerebral amyloid angiopathy: a large-scale and surface-to-depth analysis

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Sporadic cerebral amyloid angiopathy (CAA) is a common neurodegenerative disorder characterized by accumulation of β (Aβ) in the cerebrovascular wall, often coexisting with Alzheimer’s disease. CAA thought to be caused impaired efflux Aβ through small vessels. However, precise locations within spatial system remain unclear human brain because its large size and complex organization. This study aimed clarify three-dimensional (3D) distribution possible progression pattern vascular degeneration relation perivascular senile plaques CAA, employing highly tissue-clearing technique light-sheet fluorescence microscopy. We prepared formalin-fixed 0.5-cm³ tissue blocks from frontal occipital lobes postmortem brains six patients (CAA Thal stage 2 or 3 Braak III-VI) using double-immunofluorescence labeling for smooth muscle actin (SMA) Aβ_17-24. identified 1104 Aβ-positive 535 Aβ-negative units. The 3D analysis revealed that deposition was predominantly distributed leptomeningeal arteries (LMA) superficial cortical segment units (96.2% 99.5% positivity, respectively), appeared develop continuously surface deeper segments. Similar this pattern, SMA loss segments units, these had significantly larger median external diameter than those were (36.73 μm vs 25.94 μm, P<0.0001). density lower around (P<0.0001). These findings suggest develops preferentially extends layer. There may an inverse relationship between loads.

Language: Английский

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Choroid plexus cysts on 7T MRI: Relationship to aging and neurodegenerative diseases

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 28, 2024

The choroid plexus (CP) may play a crucial role in brain degeneration. We aim to assess whether CP cysts (CPCs), defined using ultra-high field magnetic resonance imaging (MRI), relate aging and neurodegeneration. used multi-sequence 7T MRI observe CPCs, characterizing their presence characteristics healthy younger controls, older controls (OCs), patients with Alzheimer's disease (AD), Parkinson's (PD), uremic encephalopathy. volume (CPV) CPC were compared across groups, associations between CPV features analyzed all subjects. AD group showed significantly higher number of CPCs other groups also had larger than OCs. size associated CPV. offers distinct advantage observing the high prevalence warrants further investigation. enables visualization fine structures plexus. Patients (AD) exhibit (CPCs) adults patient groups. serve as an auxiliary marker for AD.

Language: Английский

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