Hallmarks of neurodegenerative diseases

Cell, Journal Year: 2023, Volume and Issue: 186(4), P. 693 - 714

Published: Feb. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Language: Английский

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Lipid nanoparticles for delivery of RNA therapeutics: Current status and the role of in vivo imaging

Theranostics, Journal Year: 2022, Volume and Issue: 12(17), P. 7509 - 7531

Published: Jan. 1, 2022

Lipid nanoparticles (LNPs) have been one of the most successful nano-delivery vehicles that enable efficient delivery cytotoxic chemotherapy agents, antibiotics, and nucleic acid therapeutics.During coronavirus disease (COVID-19) pandemic, LNP-based COVID-19 messenger RNA (mRNA) vaccines from Pfizer/BioNTech Moderna successfully developed, resulting in global sales $37 billion $17.7 billion, respectively, 2021.Based on this success, development multiple therapeutics is gaining momentum due to its potential for various genetic diseases cancers.Furthermore, imaging techniques can be utilized evaluate pharmacokinetics pharmacodynamics (PK/PD) effects, which helps target discovery accelerates mRNA therapies.A thorough introduction explanation components LNPs functions along with production methods formulating are provided review.Furthermore, recent advances clinics clinical trials explored.Additionally, evaluation PK/PD current roles developing pharmaceutics through will discussed.

Language: Английский

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TSPO PET brain inflammation imaging: A transdiagnostic systematic review and meta-analysis of 156 case-control studies

Brain Behavior and Immunity, Journal Year: 2023, Volume and Issue: 113, P. 415 - 431

Published: Aug. 3, 2023

The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity TSPO to identify brain processes appears vary greatly across disorders, disease stages, applied quantification methods. To advance potential biomarker evaluate inflammation anti-inflammatory therapies, better understanding its applicability disorders needed. We conducted transdiagnostic systematic review meta-analysis all vivo human case-control studies CNS. Specifically, we investigated direction, strength, heterogeneity associated with signal pre-specified regions, explored demographic methodological sources heterogeneity.We searched English peer-reviewed articles that differences. extracted details, outcomes, technical variables procedure. A random-effects was estimate standardized mean differences (SMD) lobar/whole-brain cortical grey matter (cGM), thalamus, cortico-limbic circuitry between different illness categories. Heterogeneity evaluated I2 statistic using subgroup meta-regression analyses radioligand generation, method, age, sex, publication year. Significance set at False Discovery Rate (FDR)-corrected P < 0.05.156 individual were included review, incorporating data 2381 healthy controls 2626 patients. 139 documented meta-analysable grouped into 11 Across categories, observed significantly higher cases compared cGM (n = 121 studies, SMD 0.358, PFDR 0.001, 68%), significant difference categories (P 0.004). increases only Alzheimer's (SMD 0.693, 64%) other neurodegenerative 0.929, 73%). Cortico-limbic 97 0.541, 67%) most prominent disease, mild cognitive impairment, mood multiple sclerosis. Thalamic involvement 79 0.393, 71%) sclerosis, chronic pain functional (all 0.05). Main outcomes systemic immunological viral infections, substance use schizophrenia traumatic injury not significant. identified between-study variance including strong effect method (explaining 25% variance; VT-based 0.000 versus reference tissue-based 0.630; F 20.49, df 1;103, 0.001), patient age (9% variance), generation (5% variance).This study first overarching findings humans several regions. robust specific types which widespread or focal depending on category. also found large horizontal (positive) shift estimates studies. Our results can support future optimize experimental design power calculations, by taking account type disorder, region-of-interest, radioligand, method.

Language: Английский

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Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia

Brain, Journal Year: 2023, Volume and Issue: 146(8), P. 3221 - 3231

Published: March 7, 2023

Abstract Frontotemporal dementia is clinically and neuropathologically heterogeneous, but neuroinflammation, atrophy cognitive impairment occur in all of its principal syndromes. Across the clinical spectrum frontotemporal dementia, we assess predictive value vivo neuroimaging measures microglial activation grey-matter volume on rate future decline. We hypothesized that inflammation detrimental to performance, addition effect atrophy. Thirty patients with a diagnosis underwent baseline multimodal imaging assessment, including [11C]PK11195 PET index structural MRI quantify volume. Ten people had behavioural variant 10 semantic primary progressive aphasia non-fluent agrammatic aphasia. Cognition was assessed at longitudinally revised Addenbrooke's Cognitive Examination, an average 7-month intervals (for ∼2 years, up ∼5 years). Regional binding potential were determined, these averaged within four hypothesis-driven regions interest: bilateral frontal temporal lobes. Linear mixed-effect models applied longitudinal test scores, potentials volumes as predictors age, education performance covariates. Faster decline associated reduced increased regions, bilaterally. In negatively correlated, provided independent information, stronger predictor When included factor models, significant found for BPND left lobe (−0.70, P = 0.01), not (P &gt; 0.05), suggesting severity this region relates regardless variant. The main results validated by two-step prediction frequentist Bayesian estimation correlations, showing associations between estimated change (slope) lobe. These findings support preclinical which neuroinflammation (by activation) accelerates neurodegenerative disease trajectory. highlight immunomodulatory treatment strategies may also improve stratification trials.

Language: Английский

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Multimodal comparisons of QSM and PET in neurodegeneration and aging

NeuroImage, Journal Year: 2023, Volume and Issue: 273, P. 120068 - 120068

Published: March 31, 2023

Quantitative susceptibility mapping (QSM) has been used to study changes that may occur based on tissue composition and mineral deposition. Iron is a primary contributor in magnetic of particular interest applications QSM neurodegeneration aging. can contribute through inflammatory processes via interaction with aggregation disease-related proteins. To better understand the local observed QSM, its signal studied association other imaging metrics such as positron emission tomography (PET). The associations PET provide insight into pathophysiology disease processes, role iron aging neurodegeneration, help determine diagnostic utility an indirect indicator typically evaluated PET. In this review we discuss proposed mechanisms summarize prior studies amyloid PET, tau TSPO FDG-PET, 15O-PET, F-DOPA evaluation neurologic diseases focus neurodegeneration.

Language: Английский

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Longitudinal positron emission tomography and postmortem analysis reveals widespread neuroinflammation in SARS-CoV-2 infected rhesus macaques

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: July 29, 2023

Coronavirus disease 2019 (COVID-19) patients initially develop respiratory symptoms, but they may also suffer from neurological symptoms. People with long-lasting effects after acute infections severe syndrome coronavirus 2 (SARS-CoV-2), i.e., post-COVID or long COVID, experience a variety of manifestations. Although we do not fully understand how SARS-CoV-2 affects the brain, neuroinflammation likely plays role.

Language: Английский

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Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(4), P. 2397 - 2407

Published: Feb. 1, 2024

Abstract INTRODUCTION Evidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aβ) local neurodegeneration, resulting cognitive impairment. METHODS Florbetaben, PBR28, MK‐6240 PET, T1 magnetic resonance imaging, measures were performed 19 cognitively unimpaired older adults 22 patients mild impairment or to examine associations among activation, Aβ, tau, cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of along model. RESULTS Higher PBR28 uptake was associated higher lower MMSE score, independent mediated between early middle Braak stages, cognition. DISCUSSION Microglia are pathology cognition may mediate relationships subsequent steps progression.

Language: Английский

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Novel Development and Prospects in Pathogenesis, Diagnosis, and Therapy of Alzheimer’s Disease

Journal of Alzheimer s Disease Reports, Journal Year: 2024, Volume and Issue: 8(1), P. 345 - 354

Published: Feb. 20, 2024

Alzheimer’s disease (AD) is the most prevalent neurodegenerative with cognitive decline and behavioral dysfunction. AD will become a global public health concern due to its increasing prevalence brought on by severity of aging. It critical understand pathogenic mechanisms investigate or pursue viable therapy strategy in clinic. Amyloid-β (Aβ) accumulation abnormally hyperphosphorylated tau protein are main regulating variables pathological phase AD. And neuroinflammation activated microglia was found be one risk factor contributing changes Aβ pathology. important unique biomarkers early diagnosis advanced stage, which may help elucidate specific process provide potential novel therapeutic targets preventative measures.

Language: Английский

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Microglia Density and Its Association With Disease Duration, Severity, and Orexin Levels in Patients With Narcolepsy Type 1

Neurology, Journal Year: 2024, Volume and Issue: 102(10)

Published: April 26, 2024

Narcolepsy type 1 (NT1) is due to the loss of hypothalamic neurons that produce orexin (ORX), by a suspected immune-mediated process. Rare postmortem studies are available and failed detect any inflammation in region, but these brains were collected years after first symptoms. In vivo close disease onset lacking. We aimed explore microglia density hypothalamus thalamus NT1 compared with controls using [18F]DPA-714 PET study relationships between other regions interest (ROIs) duration, severity, ORX levels. Patients underwent standardized clinical evaluation imaging radiolabeled ligand specific 18 kDa translocator protein (TSPO). TSPO genotyping determined receptor affinity. Images processed on peripheral module interface standard uptake value (SUV) ROIs: hypothalamus, thalamus, frontal area, cerebellum, whole brain. SUV ratios (SUVr) calculated normalizing cerebellum uptake. A total 41 patients (21 adults, 20 children, 10 recent <1 year) 35 included, no significant difference groups for binding (SUV/SUVr) thalamus. Unexpectedly, significantly lower SUVr brain was found (0.97 ± 0.06 vs 1.08 0.22, p = 0.04). The same finding observed those high or mixed affinity (p 0.03 Similar trend area (0.96 0.09 1.09 0.25, 0.05). NT1, association different ROIs age, evidence increased controls, even onset, unexpectedly decrease patients. These findings do not support presence neuroinflammation destruction process neurons. ClinicalTrials.org NCT03754348.

Language: Английский

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Altered Brain Energy Metabolism Related to Astrocytes in Alzheimer's Disease

Annals of Neurology, Journal Year: 2023, Volume and Issue: 95(1), P. 104 - 115

Published: Sept. 13, 2023

Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of in energy metabolism, may contribute to altered brain metabolism. Astrocytes primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed examine alterations astrocytic activities and their association levels AD.The included 30 AD cognitively unimpaired participants. For participants, amyloid tau depositions were confirmed by positron emission tomography using [11 C]PiB [18 F]florzolotau, respectively. Myo-inositol, an astroglial marker, posterior cingulate cortex quantified magnetic resonance spectroscopy. These spectroscopy metabolites compared plasma biomarkers, including glial fibrillary acidic protein as another tomography.Myo-inositol higher patients than participants (p < 0.05). Myo-inositol correlated (r = 0.272, p 0.047). positively Clinical Dementia Rating sum-of-boxes scores Significant correlations noted between myo-inositol protein, phosphorylated at threonine 181 levels, accumulation 0.05).We found high accompanied increased patients, indicating link reflect similar changes biomarkers AD. ANN NEUROL 2023.

Language: Английский

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