Search Results (307)

Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies. Full article

Glucose is the main source of energy and the source of carbon for the biosynthesis of several molecules, such as neurotransmitters, for most mammalian cells. Therefore, the transport of glucose into cells is very important. There are described three distinct families of glucose transporters: facilitative glucose transporters (GLUTs), sodium-dependent glucose cotransporters (SGLTs), and a uniporter, the SWEET protein. Impaired function and/or expression of these transporters due to, for example, mutations in their genes, may cause severe diseases. Associations with the impaired function of glucose transporters have been described in the case of neurodegenerative diseases (NDs) such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, GLUT1-deficiency syndrome, stroke, and traumatic brain injury. Changes in the presence of glucose transporters may be a cause of NDs, and they may be the effect of NDs. On the other hand, in many cases of neurodegenerative diseases, changes in the expression of glucose transporters may be a targeted therapy in the treatment of patients with these diseases. Full article

The electrical ventricular storm (VES) is defined as multiple sustained ventricular arrhythmias arising in a short time, often refractory to standard antiarrhythmic treatment. The three pillars of the physiopathogenesis of the VES are autonomic dysfunction, triggers, and an altered ventricular substrate. Incessant or highly recurrent ventricular arrhythmia impacts the hemodynamic status by worsening heart failure and increasing mortality. A stepwise, team-based, and tailored therapeutic approach is required to stop ventricular arrhythmia and regain the hemodynamic and electric stability of the patient. The authors focused on describing all currently available therapeutic approaches for VES, intending to establish the best VES therapeutic approaches. This process involves considering the patient’s specific condition, responses to previous treatments, and the potential risks and benefits of each approach. The options range from adjusting antiarrhythmic therapy to reprogramming of the ICD, sedation, epidural anaesthesia, stellate ganglia anaesthetic block, and the use of ECMO or left ventricular assist devices and radiofrequency catheter ablation. Particular attention is paid to the detailed management of genetic primary arrhythmia syndromes like long-QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome and Wolff–Parkinson–White syndrome, early repolarisation syndrome, right ventricular arrhythmogenic dysplasia, and idiopathic ventricular fibrillation. After overcoming the acute events of VES and obtaining hemodynamic stability, the treatment should shift toward an optimal balance of heart failure therapy, controlling the substrate by revascularisation procedures and resolving other pathology-generating ventricular arrhythmias. This article provides a comprehensive overview of ESV’s current management options using the most efficient strategies known to date. Full article

This narrative review examines the effects of caffeine on brain health in older adults, with particular attention to its potential for dependence—an often-overlooked issue in geriatric care. Caffeine acts on central adenosine, dopamine, and glutamate systems, producing both stimulating and rewarding effects that can foster tolerance and habitual use. Age-related pharmacokinetic and pharmacodynamic changes prolong caffeine’s half-life and increase physiological sensitivity in the elderly. While moderate consumption may enhance alertness, attention, and possibly offer neuroprotective effects—especially in Parkinson’s disease and Lewy body dementia—excessive or prolonged use may lead to anxiety, sleep disturbances, and cognitive or motor impairment. Chronic exposure induces neuroadaptive changes, such as adenosine receptor down-regulation, resulting in tolerance and withdrawal symptoms, including headache, irritability, and fatigue. These symptoms, often mistaken for typical aging complaints, may reflect a substance use disorder yet remain under-recognized due to caffeine’s cultural acceptance. The review explores caffeine’s mixed role in neurological disorders, being beneficial in some and potentially harmful in others, such as restless legs syndrome and frontotemporal dementia. Given the variability in individual responses and the underestimated risk of dependence, personalized caffeine intake guidelines are warranted. Future research should focus on the long-term cognitive effects and the clinical significance of caffeine use disorder in older populations. Full article

Background/Objectives: Chronic manganese (Mn) exposure is a recognized environmental contributor to Parkinsonian syndromes, including Mn-induced Parkinsonism (MnIP). This study aimed to evaluate whole-blood Mn levels and investigate disease/exposure-status-related alterations in metabolomic and lipidomic profiles. Methods: A case–control study (N = 97) was conducted in Brescia, Italy, stratifying participants by Parkinsonism diagnosis and residential Mn exposure. Whole-blood Mn was quantified using ICP-MS. Untargeted metabolomic and lipidomic profiling was conducted using LC-MS. Statistical analyses included Mann–Whitney U tests, conditional logistic regression, ANCOVA, and pathway analysis. Results: Whole-blood Mn levels were significantly elevated in Parkinsonism cases vs. controls (median: 1.55 µg/dL [IQR: 0.75] vs. 1.02 µg/dL [IQR: 0.37]; p = 0.001), with Mn associated with increased odds of Parkinsonism (OR = 2.42, 95% CI: 1.13–5.17; p = 0.022). The disease effect metabolites included 3-sulfoxy-L-tyrosine (β = 1.12), formiminoglutamic acid (β = 0.99), and glyoxylic acid (β = 0.83); all FDR p < 0.001. The exposure effect was associated with elevated glycocholic acid (β = 0.51; FDR p = 0.006) and disrupted butanoate (Impact = 0.03; p = 0.004) and glutamate metabolism (p = 0.03). Additionally, SLC-mediated transmembrane transport was enriched (p = 0.003). The interaction effect identified palmitelaidic acid (β = 0.30; FDR p < 0.001), vitamin B6 metabolism (Impact = 0.08; p = 0.03), and glucose homeostasis pathways. In lipidomics, triacylglycerols and phosphatidylethanolamines were associated with the disease effect (e.g., TG(16:0_10:0_18:1), β = 0.79; FDR p < 0.01). Ferroptosis and endocannabinoid signaling were enriched in both disease and interaction effects, while sphingolipid metabolism was specific to the interaction effect. Conclusions: Mn exposure and Parkinsonism are associated with distinct metabolic and lipidomic perturbations. These findings support the utility of omics in identifying environmentally linked Parkinsonism biomarkers and mechanisms. Full article

Background/Objectives: Cognitive impairment often occurs in various parkinsonian syndromes. The course of deficits in cognitive functions ranges from mild cognitive decline to severe deterioration. Affected cognitive domains are also variable. The genetic background of patients exhibiting parkinsonism with concomitant cognitive decline is still elusive. A significant part of current research in Parkinson’s disease and other parkinsonian syndromes is targeted towards the genetic aspects of these disorders. The aim of the present review was to summarize existing studies focusing on the investigation of the interplay between genetic data in parkinsonism and associated cognitive symptoms. Methods: A review of English-language articles published between 2000 and 2024 was conducted, focusing on genetic studies of Parkinson’s disease and atypical parkinsonian syndromes with cognitive decline, using the databases PUBMED, SCOPUS, and EMBASE. Results: We have selected a clinical phenotype-wise assessment of parkinsonian conditions with cognitive deficits, including typical or early-onset Parkinson’s disease, dementia with Lewy bodies, Corticobasal Syndrome, Progressive Supranuclear Palsy, and frontotemporal dementia with parkinsonism. Both typical and atypical parkinsonian syndromes with concomitant cognitive decline were explored. Conclusions: Genetic background likely contributes to the heterogeneity of cognitive impairment in parkinsonian syndromes, with specific mutations linked to distinct cognitive symptoms. The integration of genetic data and a more thorough neuropsychological assessment with clinical, imaging, and biomarkers may enhance diagnosis and enable personalized therapies. Full article

Background: Metabolic syndrome and Parkinson’s disease have common pathophysiological denominators. This study aimed to investigate how metabolic syndrome contributes to Parkinson’s disease progression, as well as the genetic traits shared by PD and MetS. Methods: Four hundred and twenty-three newly diagnosed drug-naïve PD patients were analyzed from the Parkinson’s Progression Markers Initiative (PPMI) database. We compared longitudinal changes in the total and subscale scores of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) between PD patients with and without metabolic syndrome over a five-year follow-up. We assessed the frequency of PD-associated genetic variants in both groups. Results: At baseline, Parkinson’s patients with MetS were typically men (p < 0.01) and older (p = 0.04), with a higher Hoehn and Yahr score (p = 0.01) compared with their counterparts without MetS. They showed higher Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total scores at baseline and in follow-up years 2, 3, 4, and 5 (all p-values < 0.05) as analyzed by the Generalized Estimating Equation model. These differences were primarily driven by elevated motor scores (MDS-UPDRS Part III) (p < 0.01). MetS was associated with a higher frequency of the ZNF646.KAT8.BCKDK_rs14235 variant and a lower frequency of the NUCKS1_rs823118 and CTSB_rs1293298 variants. Conclusions: PD patients with MetS had worse motor symptomatology. Both conditions appear to share genetic susceptibility, involving genes related to lipid metabolism (BCKDK), autophagy and inflammation (CTSB), and chromatin regulation (NUCKS1). Full article

Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses—including gene transcription, cytoskeletal remodeling, and neurotransmitter release—to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting. Full article

Carriers of Gaucher disease have an increased risk of developing Parkinson’s disease (PD). Identifying PD in its prodromal stage is crucial, as early detection before motor symptoms appear allows for potential interventions to salvage neurons and slow or prevent disease progression. At the Gaucher unit at Shaare Zedek Medical Center, we are following a large cohort of obligatory carriers of GBA1 variants (GBA1 carriers) and study ways to identify those at an increased risk for developing PD. In this study, we compared non-invasive prodromal PD tests in 164 GBA1 carriers and 49 participants with no genetic predisposition to PD (controls). The proportion of abnormal tests was compared between groups, and the risk factors for having abnormal tests (at least one or ≥20%) were studied. There were no differences between GBA1 carriers and controls in the frequency of abnormalities, having at least one abnormal test or having ≥20% abnormal tests. Having ≥20% of abnormal tests was associated mainly with age. Principal component analysis identified distinct cognitive, motor, and non-motor dysfunction patterns in GBA1 carriers compared to controls, with cognition in GBA1 carriers more closely linked to motor dysfunction and less influenced by mood and sleep, while in controls, executive function was tied to emotional state and fatigue. Younger carriers outperformed older ones in motor and some cognitive tasks. Those with a family history of PD showed worse cognitive scores than participants with no family history. Sex-based analysis revealed males obtained higher scores in most of the cognition subtests of the NeuroTrax test, whereas it was females in motor and other cognitive domains, mainly in the group of GBA1 carriers. A longitudinal follow-up of GBA1 carriers is ongoing to understand PD progression in GBA1 carriers with the aim of offering targeted intervention for those at higher risk. Full article

In addition to axial motor complications such as abnormal posture, instability, falls, and gait variability, neurodegenerative diseases like Parkinsonian syndromes include executive dysfunction, Parkinson’s disease dementia, and neuropsychiatric symptoms. These motor disorders significantly affect mobility, quality of life, and well-being. Recently, physical activity of various intensities monitored both remotely and face-to-face via digital health technologies, mobile platforms, or sensory cues has gained relevance in managing idiopathic and atypical Parkinson’s disease (PD and APD). Remote monitoring solutions, including home-based digital health assessments using semi-structured activities, offer unique advantages. Real-world gait parameters like walking speed can now be continuously assessed with body-worn sensors. Developing effective strategies to slow pathological aging and mitigate neurodegenerative progression is essential. This study presents outcomes of using digital health technologies (DHTs) for remote assessment of motor function, physical activity, and daily living tasks, aiming to reduce disease progression in PD and APD. In addition to wearable inertial sensors, clinical rating scales and digital biomarkers enhance the ability to characterize and monitor motor symptoms. By reviewing recent literature, we identified emerging trends in quantifying and intervening in neurodegeneration using tools that evaluate both remote and face-to-face physical activity. Our findings confirm that DHTs offer accurate detection of motor fluctuations and support clinical evaluations. In conclusion, DHTs represent a scalable, effective strategy for improving the clinical management of PD and APD. Their integration into healthcare systems may enhance patient outcomes, support early intervention, and help delay the progression of both motor and cognitive symptoms in aging individuals. Full article

Parkinson’s disease (PD) associated with GBA1 mutations—recently termed Sidransky syndrome—differs from idiopathic PD (iPD) by earlier onset, more rapid progression, and higher rates of non-motor symptoms. Our objective was to assess whether GBA1 mutations contribute to olfactory dysfunction in PD and in asymptomatic carriers of the mutation. We compared olfactory and motor functions in 119 participants: Sidransky syndrome (n = 18), iPD (n = 30), GBA1 variant carriers without PD (n = 21), Gaucher disease patients (n = 20), and healthy controls (n = 30). All were evaluated with the Brief Smell Identification Test (BSIT^®) and the motor part of the Movement Disorders Society Unified PD Rating Scale (MDS-mUPDRS). Mean age was 59.2 ± 11.7 years. Mean disease duration was 2.5 ± 2.2 years in Sidransky syndrome and 5.4 ± 4.9 years in iPD. We found that both PD groups had significantly lower BSIT^® scores than non-PD groups (p < 0.001), particularly for leather, smoke, natural gas, pineapple, clove, rose, and lemon. Sidransky syndrome patients scored lower than iPD patients (p = 0.04). No significant olfactory deficits were observed in GBA1 carriers or Gaucher patients without PD. We conclude that hyposmia is more pronounced in Sidransky syndrome than in iPD. However, normal olfaction in non-parkinsonian GBA1 carriers suggests that GBA1 variants alone do not account for olfactory loss in PD. Hyposmia likely reflects broader PD pathology rather than a direct effect of the GBA1 mutation. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with systemic inflammation, immune dysregulation, and malnutrition, all of which may influence surgical outcomes. Subthalamic nucleus deep brain stimulation (STN DBS) is a widely used treatment for advanced PD, yet postoperative complications remain a concern. This study evaluates the predictive value of preoperative immunonutritional markers—including the Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) score, Aggregate Index of Systemic Inflammation (AISI), Lymphocyte-to-Monocyte Ratio (LMR), and systemic inflammatory response syndrome (SIRS)—for the risk of extracranial complications following STN DBS. Methods: A retrospective cohort study was conducted on 138 PD patients who underwent STN DBS. Clinical and laboratory data were analyzed to assess the association between preoperative immunonutritional markers and postoperative complications, including infections, wound healing disturbances, and surgical revisions. Logistic regression and receiver operating characteristic (ROC) analysis were performed to evaluate the predictive power of these markers. Results: SIRS emerged as the strongest predictor of complications (aOR = 6.99, 95% CI = 1.844–26.509), emphasizing the critical role of systemic inflammation in surgical outcomes. HALP, AISI, and LMR also demonstrated significant predictive potential, with HALP (AUC = 0.69) and LMR (AUC = 0.73) being the most robust predictors of complications. While albumin alone was not a significant predictor, it correlated with inflammatory markers and comorbidities, underscoring its role in broader risk assessments. Conclusions: This study underscores the value of preoperative immunonutritional markers in predicting complications following STN DBS in PD patients. Incorporating these markers into clinical risk stratification may enhance preoperative planning and personalized postoperative care, ultimately improving surgical outcomes. These findings, while promising, warrant validation through prospective, multicenter studies to refine predictive models and enhance patient outcomes. Full article

Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD) pathogenesis, contributing to increased oxidative stress and impaired endo-lysosomal-proteasome system efficiency underlying neuronal injury. Genetic studies have identified 19 monogenic mutations—accounting for ~10% of PD cases—that affect mitochondrial function and are associated with early- or late-onset PD. Early-onset forms typically involve genes encoding proteins essential for mitochondrial quality control, including mitophagy and structural maintenance, while late-onset mutations impair mitochondrial dynamics, bioenergetics, and trafficking. Atypical juvenile genetic syndromes also exhibit mitochondrial abnormalities. In idiopathic PD, environmental neurotoxins such as pesticides and MPTP act as mitochondrial inhibitors, disrupting complex I activity and increasing reactive oxygen species. These converging pathways underscore mitochondria as a central node in PD pathology. This review explores the overlapping and distinct mitochondrial mechanisms in genetic and non-genetic PD, emphasizing their role in neuronal vulnerability. Targeting mitochondrial dysfunction finally offers a promising therapeutic avenue to slow or modify disease progression by intervening at a key point of neurodegenerative convergence. Full article

Susceptibility-weighted imaging (SWI) is a magnetic resonance imaging (MRI) sequence sensitive to substances that alter the local magnetic field, such as calcium and iron, allowing phase information to distinguish between them. SWI is a 3D gradient–echo sequence with high spatial resolution that leverages both phase and magnitude effects. The interaction of paramagnetic (such as hemosiderin and deoxyhemoglobin), diamagnetic (including calcifications and minerals), and ferromagnetic substances with the local magnetic field distorts it, leading to signal changes. Neurodegenerative diseases are typically characterized by the progressive loss of neurons and their supporting cells within the neurovascular unit. This cellular decline is associated with a corresponding deterioration of both cognitive and motor abilities. Many neurodegenerative disorders are associated with increased iron accumulation or microhemorrhages in various brain regions, making SWI a valuable diagnostic tool in clinical practice. Suggestive SWI findings are known in Parkinson’s disease, Lewy body dementia, atypical parkinsonian syndromes, multiple sclerosis, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, hereditary ataxias, Huntington’s disease, neurodegeneration with brain iron accumulation, and chronic traumatic encephalopathy. This review will assist radiologists in understanding the technical framework of SWI sequences for a correct interpretation of currently established MRI findings and for its potential future clinical applications. Full article

Focused ultrasound (FUS) is an emerging noninvasive technology with significant therapeutic potential across various clinical domains. FUS enables precise targeting of tissues using mechanisms like thermoablation, mechanical disruption, and neuromodulation, minimizing damage to surrounding areas. In movement disorders such as essential tremor and Parkinson’s disease, MR-guided FUS thalamotomy has demonstrated substantial tremor reduction and improved quality of life. Psychiatric applications include anterior capsulotomy for treatment-resistant obsessive-compulsive disorder and major depressive disorder, with promising symptom relief and minimal cognitive side effects. FUS also facilitates blood-brain barrier opening for drug delivery in neurological conditions like Alzheimer’s disease. Musculoskeletal applications highlight its efficacy in managing chronic pain from knee osteoarthritis and lumbar facet joint syndrome through precise thermal ablation. Additionally, FUS has shown potential in neuropathic pain management and peripheral nerve stimulation, offering innovative approaches for amputees and cancer survivors. Cognitive and neuromodulatory research underscores its ability to enhance motor function and interhemispheric cortical balance, benefiting stroke and traumatic brain injury rehabilitation. Despite these conditions frequently leading to various kinds of disabilities, no direct exploration of the possible FUS application in rehabilitation is yet available in the literature. All this considered, this review aims to discuss how FUS could be applied in rehabilitation, exploring the current status of knowledge and highlighting future directions. Full article