Search Results (350)

Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders. Full article

Background/Objectives: Neurodegenerative proteinopathies, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB), are increasingly prevalent worldwide mainly due to population aging. These conditions are marked by complex etiologies, overlapping pathologies, and progressive clinical decline, with significant consequences for patients, caregivers, and healthcare systems. This review aims to synthesize evidence on the healthcare complexities of major neurodegenerative proteinopathies to highlight current knowledge gaps, and to inform future care models, policies, and research directions. Methods: We conducted a comprehensive literature search in PubMed/MEDLINE using combinations of MeSH terms and keywords related to neurodegenerative diseases, proteinopathies, diagnosis, sex, management, treatment, caregiver burden, and healthcare delivery. Studies were included if they addressed the clinical, pathophysiological, economic, or care-related complexities of aging-related neurodegenerative proteinopathies. Results: Key themes identified include the following: (1) multifactorial and unclear etiologies with frequent co-pathologies; (2) long prodromal phases with emerging biomarkers; (3) lack of effective disease-modifying therapies; (4) progressive nature requiring ongoing and individualized care; (5) high caregiver burden; (6) escalating healthcare and societal costs; and (7) the critical role of multidisciplinary and multi-domain care models involving specialists, primary care, and allied health professionals. Conclusions: The complexity and cost of neurodegenerative proteinopathies highlight the urgent need for prevention-focused strategies, innovative care models, early interventions, and integrated policies that support patients and caregivers. Prevention through the early identification of risk factors and prodromal signs is critical. Investing in research to develop effective disease-modifying therapies and improve early detection will be essential to reducing the long-term burden of these disorders. Full article

Alzheimer’s disease (AD) is one of the most common chronic neurodegenerative disorders worldwide. It is characterized by progressive memory loss and cognitive decline, leading to dementia. The pathogenesis of the disease is primarily attributed to two pathological protein structures: amyloid-beta (Aβ) plaques and tau protein neurofibrils. The current treatment strategies for AD are mainly symptomatic, highlighting the urgent need for the development of new, more effective therapies for the disease. The purpose of this paper is to provide a comprehensive and scientific review of the latest research regarding novel therapeutic options in the treatment of AD. In recent years, research has focused on more advanced and diversified strategies, including immunotherapy, gene therapy, tyrosine kinase inhibitors, therapies targeting mitochondrial function, and neurogenesis-related process modulation. One of the most promising treatment strategies for AD is immunotherapy. Intensive research is currently underway on both passive immunization, which involves the administration of monoclonal antibodies, and active immunization through vaccinations that stimulate the body to produce specific antibodies. Further research into novel therapeutic directions is essential, particularly concerning the role of the immune system in the pathogenesis of AD. Immunization appears to be a highly promising approach to developing effective methods for preventing AD or delaying the progression of this disease. 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

Satureja montana (SM) is acknowledged as a highly pharmacologically important species within the vast Lamiaceae family, indigenous to the Balkan area. Traditionally, this plant has been employed as a culinary spice, especially in Bulgarian gastronomy. Additionally, it is widely recognized that mental health is affected by the nature and quality of dietary consumption. Results: Ethnopharmacological research underscores the potential of SM in influencing various chronic ailments, including depression and anxiety. This plant is distinguished by a rich variety of secondary metabolites that display a broad spectrum of biological activities, such as antioxidant, antidiabetic, anti-inflammatory, analgesic, antibacterial, antiviral, and antifungal effects. Particularly, two of its active phenolic compounds, rosmarinic acid and carvacrol, reveal notable anxiolytic and antidepressive properties. This review aims to explore the capacity of SM to improve mental health through its plentiful phenolic components. Recent studies indicate their efficacy in addressing Alzheimer’s-type dementia. A notable correlation exists among depression, anxiety, and cognitive decline, which includes dementia. Considering that Alzheimer’s disease (AD) is a multifaceted condition, it requires multi-targeted therapeutic strategies for both prevention and management. Conclusions: Satureja montana is recognized as potential candidate for both the prevention and management of various mental health disorders, including dementia. Full article

Background: Severe psychiatric disorders are frequently associated with disruptions in health-related behaviors, including diet and lifestyle. This cross-sectional study aimed to assess and compare selected dietary and lifestyle behaviors among long-term psychiatric inpatients diagnosed with unspecified dementia (F03) or organic delusional disorder (F06.2) and a control group of mentally healthy individuals. Methods: A 50-item validated questionnaire was administered to 28 hospitalized patients and 10 control participants. Analyses included nutritional habits, physical activity, stimulant use, and hydration, using non-parametric tests and effect size indicators (Cramér’s V). Results: Significant differences were observed in meal regularity, frequency of meals, types of beverages consumed, and physical activity. Strong associations were found for meal types (V = 0.590) and stress-induced eating (V = 0.525). Conclusions: The observed behavioral differences may reflect disease-related effects, demographic variation, or a combination of both. Despite these limitations, the findings suggest key areas for further investigation and support the need for targeted dietary and lifestyle interventions in psychiatric settings. Full article

Alzheimer’s disease (AD), the leading cause of dementia, remains poorly understood despite decades of intensive research, which continues to hinder the development of effective treatments. As a complex multifactorial disorder, AD lacks a cure to halt the progressive neurodegeneration, and the precise mechanisms underlying its onset and progression remain elusive, limiting therapeutic options. Due to the challenges of studying neuronal cells in vivo, technologies such as clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) and human-induced pluripotent stem cells (hiPSCs) are key for identifying therapeutic targets, although they face technical and ethical hurdles in their early stages. CRISPR/Cas9 and hiPSCs are promising for disease modeling and therapy, but off-target effects and the complexity of gene editing in the brain limit their use. CRISPR technology enables specific genetic modifications in key AD-related genes, such as APP, PSEN1, PSEN2, and APOE, providing valuable insights into disease mechanisms. iPSC-derived neurons, astrocytes, microglia, and 3D organoids can recapitulate key aspects of human AD pathology, but they do not fully replicate the complexity of the human brain, limiting clinical applicability. These technologies advance studies of amyloid processing, tau aggregation, neuroinflammation, and oxidative stress, yet translating them into clinical therapies remains challenging. Despite the promise of CRISPR/Cas9 and iPSCs for precision medicine, gaps in knowledge about their long-term safety and efficacy must be addressed before clinical implementation. Full article

Background/Objectives: Gamma oscillations (30–100 Hz), which are essential for memory, attention, and cortical synchronization, remain underexplored in Alzheimer’s disease (AD) research. While resting-state EEG studies have predominantly examined lower frequency bands (delta to beta), gamma activity may more accurately reflect early synaptic dysfunction and other mechanisms relevant to AD pathophysiology. AD is a common age-related neurodegenerative disorder frequently associated with altered resting-state EEG (rEEG) patterns. This study analyzed gamma power spectral density (PSD) during eyes-open (EOR) and eyes-closed (ECR) resting-state EEG in AD patients compared to cognitively normal (CN) individuals. Methods: rEEG data from 534 participants (269 CN, 265 AD) aged 40–90 were analyzed. Quantitative EEG (qEEG) analysis focused on the gamma band (30–100 Hz) using PSD estimation with the Welch method, coherence matrices, and coherence-based functional connectivity. Data preprocessing and analysis were performed using EEGLAB and Brainstorm in MATLAB R2024b. Group comparisons were conducted using ANOVA for unadjusted models and linear regression with age adjustment using log₁₀-transformed PSD values in Python (version 3.13.2, 2025). Results: AD patients exhibited significantly elevated gamma PSD in frontal and temporal regions during EOR and ECR states compared to CN. During ECR, gamma PSD was markedly higher in the AD group (Mean = 0.0860 ± 0.0590) than CN (Mean = 0.0042 ± 0.0010), with a large effect size (Cohen’s d = 1.960, p < 0.001). Conversely, after adjusting for age, the group difference was no longer statistically significant (β = −0.0047, SE = 0.0054, p = 0.391), while age remained a significant predictor of gamma power (β = −0.0008, p = 0.019). Pairwise coherence matrix and coherence-based functional connectivity were increased in AD during ECR but decreased in EOR relative to CN. Conclusions: Gamma oscillatory activity in the 30–100 Hz range differed significantly between AD and CN individuals during resting-state EEG, particularly under ECR conditions. However, age-adjusted analyses revealed that these differences are not AD-specific, suggesting that gamma band changes may reflect aging-related processes more than disease effects. These findings contribute to the evolving understanding of gamma dynamics in dementia and support further investigation of gamma PSD as a potential, age-sensitive biomarker. Full article

Background/Objectives: We previously demonstrated that nilotinib can sufficiently enter the brain to pharmacologically inhibit discoidin domain receptors (DDR)-1 in patients with Parkinson’s and Alzheimer’s disease. We primarily hypothesized that nilotinib is safe, and may alter disease-related biomarkers to improve, motor, cognitive and/or behavioral features in dementia with Lewy bodies (DLB). Methods: Forty-three participants were randomized 1:1 into nilotinib, 200 mg, or matching placebo in a single-center, phase 2, randomized, double-blind study. Study drug was taken orally once daily for 6 months followed by one-month wash-out. Results: Of 43 individuals enrolled, 14 were women (33%); age (mean ± SD) was 73 ± 8.5 years. Nilotinib was safe and well-tolerated, and more adverse events were noted in the placebo (74) vs. nilotinib (37) groups (p = 0.054). The number of falls were reduced in the nilotinib (six) compared to placebo (21) group (p = 0.006). Cerebrospinal fluid homovanillic acid, a biomarker of dopamine levels, was increased (p = 0.004), while the ratio of pTau181/Aβ42 was reduced (p = 0.034). The Alzheimer’s Disease Assessment Scale—cognition 14 improved by 2.8 pts (p = 0.037), and no differences were observed in Movement Disorders Society–Unified Parkinson’s Disease Rating Scale parts II and III. However, part I (cognition) improved (p = 0.044) in nilotinib compared to placebo. Conclusions: Nilotinib demonstrates favorable safety, biomarkers, and efficacy outcomes in patients with DLB supporting further trials in DLB or advanced Parkinson’s disease with dementia. Full article

Background/Objectives: Old age and cognitive impairment/dementia are risk factors for falling and fall-related injuries. We have, in a previous study in persons with cognitive impairment, shown that falls were associated with frailty, reduced physical fitness, and cognitive reduction. Falls were independent of the disorders causing the impaired functions. Because most falls are innocent, knowledge of predictors of fall-related injuries seems more clinically relevant than the predictors of falls. Predictors of falls and fall-related injuries are not necessarily identical. The aim of this follow-up study to our previous one in the same population was to explore predictors of fall-related injuries in fallers and compare these predictors with those of falls. Methods: This study and our previous study used data from the “The Norwegian Registry of Persons Assessed for Cognitive Symptoms” (NorCog), a Norwegian research and quality registry with a biobank. The registry included consecutive home-dwelling persons referred to Norwegian specialist healthcare units for assessment of cognitive decline. This study included 3774 persons from our previous study who experienced falls last year and compared persons with and without a fall-related injury. A fall-related injury was defined as admittance to a hospital for the injury. Results: The annual incidence of fall-related injuries in the fallers was 884/3774 (23.4%). Female sex, older age, lower BMI, in need of public health service and walking assistance, and low Hb and Ca were independent predictors of fall-related injuries, indicating reduced physical fitness and state of health and a high burden of comorbidity. Injuries were not associated with the degree of cognitive impairment or the dementia diagnosis. Conclusions: In home-dwelling persons with impaired cognitive functions and falls, fall-related injuries were associated with reduced physical fitness and state of health. In contrast to predictors of falls, neither the degree of cognitive impairment nor the dementia diagnosis was associated with fall-related injuries. The difference is comprehensible. Persons with cognitive impairment or dementia might have reduced power of judgment and be inattentive, unconcerned and careless, which increases the fall incidence but not the risk of injury once falling. Prevention of fall-related injuries should focus on relieving comorbidities, improving physical fitness and general health rather than on cognitive improvement. Full article

Introduction: Hypoglossal nerve stimulation (HNS) “Inspire_© therapy” has garnered popularity among obstructive sleep apnea (OSA) patients seeking an alternative to continuous positive airway pressure (CPAP) therapy. The growth in HNS has been particularly high in older adults living with OSA. Consistent and proper use of HNS in the geriatric population faces unique age-associated barriers: a high rate of multiple chronic conditions (MCC) and polypharmacy (being on five or more drugs). Early recognition and patient-centered management of these barriers will allow older patients to obtain maximum benefits from HNS. HNS has distinct advantages in the geriatric population because it overcomes many concerns related to CPAP therapy adherence, such as mechanical limitations due to manual dexterity, maxillofacial anatomy, dental issues such as usage of dentures, allergy/otolaryngology-related disorders, and pre-existing post-traumatic stress disorder-related claustrophobia. This paper describes how we worked with older patients with OSA and their care partners to overcome these barriers so patients can continue to derive cardiovascular, neurologic, and quality of life benefits resulting from optimal OSA management. These benefits are especially important in the older population because of higher rates of comorbidities (dementia, coronary artery disease, and atrial fibrillation) exacerbated by sub-optimally treated OSA. In this article, we describe our clinical experience with elderly patients on Inspire_© therapy, with a focus on the everyday difficulties faced by these patients and the measures implemented to address and mitigate these barriers. Methods: A retrospective chart review was conducted to identify patients aged 65 and above who underwent hypoglossal nerve stimulator insertion. Experiences of older patients during and after the insertion procedure were documented and compared to a younger population of patients on HNS therapy. We specifically collected information on difficulties encountered during activation or follow-up visits and compared them between the different age groups. Using this information, we identified areas to improve treatment adherence from the patients’ perspectives. Results: We identified 43 geriatric (65 to 86 years old) patients who received the Inspire implant at a tertiary academic medical center and compared them to a younger population of 23 patients. Most common challenges noted—with a potential to impact adherence—included orofacial and lingual neuropraxia (ischemic or demyelination-induced neuropathy) at activation, cognitive dysfunction (memory problems), preexisting anxiety, and insomnia. Other difficulties that are less commonly reported but equally important to consistent and proper use of HNS included headaches, concerns of device malfunction, change in comfort levels after cardiac procedures, and general intolerance of the device. The older patient population had a statistically significant higher incidence of cognitive difficulties (30.2% vs. 4.4%) and a smaller social support system (62.8% vs. 91.3%) affecting device usage compared to the younger population. There were no statistically significant differences in the rates of other more commonly reported adverse effects such as headaches, dry mouth, and anxiety between the two age groups. Conclusion: Despite several challenges faced by geriatric patients, Inspire_© hypoglossal nerve stimulation remains a viable, alternative treatment option for OSA with improved tolerance and adherence compared to CPAP. After identifying less commonly reported barriers such as cognitive decline, sensory deficits, and decreased social support systems, minor adjustments and appropriate education on use allows older patients to correctly use and benefit from Inspire_© device therapy, with subsequent improvement in sleep and overall quality of life. Full article

Vascular dysfunction frequently coexists with neurodegenerative disorders such as dementia and Alzheimer’s disease (AD) in older individuals; however, the cause-and-effect relationship remains unclear. While AD is primarily characterized by neural tissue degeneration, emerging evidence suggests that aging-induced vascular dysfunction contributes to both the onset and progression of cognitive impairment and dementia by decreasing cerebral blood flow (CBF) and disrupting the blood–brain barrier (BBB). This challenges the traditional notion and underscores vascular dysfunction as an early pathogenic stimulus; thus, targeting vascular pathologies could be a promising strategy to slow dementia progression and potentially prevent AD. Conversely, aging-related neurodegeneration exacerbates vascular dysfunction, accelerating dementia pathology through oxidative stress and inflammation as well as deposition of neurotoxic substances such as beta-amyloid (Aβ) and tau in vascular walls. This bidirectional interaction creates a vicious cycle that worsens cognitive decline, underscoring the complexity of these diseases. This review aims to highlight recent advances in research on the mechanisms of aging-related vascular dysfunction in neurodegenerative diseases, focusing on vascular contributions to cognitive impairment and dementia (VCID) and AD. Additionally, we will explore the reciprocal effects and intricate relationship between vascular dysfunction and neurodegenerative pathologies, enhancing our understanding of relative disease pathogenesis and guiding the development of innovative prevention and treatment strategies. Full article

This review synthesizes the emerging understanding of the roles of glial cells and non-coding RNAs (ncRNAs) in the pathogenesis and progression of Alzheimer’s disease and related dementias (ADRDs). ADRDs encompass a spectrum of neurodegenerative disorders characterized by cognitive decline, memory impairment, and functional deterioration. The interplay between the most common types of glial cells—astrocytes, microglia, and oligodendrocytes—and ncRNAs is emerging as a critical factor in the development of ADRDs. Glial cells are essential for maintaining homeostasis within the central nervous system (CNS); however, their dysregulation can lead to neuroinflammation and neuronal dysfunction, exacerbating neurodegeneration. Reactive astrocytes and activated microglia can create neurotoxic environments that further impair neuronal health. Concurrently, ncRNAs, particularly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have emerged as significant regulators of glial gene expression, influencing inflammatory responses and glial cell function. Understanding the complex interactions between glial cells and ncRNAs is crucial for developing targeted therapeutic strategies. By elucidating the mechanisms underlying their interactions, this review aims to highlight the critical importance of glial cells and ncRNAs in the context of neurodegenerative diseases, paving the way for innovative approaches to prevent and treat ADRDs. Ultimately, enhancing our understanding of these processes may lead to novel therapies and improved outcomes for individuals affected by these debilitating conditions. Full article

Variants in the GBA1 gene, encoding the lysosomal enzyme glucosylceramidase beta 1 (GCase), are linked to Parkinson’s disease (PD) and Gaucher disease (GD). Heterozygous variants increase PD risk, while homozygous variants lead to GD, a lysosomal storage disorder. Some GBA1 variants impair GCase maturation in the endoplasmic reticulum, blocking lysosomal transport and causing glucosylceramide accumulation, which disrupts lysosomal function. This study explores therapeutic strategies to address these dysfunctions. Using Site-directed Enzyme Enhancement Therapy (SEE-Tx^®), two structurally targeted allosteric regulators (STARs), GT-02287 and GT-02329, were developed and tested in GD patient-derived fibroblasts with relevant GCase variants. Treatment with GT-02287 and GT-02329 improved the folding of mutant GCase, protected the GCase_Leu444Pro variant from degradation, and facilitated the delivery of active GCase to lysosomes. This enhanced lysosomal function and reduced cellular stress. These findings validate the STARs’ mechanism of action and highlight their therapeutic potential for GCase-related disorders, including GD, PD, and Dementia with Lewy Bodies. Full article

Hemerocallis citrina is an herbaceous perennial plant used in Asian cuisine and Traditional Chinese Medicine. Here, we tested the therapeutic potential of extracts (HCE30%, HCE50%, and HCN) in vivo, using models of two human genetic neurodegenerative diseases—Machado–Joseph Disease/Spinocerebellar Ataxia type 3 (MJD/SCA3) and Frontotemporal Dementia with Parkinsonism associated to chromosome 17 (FTDP-17). Chronic treatment with HCE30% extract ameliorated the motor deficits typically observed in these models. Interestingly, we found that the effect on the motor phenotype of the MJD/SCA3 model was dependent on serotonergic signaling and on the action of the HLH-30/TFEB transcription factor, known to regulate the cellular response to amino acid starvation, the autophagy and mitophagy pathways, lysosome localization and biogenesis, exocytosis, and mitochondrial biogenesis. Altogether, our findings reinforce the idea that phytochemicals act through the modulation of serotonergic neurotransmission and introduce a novel layer to the HLH-30/TFEB regulatory network. Thus, it also strengthens the use of these pathways as therapeutic targets for protein-related neurodegenerative disorders and confirms the utility of medicinal plants as a source of innovation in the quest for new therapeutic agents. Full article