Search Results (1,346)

Dementia, including Alzheimer’s disease (AD), represents one of the most pressing public health challenges of the 21st century, affecting more than 55 million individuals worldwide, with projections reaching 139 million by 2050. Current pharmacological treatments offer limited efficacy and significant side effects, driving intense interest in plant-derived natural products as both preventive and therapeutic agents. This review synthesizes preclinical and clinical evidence for key phytochemical classes, including polyphenols, phenolic acids, flavonoids, terpenoids, and alkaloids, in the context of dementia and age-related cognitive decline. Molecular mechanisms are examined in detail, including effects on antioxidant defense and redox homeostasis, suppression of neuroinflammation, and enhancement of synaptic plasticity and neurotransmission. Despite promising preclinical and epidemiological evidence, most clinical trials remain limited in scale and duration and provide mixed results on the efficacy of using phytochemicals for cognitive health. Among the compounds with the most consistent clinical support are the ginkgo diterpene extract EGb 761, saffron carotenoids, curcumin, and rosmarinic acid. A dedicated section addresses the emerging evidence for aromatherapy as a non-pharmacological intervention for behavioral and cognitive symptoms of dementia. Future directions include strategies to improve bioavailability of phytochemicals, the utilization of aromatherapy together with oral supplements, and the need for larger randomized controlled trials using well-characterized and reproducibly manufactured formulations and purified active compounds. Priority areas for future investigation include resolving pharmacokinetic barriers to central nervous system (CNS) delivery, standardizing herbal product composition, and conducting adequately designed clinical trials in well-defined patient populations. Full article

Background/Objectives: Post-stroke dysphagia (PSD) is a common complication following cerebrovascular events, and many affected patients also present with pre-existing dementia or post-stroke cognitive impairment (PSCI). PSD primarily affects the oropharyngeal phase of swallowing, whereas cognitive impairment often compromises the oral phase. This overlap complicates diagnosis and highlights the importance of accurate assessment to guide appropriate treatment strategies. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising therapeutic intervention for both cognitive impairment and dysphagia. Methods: In this study, we report a case of a patient with pre-existing dementia who experienced an ischemic stroke, resulting in PSD and PSCI. Videofluoroscopic swallowing study (VFSS) revealed oral-phase-predominant dysphagia. rTMS targeting the dorsolateral prefrontal cortex (DLPFC) was administered with the aim of enhancing cognitive function. Results: Following two cycles of rTMS in combination with ongoing swallowing therapy, the patient demonstrated notable improvement in both cognitive and swallowing function. Conclusions: Although limited by a single-case design and the possibility of spontaneous recovery, this case demonstrates that rTMS targeting the DLPFC combined with swallowing therapy may be a potential intervention for managing concurrent post-stroke dysphagia and cognitive impairment. Full article

Background: Chronic obstructive pulmonary disease (COPD) is commonly managed alongside multimorbidity, polypharmacy, recurrent treatment escalation, and older age, all of which increase vulnerability to drug–drug interactions (DDIs). We aimed to synthesize the main DDI domains relevant to COPD pharmacotherapy and to distinguish harmful DDIs from beneficial combination therapy and formal compatibility findings. Methods: We performed a narrative review using structured literature searches and citation tracking to evaluate COPD-related studies. We prioritized direct COPD-specific DDI evidence, while also including mechanistic, class-specific, and contextual studies when direct evidence was lacking. Retained evidence included observational cohorts, prescribing studies, pharmacokinetic trials, case reports, and systematic reviews. Results: The reviewed literature indicates that DDI vulnerability in COPD is driven less by isolated drug pairs than by overall regimen complexity, multimorbidity, aging, fragmented prescribing, and high-intensity treatment periods such as exacerbations, hospitalization, and discharge. Key DDI domains included cardiopulmonary co-treatment, QT-related vulnerability, and potential or clinically relevant interactions amplified during exacerbations. Inhaled therapies are not universally interaction-free, particularly with strong metabolic inhibitors. Psychotropics, frailty, dementia, and palliative care further increase clinical complexity. However, beneficial bronchodilator combinations and formal compatibility studies demonstrate that not all multidrug COPD regimens are harmful. Conclusions: In COPD, DDI assessment should focus on the full treatment regimen and not be limited to a set of iconic drug pairs. Clinicians must focus on exacerbation-related prescribing, QT-active drugs, theophylline exposure, psychotropic co-medication, and vulnerable subgroups such as older, frail, and palliative patients. Pharmacist-supported drug review, drug reconciliation, and selective deprescribing are key strategies for reducing clinically relevant DDI burden in COPD. Full article

Behavioral and psychological symptoms of dementia (BPSD) affect the majority of patients with Alzheimer’s disease (AD), substantially increasing caregiver burden and the likelihood of institutionalization. The clinical management of BPSD remains challenging because of its poorly understood pathogenesis, the limited efficacy of conventional interventions, and significant safety concerns associated with current treatments. These limitations underscore the urgent need to identify novel therapeutic targets and develop glia-centered treatment strategies. As essential components of the central nervous system, glial cells maintain neural homeostasis, regulate neurotransmission, and mediate neuroinflammatory responses. Increasing evidence suggests that glial dysfunction contributes to the development of BPSD, thereby linking AD neuropathology and neuropsychiatric symptoms. Aberrant microglial activation, astrocytic dysfunction, and oligodendrocyte injury collectively compromise neural circuit integrity, disrupt neurotransmitter balance, and impair neuron–glia communication, ultimately promoting the progression of diverse BPSDs. Given the critical role of glial cells in regulating neurotransmitter systems, the dysregulation of which is closely associated with BPSD, this review summarizes the involvement of glial cells in BPSD, elucidates the underlying molecular mechanisms, and discusses recent advances in glia-based therapeutic strategies, thereby providing insights into the pathogenesis of BPSD in AD. Full article

Background/Objectives: Alzheimer’s disease (AD) is the most common cause of dementia worldwide; however, there is incomplete understanding of AD pathogenesis, and there are few disease-modifying treatments for AD. Research has begun to demonstrate that necroptosis, which is a regulated type of cell death mediated by receptor-interacting protein kinase 1 (RIPK1), plays a significant role in neurodegeneration and neuropathology associated with AD. The purpose of this review is to summarize current research regarding the role of RIPK1 in AD and possible therapeutic uses of RIPK1 inhibitors. Methods: This study is a narrative review of the literature summarizing experimental and clinical studies on RIPK1 signaling, necroptosis, neuroinflammation, and blood–brain barrier (BBB) dysfunction in AD. Results: The cumulative evidence demonstrates that RIPK1 activation associates with common AD pathways and particularly increases the severity of amyloid-β (Aβ) and tau pathology; promotes microglial activation; decreases the integrity of the BBB; and increases neuroinflammatory signaling in AD. Preclinical studies have shown that inhibiting RIPK1 genetically or pharmacologically in preclinical models decreased the extent of neurodegeneration and the rate of cognitive decline. Conclusions: RIPK1 is a key molecular link between necroptosis and neuroinflammation in AD. While the preclinical data are encouraging, further clinical research will be necessary to investigate RIPK1 changes in the brain, which may help better understand AD and establish the safety and effectiveness of potential therapeutic RIPK1 inhibitors in AD. Full article

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play essential roles in the brain, influencing neuronal and dendritic growth, as well as neurotransmission. These effects persist throughout life. Numerous studies in animals and humans have demonstrated the beneficial effects of GH therapy on memory and cognitive function, as well as on the restoration of neuronal function following injury. All nerve cells, including neurons, glia, endothelial, epithelial, and perivascular cells, are affected by the actions of GH/IGF-1. IGF-1, in particular, has been associated with cognitive function. The GH-IGF-1 axis increases the proliferation of neuronal progenitor cells and the formation of new neurons, oligodendrocytes, and astrocytes. In this study, we searched databases such as PubMed, Google Scholar, and Embase for human clinical trials evaluating the effect of growth hormone (GH) therapy on dementia, Alzheimer’s disease (AD), post-traumatic brain injury (PTI), and stroke. The following search terms were used: “GH and dementia,” “GH and Alzheimer’s disease,” “GH and TBI,” and “GH and stroke.” Inclusion criteria were all randomized controlled trials and observational studies. Exclusion criteria included the lack of cognitive and memory assessments. We found 28 articles. Most studies show the beneficial effects of GH therapy on memory and recovery of brain function after traumatic injury and stroke; however, consistent data are still lacking. The limited number of clinical trials, the small number of patients, and the lack of data on plasma levels of sex hormones that clearly contribute to brain function are limiting factors. This is the case, for example, with androgens. Other critical factors are dosage and treatment duration. Prolonged administration and supraphysiological doses are more effective in inducing positive clinical changes. Growth hormone (GH) therapy is a very promising intervention for preventing and treating dementia and early-stage Alzheimer’s disease, and it contributes significantly to the recovery of brain function in patients after traumatic injury and stroke. Further studies with more robust methodologies are needed to confirm these results. Full article

Neuromuscular and neurodegenerative (NMND) disorders are diseases that cause progressive damage to the central nervous system leaving patients with symptoms that negatively affect everyday living with death almost inevitable. These include amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), and Parkinson’s disease (PD) with cases expected to increase in the future. Intranasally administered stem cell-derived exosomes/secretome have been seen as potential therapeutic options for these disorders in preclinical animal models. This study sought to observe the efficacy of mesenchymal stem cell-derived exosomes/secretome in patients with ALS, LBD, and PD. Based off these preclinical studies, we conducted a case-controlled series experiment with 86 patients with ALS, LBD, or PD, with the independent variable being the treatment and the dependent variable being the clinical response. These patients were recruited and given intranasal instillations of various MSC-derived exosome/secretome products. Subsequent treatments were given to patients who did not have a response to one product. Patients were followed up at one week, one, two, three, and six months post-treatment. Historical external controls were used for comparison to clinical outcomes. There were no serious adverse events in any patient. A total of 67 of 86 (77%) patients showed a positive clinical response to at least one product. Outcomes were strongly associated with greater treatment frequency for ALS and LBD. Intranasal administration of MSC-derived exosome/secretome products were safe, and most patients showed overall improvement with at least one product. Some patients also saw a substantial decrease in the rate of decline compared to historical controls. These results also give rise to the hypothesis: do MSC-derived exosomes/secretome treatments show efficacy in other NMND disorders? The primary limitation of this study is the 6-month follow-up. Full article

Neurodegenerative diseases are among the most consequential disorders of later life, not only because of their increasing prevalence, rising from approximately 1–2% at age 65 to over 30% by age 85, but also because they develop within the broader clinical context of ageing, multimorbidity, frailty, and polypharmacy. In older adults, these conditions rarely present as isolated and static diagnostic entities; rather, they unfold as dynamic clinical trajectories involving the progressive interaction of cognitive decline, behavioural-neuropsychiatric symptoms, and extrapyramidal-motor dysfunction. In this review, we propose a trajectory-based framework for the interpretation and management of major neurodegenerative disorders in later life, including Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease and Parkinson’s disease dementia, dementia with Lewy bodies, and vascular cognitive impairment. Building on a conceptual model organized around three major symptom spheres: cognitive, behavioural-neuropsychiatric, and extrapyramidal-motor, we argue that each disorder can be understood according to the relative predominance and temporal evolution of these domains. Alzheimer’s disease is typically cognition-led, frontotemporal dementia behaviour-led, and Parkinsonian syndromes motor-led, whereas dementia with Lewy bodies shows early multidomain convergence across all three spheres simultaneously. Vascular and mixed dementias follow more heterogeneous trajectories shaped by lesion burden, network disruption, and copathology. This framework has direct implications for diagnosis, prognostic stratification, and treatment selection, because interventions targeting one sphere may destabilize another and generate prescription cascades, delirium, or functional decline. We further discuss how biomarker-based diagnosis, disease-modifying therapies, non-pharmacological interventions, multidisciplinary care, deprescribing strategies, and palliative planning can be integrated within a trajectory-based approach. Interpreting neurodegeneration through clinical trajectories rather than diagnostic labels alone offers a more realistic and therapeutically useful model for precision geriatric neurology across the full course of disease. Full article

HIV-associated neurocognitive disorders (HAND) arise from HIV infection of the central nervous system, resulting in chronic neuroinflammation and progressive neuronal damage that impair cognitive, motor, and behavioral functions. Clinically, HAND encompasses a spectrum of neurological impairments ranging from asymptomatic neurocognitive impairment to severe HIV-associated dementia. Despite the widespread use of combination antiretroviral therapy (cART) and significant improvements in the life expectancy of people living with HIV, HAND remains prevalent and continues to pose a major clinical challenge. One of the primary limitations of cART is the limited penetration of many antiretroviral drugs across the blood–brain barrier (BBB), thereby allowing the persistence of viral reservoirs within the CNS and contributing to sustained neuroinflammation and neuronal damage. To address these challenges, novel nanotherapeutic strategies have been developed to enhance the delivery of antiretroviral agents to the brain. These approaches include targeted delivery systems and the co-delivery of therapeutics across the BBB through mechanisms such as receptor-mediated transcytosis and other transport pathways. In this review, we discuss the pathophysiological challenges associated with HAND and recent advances in nanotherapeutic approaches designed to improve treatment efficacy. We also discuss the current state of the art in vitro and in vivo models used to test the efficacy of these advanced therapeutics. Finally, we outline the remaining challenges and future prospects for the development of nanotherapeutics to improve the treatment of HAND. Full article

Psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), comprise a heterogenous group of severe mental illnesses (SMIs) characterized by disturbances in cognition, emotional regulation, or behavior. Cognitive impairment represents an accompanying feature of many SMIs, often interfering with or limiting essential daily life activities. SMIs arise from a complex interplay of genetic, epigenetic, developmental, and environmental factors that disrupt neural and cellular processes. SMIs often present with overlapping symptoms and sometimes co-occur, making misdiagnosis a common clinical challenge. To date, there is a lack of reliable and specific biological markers to aid in the differential diagnosis of cognitive impairment in SMIs and for distinguishing neurodegenerative dementias from SMIs with overlapping symptoms. In this context, blood-based biomarkers of the ATX(N) system associated with cognitive deficits in neurodegenerative diseases, such as neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), amyloid beta (Aβ), and tau proteins, may help to understand the biological basis of cognitive dysfunction in SMIs and support differential diagnosis. This narrative review summarizes the current evidence on the application of blood-based biomarkers of neurodegenerative dementias in SMIs and their association with the cognitive deficits observed in these conditions, as well as their relevance for differential diagnosis, disease monitoring, and the evaluation of treatment efficacy in psychiatric disorders. Full article

Introduction: Delirium in older adults is strongly associated with and can predate dementia. While GLP-1 receptor agonists (GLP-1 RAs) may provide neuroprotective benefits, their role in reducing dementia risk among older patients with type 2 diabetes mellitus (T2DM) and prior delirium is unclear. This study compares the effectiveness of GLP-1 RAs and metformin in preventing dementia among patients with a history of delirium using an extensive healthcare database. Methods: A retrospective cohort study was conducted from 2005 to 2025 using data from the TriNetX Global Federated Research Network. We identified adults aged 65 and older with T2DM and delirium, who received either GLP-1 RAs (exposure) or metformin (control). Propensity score matching (PSM) was performed. We determined dementia outcomes and all-cause mortality using Kaplan–Meier survival curves, Cox proportional hazards models, and estimated odds ratio (OR). Subgroup analyses were conducted by age, sex, race, body mass index (BMI), and dementia types. Results: In a study involving 23,980 patients treated with GLP-1RAs and 23,980 matched patients treated with metformin, the mean age was 74 years, with 53% being female. The use of GLP-1RAs therapy was associated with a significantly lower risk of dementia compared to metformin among adults aged 65 years and older with T2DM with delirium with the adjusted hazard ratio (AHR) for dementia was 0.778 [95% confidence interval (CI): 0.736–0.822 p < 0.0001], and OR was 0.617 (95% CI: 0.582–0.655 p < 0.0001). The reduction in dementia risk varied by age, race, BMI, and dementia type. We observed a time-dependent decrease in mortality risk with GLP-1 RA users. Conclusions: In older adults with T2DM and delirium, GLP-1 RA therapy was associated with a reduced risk of dementia compared with metformin. Variations in subgroups suggest individualized treatment. Prospective randomized controlled trials are needed to confirm these findings and clarify differential effects across various subgroups. Full article

Frontotemporal dementia (FTD) is a heterogeneous disorder for which disease-modifying treatments are lacking. Non-invasive brain stimulation (NIBS) has emerged as a potential therapeutic approach to modulate dysfunctional neural networks and support residual plasticity. This systematic review aims to provide an updated overview of current NIBS applications across the main clinical syndromes associated with FTD, namely behavioral variant FTD (bvFTD), semantic variant of primary progressive aphasia (svPPA), and nonfluent variant of PPA (nfvPPA). According to PRISMA guidelines, twenty-seven studies investigating NIBS interventions in major FTD phenotypes met the inclusion criteria, predominantly employing transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS). tDCS, particularly when combined with language therapy, consistently improved several language abilities in PPA, with some evidence of maintenance over time. Benefits were most consistently reported in nfvPPA, whereas effects in svPPA were more limited and domain-specific. rTMS studies showed short-term improvements in language and executive functions, especially following stimulation of left frontal regions. In bvFTD, findings were heterogeneous, with social–cognitive outcomes appearing more sensitive to stimulation, whereas global cognitive measures showed more variable effects. NIBS, particularly tDCS combined with behavioral interventions, shows symptomatic potential in selected FTD phenotypes, but methodological heterogeneity and small samples warrant larger, well-controlled trials. Full article

Background and Objectives: Vascular dementia (VaD) and mixed dementia (MD) represent prevalent causes of cognitive decline in the elderly, as they share similar pathological pathways and clinical features. Distinguishing between these two conditions remains a challenge, due to their frequent clinical and neuroimaging overlap. Nevertheless, it is important from a prognostic perspective. Materials and Methods: The study comprised 114 participants, including patients with VaD (n = 33), MD (n = 26), Alzheimer’s disease (AD; n = 26), and 29 cognitively healthy controls (C). We evaluated routinely used cerebrospinal fluid (CSF) biomarkers (total tau, p-tau181, Aβ_1–42) and their ratios to assess inter-group differences, diagnostic accuracy, and correlations with cognitive score. Results: Patients with MD demonstrated significantly higher levels of t-tau and p-tau181, and lower levels of Aβ_1–42, compared to VaD (p < 0.004 for all analyses). With the exception of p-tau181/t-tau, all calculated ratios enabled differentiation between these groups. ROC analysis confirmed the high diagnostic accuracy of CSF Aβ_1–42 and t-tau (AUC 0.82 and 0.79 respectively) for detecting AD pathology in dementia patients. Furthermore, the t-tau/Aβ_1–42, p-tau181/Aβ_1–42 ratios were the most effective in differentiating AD-related from vascular pathologies (AUC 0.78 and 0.80 respectively), and in differentiating MD from VaD (AUC 0.79 and 0.77 respectively). A significant correlation was observed between CSF biomarkers (especially tau markers) and cognitive impairment severity. Conclusions: CSF biomarkers effectively differentiate mixed from vascular dementia by identifying underlying AD pathology independent of the clinical phenotype. This supports the use of CSF biomarkers in clinical practice to reveal the neurodegenerative component in patients with cerebrovascular disease, which is of fundamental importance for emerging disease-modifying treatment strategies in mixed neuropathologies. Full article

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by progressive dementia, constituting one of the leading causes of global mortality. Although the current treatments help attenuate the symptoms associated with AD, they are unable to stop the long-term progression of the disease, and consequently, no cure exists. One of the main reasons for the lack of cure and, therefore, one of the biggest challenges in its treatment, is the blood–brain barrier (BBB). This protective barrier limits the entry of foreign substances, including drugs, into the central nervous system. Different types of engineered nanoparticles (NPs) have been demonstrated to be able to penetrate this barrier and serve as efficient drug delivery systems (DDS) into the brain, making them a promising solution for future therapeutic development. Therefore, the purpose of this paper is to provide valuable insights into challenges faced by DDS in treating AD, highlight the nanotechnology-based approach, and discuss the advances in strategies being employed to enhance the crossing of NPs through the BBB. Furthermore, some up-to-date NP systems are presented, along with the latest therapeutic agents targeting AD, and finally, it underscores innovative approaches under investigation. Ultimately, the barriers hindering the clinical translation of NP-based strategies into human patients are discussed. Full article

Background and clinical significance: Autoimmune encephalitis (AE) is an inflammatory brain disorder that manifests through a diverse, unspecific range of neuropsychiatric symptoms. When AE occurs alongside a primary neurodegenerative disorder, the shared symptoms can create a mixed clinical profile, making diagnosis more difficult and potentially postponing effective management and treatment. Case presentation: We describe the case of a 58-year-old female with a one-year history of progressive behavioral and personality changes who presented a subacute confusional state, psychomotor retardation alternating with psychomotor agitation, apathy, visual hallucinations, and motor symptoms. Examination revealed Parkinsonian symptoms and frontal lobe signs. Neuroimaging showed frontotemporal atrophy, while cerebrospinal fluid analysis excluded infection but demonstrated elevated phosphorylated tau, supporting an underlying neurodegenerative process. An electroencephalogram revealed asymmetric temporal slowing without overt epileptiform activity. An initial diagnosis of behavioral variant frontotemporal dementia (bvFTD) was established. Due to rapid clinical deterioration and fluctuating cognition, autoimmune testing was expanded to a full antibody panel, which identified elevated serum anti-glutamic acid decarboxylase 65 (anti-GAD65) antibodies (60 UI/mL, reference range 0–5 UI/mL), establishing a possible coexisting diagnosis of anti-GAD65 autoimmune encephalitis. Initial treatment with intravenous immunoglobulin produced minimal improvement; however, therapeutic plasma exchange led to the remission of psychosis and significant improvement in rigidity, bradykinesia, and attention, with modest amelioration in global cognition. Conclusions: This case highlights the diagnostic challenges posed by overlapping AE and bvFTD clinical pictures, especially when neurodegenerative features obscure an underlying autoimmune process. Early, panel-based neural antibody testing—and consideration of AE even in patients already diagnosed with a major neurocognitive disorder—is critical for avoiding delays in immunotherapy. Prompt recognition and treatment of AE may substantially improve clinical outcomes, even in complex cases with suspected overlap. Full article