Search Results (153)

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

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked by shared genetic mutations and overlapping clinical features, forming a clinical spectrum. This systematic review and meta-analysis analysed 97 studies, including 3212 patients with key ALS/FTD gene mutations, to identify gene-specific behavioural profiles. Chromosome 9 open reading frame 72 (C9orf72) mutations were strongly associated with psychotic symptoms and aggression, while superoxide dismutase 1 (SOD1) mutations had minimal cognitive effects. Progranulin (PGRN) mutations correlated with apathy and hallucinations, microtubule-associated protein tau (MAPT) mutations with disinhibition, and charged multivesicular body protein 2B (CHMP2B) with social impairments. Fused in sarcoma (FUS) mutations caused early sleep disturbances, TANK-binding kinase 1 (TBK1) led to disinhibition, and presenilin 1 and 2 (PSEN1/2) was linked to severe aggression. Prodromal cognitive changes in PGRN, MAPT, and CHMP2B mutations suggested early disease onset. Despite overlapping symptoms and clinical heterogeneity, understanding gene-specific patterns could inform tailored care strategies to enhance the quality of life for ALS and FTD patients. This study calls for refined guidelines integrating genetic behavioural profiles to improve patient and family support. 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

Nowadays, scientists are making efforts to elucidate the mechanisms involved in the phenotypic changes underlying the aging process in order to develop favorable therapeutical interventions. Epigenetic modifications, in particular DNA methylation, play a crucial role in the aging process, and this parameter has been used to set epigenetic clocks, algorithms that predict an individual’s biological age based on a defined set of CpGs. In this review, we focus on the most recent literature to discuss the use of epigenetic clocks in the context of cognitive decline and dysregulation of Alzheimer’s disease (AD)-related gene expression. We have summarized all published scientific papers in which epigenetic clocks have been applied to measure age acceleration in blood and brain specimens from patients affected with AD. Progressive age acceleration, consistent with a specific DNA methylation signature, was observed in patients affected by AD, and it was correlated with the onset of complex diseases, mitochondrial alterations, dementia and cognitive decline, even in the early stages of these conditions. The use of epigenetic clocks might be a valuable biomarker to enable an earlier identification of ideal measures to reverse modifications caused by aging and to mitigate multiple aspects of disease/aging mechanisms. Full article

Background and Objectives: Identifying carriers of Pathogenic/Likely Pathogenic Variants in patients with dementia is crucial for risk stratification, particularly in individuals with a family history. This study developed and validated a clinical prediction model using whole-exome sequencing-confirmed cohorts. Methods: A total of 601 Chinese patients with dementia and a family history were enrolled at Peking Union Medical College Hospital, with 476 in a retrospective derivation cohort and 125 in a temporal validation cohort. Predictive factors included age at onset, APOE ε4 status, and family history characteristics. Model performance was assessed using discrimination and calibration metrics. Results: In the derivation cohort (median age at onset 66 years), 10.3% carried Pathogenic/Likely Pathogenic Variants. Among patients with dementia, those with age at onset < 55 years (OR 2.56, p = 0.0098), more than two affected relatives (OR 3.32, p = 0.0039), parental disease history (OR 4.72, p = 0.015), and early-onset cases in the family (OR 2.61, p = 0.0096) were positively associated with Pathogenic/Likely Pathogenic Variant carriage, whereas APOE ε4 carriage was inversely associated (OR 0.36, p = 0.0041). The model achieved an area under the curve of 0.776 (95% CI, 0.701–0.853) in the derivation cohort and 0.781 (95% CI, 0.647–0.914) in the validation cohort (median age at onset 58 years), with adequate calibration. Conclusions: This model demonstrated strong predictive performance for Pathogenic/Likely Pathogenic Variant carriage, supporting its clinical utility in guiding genetic testing. Further research is needed to refine the model. 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

Background: Late-onset depression (LOD) has been increasingly recognized as a risk factor for dementia, yet the temporal and causal nature of this relationship remains unclear. Objective: The purpose of this review is to investigate the temporal association between LOD and dementia. Methods: A comprehensive search for studies examining the temporal relationship between LOD and dementia was conducted using MEDLINE via Ovid. The end date of the search was 9 September 2024. A total of 3450 studies were identified, of which 27 met the inclusion criteria. This review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and an article quality assessment was completed. Results: The review demonstrated a significant temporal association between LOD and the risk of dementia, with the highest risk observed within the first decade following depression onset. LOD was consistently associated with an increased likelihood of developing dementia, particularly Alzheimer’s disease, compared to depression at earlier life stages. Conclusions: This systematic review highlights the significant association between LOD and dementia risk, emphasizing the need for early recognition and intervention. Future research should investigate the age at which LOD becomes a risk factor for dementia, the relationship between depression severity, family history of dementia, and dementia risk, as well as the efficacy of preventative treatments. Full article

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons, leading to muscle atrophy, paralysis, and respiratory failure. This comprehensive review synthesizes the current knowledge on ALS pathophysiology, clinical heterogeneity, diagnostic frameworks, and evolving therapeutic strategies. Mechanistically, ALS arises from complex interactions between genetic mutations (e.g., in C9orf72, SOD1, TARDBP (TDP-43), and FUS) and dysregulated cellular pathways, including impaired RNA metabolism, protein misfolding, nucleocytoplasmic transport defects, and prion-like propagation of toxic aggregates. Phenotypic heterogeneity, manifesting as bulbar-, spinal-, or respiratory-onset variants, complicates its early diagnosis, which thus necessitates the rigorous application of the revised El Escorial criteria and emerging biomarkers such as neurofilament light chain. Clinically, ALS intersects with frontotemporal dementia (FTD) in up to 50% of the cases, driven by shared TDP-43 pathology and C9orf72 hexanucleotide expansions. Epidemiological studies have revealed a lifetime risk of 1:350, with male predominance (1.5:1) and peak onset between 50 and 70 years. Disease progression varies widely, with a median survival of 2–4 years post-diagnosis, underscoring the urgency for early intervention. Approved therapies, including riluzole (glutamate modulation), edaravone (antioxidant), and tofersen (antisense oligonucleotide), offer modest survival benefits, while dextromethorphan/quinidine alleviates the pseudobulbar affect. Non-pharmacological treatment advances, such as non-invasive ventilation (NIV), prolong survival by 13 months and improve quality of life, particularly in bulb-involved patients. Multidisciplinary care—integrating physical therapy, respiratory support, nutritional management, and cognitive assessments—is critical to addressing motor and non-motor symptoms (e.g., dysphagia, spasticity, sleep disturbances). Emerging therapies show promise in preclinical models. However, challenges persist in translating genetic insights into universally effective treatments. Ethical considerations, including euthanasia and end-of-life decision-making, further highlight the need for patient-centered communication and palliative strategies. Full article

Within the phenotypic spectrum of Alzheimer’s disease (AD), Creutzfeldt–Jakob disease (CJD) and cerebral amyloid angiopathy (CAA), dementia that is attributed to iatrogenic transmission has increasingly gained scientific attention recently. Newly recognized, this treatment-induced form of dementia may result from exposure to certain medical or surgical procedures. The present review aims to explore the distinct features of acquired dementia encompassing a history of potential exposure and relatively early age of onset, highlighting transmission potential with a rather prion-like pattern. Having reviewed all available relevant literature, dementia of iatrogenic etiology represents a new disease entity that requires an individualized investigation process and poses a great clinical challenge as far as patients with AD, CJD and CAA are concerned. Understanding the underlying pathophysiology of these rare forms of dementia may significantly enhance awareness within clinical field of neurodegenerative diseases and facilitate their prompt management. Full article

Alzheimer’s disease (AD) is a persistent neurologic disorder that has no cure. For a successful treatment to be implemented, it is essential to diagnose AD at an early stage, which may occur up to eight years before dementia manifests. In this regard, a new predictive machine learning model is proposed that works in two stages and takes advantage of both unsupervised and supervised learning approaches to provide a fast, affordable, yet accurate solution. The first stage involved fuzzy partitioning of a gold-standard dataset, DARWIN (Diagnosis AlzheimeR WIth haNdwriting). This dataset consists of clinical features and is designed to detect Alzheimer’s disease through handwriting analysis. To determine the optimal number of clusters, four Clustering Validity Indices (CVIs) were averaged, which we refer to as cognitive features. During the second stage, a predictive model was constructed exclusively from these cognitive features. In comparison to models relying on datasets featuring clinical attributes, models incorporating cognitive features showed substantial performance enhancements, ranging from 12% to 26%. Our proposed model surpassed all current state-of-the-art models, achieving a mean accuracy of 99%, mean sensitivity of 98%, mean specificity of 100%, mean precision of 100%, and mean MCC and Cohen’s Kappa of 98%, along with a mean AUC-ROC score of 99%. Hence, integrating the output of unsupervised learning into supervised machine learning models significantly improved their performance. In the process of crafting early interventions for individuals with a heightened risk of disease onset, our prognostic framework can aid in both the recruitment and advancement of clinical trials. Full article

(1) Background/Objectives: The pathogenic process of Alzheimer’s disease (AD) is known to begin decades before its clinical onset. This period, although imperceptible to the patient, encompasses a gradual neuronal loss. The first symptoms of dementia, often classified as mild cognitive impairment (MCI), in many cases converts into incipient AD, but can also remain stable or even reverse to cognitive norm. An easy and fast blood-based method of identifying patients at risk of conversion to AD would allow for the application of disease-altering therapies. This preliminary study focuses on the identification and assessment of the relationship between plasma amyloid beta (Aβ) and cognitive performance in older Polish adults with respect to its adequacy as a biomarker of an early cognitive deterioration. (2) Methods: The preliminary research sample consisted of 230 participants, 109 females and 121 males, aged 65 plus. The association between plasma Aβ concentrations with cognitive status, gender, and age were assessed. The analyses were conducted in three categories of cognitive performance: cognitive norm, mild cognitive impairment, and mild dementia, based on results of the Mini-Mental State Examination (MMSE) and functional tests. (3) Results: No significant differences in plasma Aβ levels for different cognitive statuses were identified. No significant differences were found in Aβ levels based on age or gender. (4) Conclusions: In order to thoroughly explore the power of research on plasma Aβ with respect to early cognitive deterioration, further prospective studies are required. Full article

Prion diseases are fatal neurological disorders characterized by abnormal protein accumulation in the brain, leading to neurodegeneration, dementia, and ataxia. Sporadic Creutzfeldt–Jakob disease (sCJD), the most common form, accounts for 80–90% of cases and progresses rapidly, with most patients surviving <6 months to a year after symptom onset, indicating the importance of early diagnosis. The disease is classified into six subtypes based on PRNP gene polymorphisms, with differences in protein degradation patterns contributing to the diversity of clinical symptoms. However, diagnosis remains challenging because of the variability in clinical presentation and disease duration. Traditional diagnostic criteria established by the World Health Organization (WHO) rely on clinical findings, electroencephalogram, and cerebrospinal fluid tests, such as the 14-3-3 protein assay. However, these criteria require pathological confirmation, often delaying diagnosis. The recently proposed Hermann’s criteria represent a significant advancement by incorporating newer biomarkers, including magnetic resonance imaging, real-time quaking-induced conversion assay, tau protein, and neurofilament light chain. These criteria improve diagnostic sensitivity and specificity but have a slightly higher risk of false positives. This review compares the effectiveness of these biomarkers with the WHO criteria and highlights the importance of early diagnosis for improving patient care. Full article

Background: In search of indicators for dementia, this study investigated the association of cerebrospinal fluid (CSF) biomarkers and neuropsychological test results with disease stage in patients with early manifestations of dementia. Methods: In 190 consecutive patients with symptoms of dementia, the CSF parameters amyloid-β 1-42 (Aβ1-42), phosphorylated tau protein (pTau), total tau protein (tTau), neuron-specific enolase (NSE), protein S100B (S100B), and Aβ (1-42)/(1-40) ratio (Aβ ratio), as well as the results of the CERAD-Plus test battery supplemented by the Clock Drawing Test (CDT), were analysed. Patients were divided into two groups based on the median duration of reported symptom onset. Results: Most prominent in the early phase of the disease were the relationships between Aβ1-42 and neuropsychological memory subtests, which were absent in the later phase. Less pronounced relationships to memory function were detectable for Aβ ratio and pTau. Conclusions: The results substantiate the relevance of Aβ1-42 for memory deficits and support the amyloid cascade hypothesis for Alzheimer’s dementia (AD). Our data suggest other pathomechanisms for visuospatial impairments in AD. Full article

Oxidative stress (OS), generated by the overrun of reactive species of oxygen and nitrogen (RONS), is the key cause of several human diseases. With inflammation, OS is responsible for the onset and development of clinical signs and the pathological hallmarks of Alzheimer’s disease (AD). AD is a multifactorial chronic neurodegenerative syndrome indicated by a form of progressive dementia associated with aging. While one-target drugs only soften its symptoms while generating drug resistance, multi-target polyphenols from fruits and vegetables, such as ellagitannins (ETs), ellagic acid (EA), and urolithins (UROs), having potent antioxidant and radical scavenging effects capable of counteracting OS, could be new green options to treat human degenerative diseases, thus representing hopeful alternatives and/or adjuvants to one-target drugs to ameliorate AD. Unfortunately, in vivo ETs are not absorbed, while providing mainly ellagic acid (EA), which, due to its trivial water-solubility and first-pass effect, metabolizes in the intestine to yield UROs, or irreversible binding to cellular DNA and proteins, which have very low bioavailability, thus failing as a therapeutic in vivo. Currently, only UROs have confirmed the beneficial effect demonstrated in vitro by reaching tissues to the extent necessary for therapeutic outcomes. Unfortunately, upon the administration of food rich in ETs or ETs and EA, URO formation is affected by extreme interindividual variability that renders them unreliable as novel clinically usable drugs. Significant attention has therefore been paid specifically to multitarget EA, which is incessantly investigated as such or nanotechnologically manipulated to be a potential “lead compound” with protective action toward AD. An overview of the multi-factorial and multi-target aspects that characterize AD and polyphenol activity, respectively, as well as the traditional and/or innovative clinical treatments available to treat AD, constitutes the opening of this work. Upon focus on the pathophysiology of OS and on EA’s chemical features and mechanisms leading to its antioxidant activity, an all-around updated analysis of the current EA-rich foods and EA involvement in the field of AD is provided. The possible clinical usage of EA to treat AD is discussed, reporting results of its applications in vitro, in vivo, and during clinical trials. A critical view of the need for more extensive use of the most rapid diagnostic methods to detect AD from its early symptoms is also included in this work. Full article

Background: Parkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders among older adults, yet its long-term impact on mortality within population-based cohorts remains insufficiently characterized. This study leverages data from the Neurological Disorders in Central Spain (NEDICES) cohort to provide a comprehensive 23-year mortality analysis in a Spanish population. Methods: In this prospective cohort study, 5278 individuals aged 65 years and older were evaluated across two waves: baseline (1994–1995) and follow-up (1997–1998). At baseline, 81 prevalent PD cases were identified, while 30 incident cases, likely in the premotor phase at baseline, were detected during follow-up. Mortality was tracked over 23 years, and Cox proportional hazard models were employed to estimate hazard ratios (HRs) for mortality, adjusting for relevant demographic and clinical variables. Results: Fifty-three individuals from the cohort in the reference group (without PD) were excluded due to unreliable mortality data. Among 111 PD cases, 109 (98.2%) died during follow-up compared to 4440 (86.8%) of 5114 without the disease. PD was associated with a significantly increased mortality risk (adjusted HR = 1.62; 95% confidence interval [CI] = 1.31–2.01). Patients with both PD and dementia had an even higher risk (HR = 2.19; 95% CI = 1.24–3.89). Early-onset PD (<65 years) showed heightened mortality risk (HR = 2.11; 95% CI = 1.22–3.64). Cardiovascular and cerebrovascular diseases were the leading causes of death in both PD and non-PD participants. PD was significantly more often listed as the primary cause of death in PD patients compared to the reference group (14.7% vs. 0.4%, p < 0.001). Conclusions: PD significantly increases mortality risk over 23 years, particularly among those with early onset and dementia. These findings underscore the importance of a multidisciplinary approach to PD care, targeting both motor and non-motor symptoms to enhance long-term outcomes. Full article