Search Results (538)

Background and Objectives: Parkinson’s disease (PD) entails the progressive degeneration of dopaminergic neurons in the substantia nigra (SN), accompanied by α-synuclein (α-syn)-enriched Lewy bodies. ITGA7 mediates cell–extracellular matrix adhesion and modulates apoptosis, though its involvement in PD pathogenesis warrants further investigation. Although acupuncture demonstrates neuroprotective effects in PD models, its precise molecular mechanisms remain incompletely understood; therefore, in this study, we explored the relationship between ITGA7 and α-synuclein expression in an MPTP-induced PD mouse model to determine the association between LR3/GB34 acupuncture-induced changes in α-synuclein levels and ITGA7 modulation. Materials and Methods: In the in vivo model, MPTP-induced PD mice underwent immunohistochemistry, immunofluorescence, and Western blotting to assess ITGA7, α-synuclein, and TH levels in the SN and striatal tissues following LR3/GB34 acupuncture. In parallel, for the in vitro mechanistic study, SH-SY5Y neuroblastoma cells treated with MPP⁺ and transfected with ITGA7-siRNA were utilized to examine the involvement of apoptosis-related signaling pathways. Results: In the in vivo model, MPTP administration downregulated ITGA7 and upregulated α-synuclein in SN tissues. Similarly, in vitro exposure of SH-SY5Y cells to MPP⁺ yielded comparable results, revealing an inverse correlation between ITGA7 and α-synuclein. LR3/GB34 acupuncture treatment in the mouse model significantly increased ITGA7 and TH expression while reducing α-synuclein accumulation. To further understand the specific role of ITGA7 observed in these animal findings, we silenced ITGA7 in the MPP⁺-treated cellular model. ITGA7 silencing exacerbated the neurotoxic effects, leading to further TH downregulation, α-synuclein upregulation, Bcl-2 reduction, and Bax/Bcl-2 ratio elevation. Conclusions: Collectively, the histological preservation of dopaminergic neurons following LR3/GB34 acupuncture in the PD mouse model appears to be linked to ITGA7 upregulation. Furthermore, our in vitro findings implicate ITGA7 in the regulation of apoptosis-related signaling cascades, supporting its potential role in mitigating α-synuclein pathology. Full article

Neurodegenerative diseases feature diverse pathological protein aggregates, including Lewy bodies in Alzheimer’s disease (AD) and skein-like filaments in amyotrophic lateral sclerosis (ALS). The physical mechanisms underlying this morphological diversity remain unclear. Here, we demonstrate that aggregation of the prion-like domain of hnRNPA1 (A1PrD), implicated in AD and ALS, is driven by solution composition and phase transition dynamics. Utilizing 3D timelapse and fluorescence lifetime imaging microscopy, we show that solution conditions modulate phase separation, gelation, and fibrillation, resulting in distinct structures such as fibril, gel, and starburst morphologies. Homotypic and heterotypic interactions between A1PrD and RNA were observed to shift the balance between pathological and physiological condensates. Importantly, amyloid-rich starbursts displayed prion-like infection capabilities toward amyloid-poor condensates. Our findings highlight how the interplay between solution composition and kinetic balances of liquid-liquid phase separation, gelation, and fibrillation shapes the diverse pathological aggregate morphologies characteristic of neurodegenerative diseases. Full article

The Benson Complex Figure Test (BCFT) is a neuropsychological tool designed to assess visuospatial construction and visual memory with lower complexity than traditional tests. This study evaluated its ability to differentiate between major dementia subtypes. In a retrospective cross-sectional analysis of 1428 participants from a Greek third-age day center (healthy participants [Controls]; patients diagnosed with Alzheimer’s disease dementia [ADD], Lewy body dementia [LBD], Frontotemporal dementia [FTD: behavioral variant (BV), non-fluent variant (NFV), semantic variant (SV)], Corticobasal dementia [CBD], Parkinson’s disease dementia [PDD], and mixed Cardiovascular dementia with Alzheimer’s disease [CVD/AD]), all participants completed the BCFT and the Mini-Mental State Examination (MMSE). Multinomial logistic regression, adjusted for age, sex, and education, revealed distinct BCFT profiles across dementia subtypes. Patients with CBD showed significantly lower copy scores than those with ADD (p = 0.006). The FTD-NFV group exhibited superior memory scores compared to all other dementia subtypes (p < 0.001). Poorer BCFT recognition performance was strongly associated with diagnoses of ADD (OR = 0.39, p = 0.012), FTD-BV (OR = 0.22, p = 0.025), and PDD (OR = 0.26, p < 0.001). Classification accuracy was highest for controls and ADD (sensitivity > 89%) but low for rarer subtypes (<25%), partly reflecting sample size limitations. In conclusion, the BCFT captures distinct visuospatial and memory profiles across dementia syndromes, supporting its potential utility in differential diagnosis, particularly for common subtypes such as ADD. Its simpler design may facilitate assessment in older adults, although validation in larger and more balanced cohorts is required for rarer dementias. Full article

Pareidolia is often framed as a viewer-side illusion: a tendency to perceive meaningful forms—especially faces—in ambiguous inputs. This Concept Paper argues that pareidolia can also be deliberately engineered and therefore provides a tractable entry point into the neurophysiology of visual creativity. We propose a unifying construct in which engineered pareidolia functions as externally scaffolded mental imagery: minimal visual constraints recruit internally generated templates and top-down inference while remaining anchored to sensory input. To strengthen theoretical rigor, we define necessary and sufficient features that distinguish this construct from adjacent accounts (scaffolded cognition; perceptual scaffolding; bistable perception). Using Arcimboldo’s composite portraits and Dürer’s embedded face in View of the Arco Valley, plus a canonical Renaissance example (Leonardo’s Bacchus/Saint John the Baptist), we outline distinct “design regimes” that modulate cue validity, attentional release, and interpretive switching. We then connect engineered pareidolia to creativity research by linking pareidolia design and detection to measurable constructs in divergent/creative perception, including but not limited to Torrance-style domains, and we propose feasible behavioral and neurophysiological paradigms that control for artistic skill and clinical status. Finally, we distinguish benign pareidolia from hallucination, discuss clinical resonance in dementia with Lewy bodies where pareidolia can be quantified, and outline an empirically testable research program that reframes pareidolia as a bridge between imagination, perception, and creativity. Full article

Architecture, as a profession, discipline and practice, has played a vital role in designing, constructing and maintaining modern culture. The creative work of imagining and building places, infrastructure and dwellings for the complex activities of contemporary life has contributed to the global world we now inhabit. There are, however, indications that this edifice of modernity is cracking because of external and internal forces that undermine our global society. Climate change, species extinction, and worldwide threats to democracy and governance, along with new technologies, converge and reveal the uncomfortable possibility that modern industrial global culture and civilization may collapse. As a response, an expanding body of ‘stories of collapse’ has emerged to interpret causes, processes, and scenarios. This essay engages with key voices (Rees, Bendell, Lewis, Hagens, de Oliveira, and Macy), to describe in what ways architecture is complicit in this moment, and suggests what ethical and place-based responsibilities may be required of architects and placemakers as collapse unfolds. Full article

Alpha-synuclein (αSyn) is one of the most abundant proteins in the nervous system and is currently associated with devastating synucleinopathies, yet its biology extends far beyond this. In this review, we suggest that αSyn-driven disease emerges within specific neural circuits through the combined effects of cell-type-specific roles, subcellular environments, post-translational modifications (PTMs), and co-pathology. These interacting and additive dimensions, rather than αSyn alone, generate the pathological diversity, shaping whether pathology manifests as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), or mixed dementia phenotypes. We integrate recent advances on the physiological roles of αSyn in neurons and glia (astrocytes, oligodendrocytes, and microglia), its compartment-dependent (e.g., synaptic and nuclear) functions, and the molecular transitions (e.g., mediated by pS129) that convert functional assemblies into pathogenic conformers. Building on this foundation, we outline mechanisms through which these factors contribute to disease-specific vulnerability, progression, and clinical heterogeneity. Finally, we highlight how this multidimensional perspective on αSyn biology can inform the development of next-generation biomarkers that support precision therapies across distinct disorders. Full article

Background: Decreased dopaminergic cells and tyrosine hydroxylase (TH) in the substantia nigra (SN) lead to Parkinson’s disease (PD); but its cause remains unknown. PD is characterized by α-synuclein (α-syn) accumulation in Lewy bodies; most of which is phosphorylated at Ser129 (pSer129 α-syn). Serping1 is an important gene for controlling blood vessel maintenance; including the process of inflammation. Methods: Increased expression of Serping1 affects dopaminergic cell death in the SN of a chronic PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); and Serping1 siRNA treatment has a therapeutic effect in this model. Results: We demonstrated that this treatment shows a normal status in the motor ability test and TH level in the SN and striatum. Serping1 siRNA was found to react to decreased Serping1 levels in the SN. In the pSer129-α-syn level of the SN region; Serping1 siRNA had a greater positive effect on PD than N-acetylcysteine by inhibiting pSer129-α-syn formation. Cyclooxygenase-2 and inducible nitric oxide synthase levels were decreased by Serping1 siRNA treatment; thereby indicating its effect on inflammation. Conclusions: Our findings suggest that Serping1 siRNA may represent a potential therapeutic approach for PD; warranting further investigation. Full article

Parkinson’s disease (PD) and associated synucleinopathies are preceded by a prolonged prodromal phase during which neurodegenerative processes evolve years before the onset of motor or cognitive symptoms. Identifying biologically specific and accessible biomarkers during this window is critical for early diagnosis, risk stratification, and the development of disease-modifying therapies. Increasing evidence supports the skin as a key peripheral tissue involved in synucleinopathy, offering a minimally invasive source for in vivo detection of pathological α-synuclein. This review summarizes current evidence on skin-derived biomarkers across the prodromal continuum of PD, with particular emphasis on skin biopsy-based detection of phosphorylated α-synuclein and α-synuclein seed amplification assays (SAAs). Findings in high-risk prodromal phenotypes, including idiopathic REM sleep behavior disorder (iRBD) and pure autonomic failure (PAF), are critically reviewed. Emerging data suggest that cutaneous α-synuclein pathology may precede nigrostriatal dopaminergic degeneration and may predict phenoconversion to overt synucleinopathies. Important knowledge gaps are highlighted, including the lack of data in other prodromal phenotypes such as hyposmia. Overall, skin-based biomarkers appear to represent promising, scalable tools for biological diagnosis, prognostication, and enrichment of prodromal PD cohorts in clinical trials. Full article

Transcranial sonography is one of the methods of examination used in atypical parkinsonian syndromes. The assessment is not indicated in the diagnostic criteria of entities in this group e.g., Progressive Supranuclear Palsy, Corticobasal Degeneration, Multiple System Atrophy and Dementia with Lewy Bodies. Atypical parkinsonisms are a group of diseases affected by diverse pathologies including alpha-synuclein or tau among others. Recently broader attention was brought to less common atypical parkinsonisms as Perry syndrome. Atypical parkinsonisms are related to poor response to levodopa treatment, rapid deterioration and unfavorable prognosis. Additionally, the entities often overlap in terms of clinical manifestation, especially in the early stages. Though atypical parkinsonisms are affected by the lack of possibility of obtaining definite in vivo diagnosis, growing interest is associated to supplementary evaluations including neuroimaging. Among these methods could be mentioned magnetic resonance imaging, positron emission tomography, single photon emission computed tomography and transcranial sonography. Transcranial sonography is associated with high accessibility and low cost. The goal of this paper is to highlight the strengths and weaknesses of transcranial sonography in the examination of atypical parkinsonisms. Full article

Parkinson’s disease (PD) is a heterogeneous clinical syndrome representing the final stage of a complex and long-lasting neurodegenerative process that involves not only dysfunction of the dopaminergic system but also impairments in other neurotransmitter systems. The diversity of the clinical presentation of PD, together with the existence of Parkinsonian syndromes and atypical Parkinsonism—such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB)—has important implications for rehabilitation outcomes and underscores the need for individualized, stage-dependent therapeutic approaches. Juggling is a complex motor activity that integrates cognitive, visuomotor, and balance processes, requiring a high level of concentration, precision, and motor adaptation. In recent years, there has been growing interest in this form of activity as a potential tool for supporting neuroplasticity, cognitive functions, and neurological rehabilitation. The aim of this review was to summarize current scientific evidence on the effects of juggling training on cognitive functions, visuomotor coordination, and balance, as well as to discuss the potential benefits of combining it with controlled hypoxia in patients with Parkinson’s disease (PD). This narrative review additionally considers how disease heterogeneity and stage of progression may influence the effectiveness of such multimodal interventions. This paper reviews the literature concerning the neurophysiological basis of learning to juggle and the mechanisms of brain plasticity, including increases in gray matter volume, improvements in white matter integrity, and reorganization of neuronal networks in motor and associative regions. Attention is drawn to the synergistic potential of combining juggling training with exposure to moderate, controlled hypoxia, which may induce an adaptive response involving the transcription factor HIF-1α, enhance the expression of brain-derived neurotrophic factor (BDNF), and promote angiogenesis and mitochondrial biogenesis. Although juggling and hypoxia are not directly related to training stimuli, both interventions activate overlapping and complementary neuroplastic pathways, providing a conceptual rationale for their parallel consideration and potential integration within future rehabilitation protocols. Juggling delivers task-specific motor–cognitive learning, whereas hypoxia may amplify molecular plasticity signaling, potentially enhancing responsiveness to motor interventions, particularly in patients at early stages of PD when compensatory mechanisms and neuroplastic capacity are relatively preserved. Findings from existing studies suggest that juggling under controlled hypoxic conditions may represent an innovative, safe, and multimodal form of training that supports both cognitive and motor components. Such effects may be particularly relevant in patients at early stages of PD, when compensatory mechanisms and neuroplastic potential are relatively preserved. Such an intervention may contribute to improvements in balance, attention, executive functions, and cognitive flexibility, which is particularly relevant in the context of rehabilitation for patients with neurodegenerative diseases. Importantly, to date, no randomized clinical trials have directly examined juggling performed under controlled hypoxic conditions in PD. Therefore, the present concept should be regarded as translational and exploratory, integrating evidence from juggling-induced neuroplasticity and hypoxia-related physiological adaptations. In this context, the proposed approach represents a proof-of-concept framework for future multimodal interventions rather than an established therapeutic strategy. Available evidence suggests that combining complex sensorimotor skill training with physiological modulation of the internal environment may constitute a novel direction in PD rehabilitation, extending beyond conventional exercise-based models. Despite promising reports, further well-designed clinical studies are needed to determine the optimal training parameters (frequency, intensity, duration, and degree of hypoxia), to evaluate the long-term sustainability of therapeutic effects, and to account for the heterogeneity of PD and related Parkinsonian disorders. Full article

This narrative review integrates longitudinal cohort studies, neuroimaging and biomarker research, and major clinical trials to examine how depression and cognitive decline interact across the dementia continuum. Depression and cognitive impairment frequently co-occur in late life and exhibit substantial clinical and biological overlap. Meta-analytic and large population-based cohort studies consistently show that late-life depression increases the risk of mild cognitive impairment and dementia, with stronger associations observed for vascular dementia than for Alzheimer’s disease. Neurobiological studies implicate cerebrovascular pathology, neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and fronto-subcortical circuit dysfunction as key mechanisms linking depressive symptoms to later cognitive decline. In a subset of older adults, new-onset depression—particularly when accompanied by executive dysfunction, subjective cognitive decline, or high white-matter hyperintensity burden—are associated with an increased likelihood of near-term cognitive decline and dementia, although evidence for a definitive prodromal state remains limited. Depression is also highly prevalent as part of the behavioral and psychological symptoms of dementia, occurring in 30–50% of individuals with Alzheimer’s disease and even higher proportions in dementia with Lewy bodies or frontotemporal dementia. Comorbid depression in dementia accelerates cognitive and functional decline, increases neuropsychiatric burden, and worsens quality of life for patients and caregivers. Therapeutically, antidepressant treatment may confer modest benefits on mood and selected cognitive domains (e.g., processing speed and executive function) in non-demented older adults, whereas in established dementia, antidepressant efficacy is limited. In contrast, cholinesterase inhibitors, memantine, and multimodal non-pharmacological interventions yield small but measurable improvements in depressive or apathy-related symptoms. Emerging disease-modifying therapies for Alzheimer’s disease have demonstrated cognitive benefits, but current trial data provide insufficient evidence regarding effects on depressive symptoms, highlighting an important gap for future research. These findings underscore the need for stage-specific, integrative strategies to address the intertwined trajectories of mood and cognition in aging. Full article

Background: Research has shown that disordered eating behaviors—including binge eating, night eating syndrome, and food addiction—contribute to the heterogeneity of obesity and assist in phenotyping patients for more tailored interventions. The Eating Behavior Assessment for Obesity (EBA-O) is a recently developed 18-item questionnaire that assesses five pathological eating-behavior domains among individuals with obesity (night eating, food addiction, sweet eating, hyperphagia, and binge eating). The present study aimed to translate, culturally adapt, and validate the Persian (Farsi) version of the EBA-O. Methods: The original English EBA-O was translated into Persian following a standardized forward–backward translation procedure, with cultural adaptations implemented to ensure linguistic accuracy and conceptual clarity. A cross-sectional sample of 278 Iranian adults with overweight or obesity (body mass index [BMI] ≥ 25 kg/m²) completed the Persian EBA-O. Confirmatory factor analysis (CFA) was conducted to verify the five-factor model in the Persian sample. Internal consistency was evaluated using Cronbach’s alpha and composite reliability (CR). Convergent validity was assessed using the average variance extracted (AVE), and discriminant validity was examined with the Heterotrait–Monotrait ratio (HTMT). Model fit indices, including the Comparative Fit Index [CFI], Tucker–Lewis Index [TLI], Normed Fit Index [NFI], Goodness-of-Fit Index [GFI], the Standardized Root Mean Square Residual [SRMR] and relative chi-square value [χ²/df] were used to determine the adequacy of the factor structure. Results: The Persian EBA-O demonstrated a clear and stable five-factor structure consistent with the original instrument. CFA indicated good model fit (CFI = 0.95, TLI = 0.94, NFI = 0.91, GFI = 0.92, SRMR = 0.05, χ²/df = 1.94), confirming the presence of the intended domains. Internal consistency was acceptable to high across all subscales (Cronbach’s α = 0.78–0.86; CR > 0.70), and the total scale showed strong reliability. Three of the five factors demonstrated acceptable convergent validity (AVE = 0.54–0.68), while Food Addiction (AVE = 0.46) and Night Eating (AVE = 0.43) fell slightly below the 0.50 threshold; however, their adequate CR and α values indicate that these constructs remain coherent and psychometrically sound. All inter-factor correlations satisfied discriminant validity criteria (HTMT < 0.90), with the highest association observed between the Binge Eating and Hyperphagia factors. Overall, the psychometric properties of the Persian EBA-O were comparable to those reported in the original validation and subsequent translations. Conclusions: The Persian version of the EBA-O is a valid and reliable instrument for assessing pathological eating behaviors among individuals with obesity. It preserves the original questionnaire’s five-factor structure and demonstrates acceptable internal consistency and construct validity in a Persian-speaking population. This validated tool will support both clinical assessment and research on eating-behavior phenotypes and may contribute to the development of more personalized and effective obesity-management strategies among Persian-speaking individuals. Full article

Neurodegenerative synucleinopathies—including Parkinson’s disease, multiple system atrophy, pure autonomic failure, and dementia with Lewy bodies—often feature cardiovascular autonomic dysfunction. Neurogenic orthostatic hypotension (nOH) is common and symptomatic, while neurogenic supine hypertension (nSH) is less frequent but may carry long-term cardiovascular risks. Lifestyle measures are first-line for managing nSH, yet persistent hypertension unresponsive to nonpharmacological strategies presents a treatment dilemma. Limited trial data and unclear guidelines make it difficult to determine when antihypertensive therapy is appropriate. Evidence from studies on hypertension-mediated organ damage (HMOD)—assessed through markers such as carotid intima-media thickness, pulse wave velocity, left ventricular hypertrophy, estimated glomerular filtration rate, and white matter hyperintensities—suggests that nSH, rather than the underlying neurodegenerative disorder, drives vascular, cardiac, renal, and cerebral injury. Therefore, treatment decisions should be individualized. While antihypertensive therapy may help prevent subclinical organ damage, clinicians must balance this benefit against the risk of worsening nOH and further compromising overall prognosis. Full article

Dementia is a neurodegenerative condition marked by progressive cognitive decline, which affects people worldwide. Studies on dementia typically continue over years of uncertainty. Different types of dementia, like Alzheimer’s disease dementia, Lewy body dementia, frontotemporal dementia, and vascular dementia, exhibit different pathological features, yet their downstream inflammatory pathways involve similar inflammatory mediators. As an initial trigger, microglial cells and astrocytes become activated by protein aggregates, mutations, or any other cause, and release pro-inflammatory cytokines, which can lead to synaptic dysfunction, neuronal degeneration, and impaired cognitive function. Neuroinflammation plays a critical role in the pathogenesis of all forms of dementia. Despite their distinct neuropathological features, inflammatory processes may coincide at a point and lead to neuronal degeneration and cognitive decline. Recent advancements in neuroimaging techniques and biomarker discovery revealed potential therapeutic targets that may mitigate neuroinflammation. The primary objective of this review is to explore the underlying mechanisms linking neuroinflammation to various types of dementia. This review focuses on shared and distinct neuroinflammatory mechanisms to unravel significant therapeutic strategies for dementia. Full article

Background/Objectives: Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of misfolded alpha-synuclein protein in the brain. Mutations in the glucocerebrosidase 1 (GBA1) gene have been identified as a significant genetic risk factor for both PD and DLB. GBA1 encodes for the lysosomal enzyme glucocerebrosidase, which is responsible for the breakdown of glucosylceramide (GC). Deficiencies in glucocerebrosidase activity lead to the accumulation of glucosylceramide within lysosomes, contributing to lysosomal dysfunction and impaired protein degradation. The aim of this narrative review is to update the underlying mechanisms by which GBA1 mutations contribute to the pathogenesis of PD and DLB. Methods: A comprehensive literature search was conducted across four major electronic databases (PubMed, Web of Science (Core Collection), Scopus, and Embase) from inception to 8 November 2025. The initial search identified approximately 1650 articles in total, with the number of hits from each database being as follows: PubMed (~450), Web of Science (~380), Scopus (~520), and Embase (~300). Results: The mechanism by which mutations in the GBA1 gene contribute to PD involves both loss-of- function and gain-of-function pathways, which are not mutually exclusive. Typically, GBA1 mutations lead to a loss of function by reducing the activity of the GCase enzyme, impairing the autophagy- lysosomal pathway and leading to α-synuclein accumulation. However, some mutant forms (GBA1L444P) of the GCase enzyme can also acquire a toxic gain of function, contributing to α-synuclein aggregation through mechanisms like endoplasmic reticulum stress and misfolding. While Venglustat effectively reduced GC levels, a key marker associated with GBA1-PD, the lack of clinical improvement led to the discontinuation of its development for this indication. Conclusions: GBA1-mediated lysosomal and lipid dysregulation represents a key pathogenic axis in PD and DLB. Understanding these mechanisms provides crucial insight into disease progression and highlights emerging therapeutic strategies—such as pharmacological chaperones, substrate reduction therapies, and gene-targeted approaches—aimed at restoring GCase function and lysosomal homeostasis to slow or prevent neurodegeneration. Full article