Search Results (281)

Background/Objectives: Dementia with Lewy bodies (DLB) is a clinically heterogeneous neurodegenerative disorder characterized by cognitive, neuropsychiatric, motor, and autonomic manifestations. Reduced striatal dopamine transporter availability on ¹²³I-ioflupane single-photon emission computed tomography (SPECT) is an established indicative biomarker of DLB. However, the associations among expert visual interpretation, regional semiquantitative dopamine transporter measurements, autonomic manifestations, and dementia severity remain incompletely characterized. This study aimed to evaluate the relationship between visual ¹²³I-ioflupane SPECT classification and regional DaTQUANT z-scores in patients with clinically probable DLB and to explore their associations with autonomic manifestations and dementia severity. Methods: This retrospective, cross-sectional study included 30 patients who received a clinical diagnosis of probable DLB according to the 2017 DLB Consortium criteria before the ¹²³I-ioflupane SPECT results became available. SPECT images were assessed visually by experienced nuclear medicine physicians and semiquantitatively using DaTQUANT software. Bilateral striatal, putaminal, caudate, and putamen-to-caudate ratio z-scores were analyzed in relation to visual scan classification, Clinical Dementia Rating (CDR) scores, and retrospectively ascertained autonomic manifestations, including orthostatic hypotension, delayed orthostatic hypotension, supine hypertension, postprandial hypotension, constipation, and urinary incontinence. Results: Scans were visually classified as supportive of nigrostriatal dopaminergic degeneration in 23 of 30 patients (76.7%) and as non-supportive in seven (23.3%). Bilateral striatal, putaminal, and caudate z-scores were significantly lower in visually supportive scans than in non-supportive scans (all p < 0.001), whereas putamen-to-caudate ratio z-scores did not differ significantly between the groups. None of the evaluated autonomic manifestations was significantly associated with either visual scan classification or regional DaTQUANT measurements. No regional DaTQUANT measurement was significantly associated with dementia severity. A modest positive correlation was observed between the left putamen-to-caudate ratio z-score and CDR (Spearman’s ρ = 0.373, nominal p = 0.050); however, given the small sample size and multiple regional comparisons, this borderline finding was considered exploratory. Conclusions: Regional DaTQUANT measurements were consistent with expert visual interpretation of ¹²³I-ioflupane SPECT in patients with clinically probable DLB. Associations of dopaminergic imaging measurements with autonomic manifestations and dementia severity were limited. Semiquantitative analysis may complement visual interpretation, but its findings should be interpreted within the broader clinical and biomarker context. Larger prospective studies incorporating standardized autonomic testing, appropriate control groups, longitudinal follow-up, and complementary biomarkers are warranted. Full article

Dementia with Lewy bodies (DLB) is increasingly conceptualised not merely as a disorder of neuronal death but as a primary synaptopathy in which the functional collapse of synaptic transmission and plasticity precedes, and predicts, neurodegeneration and clinical decline. Two genetic determinants dominate the heritable risk architecture of DLB: the α-synuclein gene SNCA, in which both copy-number variation and missense mutations exert dose- and conformation-dependent effects, and GBA1, encoding the lysosomal hydrolase glucocerebrosidase (GCase), the single most influential genetic risk factor for the disease. Here we synthesise evidence that these loci converge on a shared pathogenic endpoint—the impairment of activity-dependent synaptic plasticity. We argue that GBA1 loss-of-function and the resulting accumulation of glucosylceramide stabilise specific neurotoxic α-synuclein proteoforms, including soluble oligomers and self-templating conformational strains bearing defined post-translational modifications. These proteoforms are trafficked to, and enriched within, presynaptic terminals, where they disrupt SNARE-complex assembly and synaptic-vesicle dynamics, while postsynaptically they perturb NMDA and AMPA receptor trafficking, dysregulate dendritic calcium, and compromise synaptic mitochondrial bioenergetics. The net consequence is a metaplastic shift away from long-term potentiation (LTP) and toward aberrant long-term depression (LTD), a signature of synaptic failure detectable before frank pathology. We map these molecular events onto disease-relevant circuits—particularly the cholinergic basal forebrain and hippocampal–cortical and thalamocortical networks—and relate them to the defining neuropsychiatric features of DLB, including cognitive fluctuations and recurrent visual hallucinations. Finally, we evaluate emerging therapeutic strategies that target the GBA1–α-synuclein axis and that aim to restore synaptic plasticity directly. Positioning DLB within the framework of genetically determined plasticity deficits clarifies its kinship with other neuropsychiatric disorders and identifies the synapse as the most tractable node for early, disease-modifying intervention. We further examine how GBA1 allele severity and zygosity grade the phenotype, which genetic and environmental factors modify penetrance in carriers, and what distinguishes this synaptopathy from those driven by PSEN1/PSEN2, MAPT, or HTT, and we summarise the therapeutic pipeline—including enzyme augmentation and adeno-associated viral GBA1 gene therapy—that targets it. Full article

Dementia with Lewy Bodies (DLB) is the most common neurodegenerative dementia after Alzheimer’s disease (AD), but it remains challenging to diagnose due to overlapping symptoms and mixed pathologies. This pilot study tested whether DLB has different metabolic blood proteomic profiles compared to AD and controls. Serum was analysed from people with DLB (n = 20), a group with AD (either with Alzheimer’s disease dementia or Mild Cognitive Impairment with a positive amyloid positron emission tomography scan (MCI+/AD) (n = 15), and similarly aged controls (n = 15) using the Olink Metabolism panel encompassing 92 proteins. Six proteins (PILRB, LRIG1, NECTIN2, TINAGL1, SSC4D, and FKBP4) were significantly different in DLB compared with the controls, and one protein (SERPINB8) was differentially expressed when compared with MCI+/AD. Receiver operating characteristic curves for biologically relevant proteins that have previously established roles in neurodegenerative and cognitive properties showed that RNASE3 levels could differentiate DLB from MCI+/AD (area under the curve (AUC) = 0.717, sensitivity = 0.850, and specificity = 0.600). A multimarker model incorporating RNASE3 with phosphorylated tau 217 (pTau217) and polygenic risk scores for LBD achieved improved accuracy in discriminating DLB from MCI+/AD (AUC = 0.963, sensitivity = 1.000, and specificity = 0.900). Pathway analyses revealed dysregulation in cortisol signalling, inflammation resolution, and ErbB4-mediated neuroplasticity, which point towards peripheral protein alterations related to the adaptation to stress, immune regulation, and synaptic integrity in DLB. The present exploratory study highlights potential pathophysiological mechanisms implicated in DLB, suggesting that a multimodal biomarker panel may perform better compared to single proteins. Considering the small sample sizes, the findings will need to be replicated in larger cohorts. Full article

Neurodegenerative diseases represent a major and growing global health burden. Although these disorders are often clinically defined by symptoms and affected brain regions, many are mechanistically linked to abnormal protein accumulation, misfolding, impaired proteostasis, RNA dysregulation, mitochondrial dysfunction, and neuroinflammation. In this Perspective article, I discuss major neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease, prion diseases, spinocerebellar ataxias, and spinal muscular atrophy, through the lens of disease-associated proteins and experimental modeling. I argue that a protein-centered framework provides a useful approach for understanding disease mechanisms and selecting transgenic mouse models, while recognizing that aging, cellular context, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and other disease modifiers also shape neurodegeneration. Transgenic and genetically engineered mouse models have been essential for dissecting the pathogenic roles of amyloid-β, tau, α-synuclein, TDP-43, SOD1, FUS, C9ORF72-associated dipeptide repeat proteins, mutant huntingtin, prion protein, ataxins, and SMN deficiency. However, these models have important limitations, including artificial overexpression, familial mutation bias, species differences, and incomplete representation of aging-related sporadic diseases. Rather than seeking a single “best” model, a more productive strategy is to adopt model portfolios tailored to specific biological questions and to integrate mouse studies with human cellular models, postmortem tissue, omics approaches, and biomarker-based validation. Such an approach may improve mechanistic insight, strengthen translational relevance, and enhance the predictive value of preclinical neurodegenerative disease research. Full article

The assessment of consciousness has been shaped largely by research on acquired disorders of consciousness after acute or chronic brain injury, but similar problems of unreliable behavioral expression increasingly arise in neurodegenerative disease. This translational overlap is especially relevant when preserved cognition, awareness, or intentionality cannot be reliably expressed because of severe motor impairment, fluctuating arousal, cognitive decline, aphasia, apraxia, or impaired cooperation. In neurodegenerative disease, degeneration of arousal systems, large-scale brain networks, cognition, and motor pathways may similarly make observable behavior an unreliable measure of awareness. The challenge is not only to determine if a patient responds, but also to ask if residual awareness, intentionality, or covert cognition can still be detected through physiological signals. This review discusses how contemporary modalities reshape this assessment. Electroencephalography has moved from a descriptive measure of background activity to a bedside tool capable of probing event-related responses, network organization, and cortical complexity. Magnetic resonance methods reveal altered connectivity within thalamocortical and default mode network systems, while functional near-infrared spectroscopy adds a portable hemodynamic approach that may be repeated at the bedside and integrated with active paradigms. Brain–computer interfaces provide a translational step by converting neural responses into evidence of command following or, in selected patients, into communication, and artificial intelligence strengthens these approaches by extracting clinically meaningful patterns from complex neural and hemodynamic data. Additionally, autonomic measures, including heart rate variability and baroreflex indices, are considered as auxiliary physiological context for arousal and engagement, and not as direct markers of awareness. Because the most mature evidence for covert awareness and cognitive-motor dissociation comes from acquired disorders of consciousness, this review treats brain injury literature as a methodological foundation instead of as directly interchangeable evidence for neurodegenerative disease. It then examines how these approaches may be adapted to neurodegenerative contexts, especially ALS, severe dementia, Lewy body disease with fluctuating cognition, and conditions in which communication or motor output becomes unreliable. Full article

Background/Objectives: Dementia is a progressive, multifactorial neurodegenerative syndrome that poses a major public health challenge, with an increasing number of cases due to an aging population. Vitamin D (vitD) is crucial not only for bone and calcium homeostasis, but also as a neuroactive steroid that influences brain functions such as neurotransmission, neuroprotection and immunomodulation. Emerging evidence suggests that vitD deficiency may be a modifiable risk factor for the development of dementia. Thus, the aim of this review is to understand the possible role of vitD as a modifiable risk factor in the prevention of dementia. Methods: Research was conducted in the PubMed and Scopus databases using combinations of the MeSH terms ‘calcitriol’, ‘dementia’, ‘vitamin D receptors’, and ‘brain function’ for articles from 2014 until 2026. Results: The analysis of the 30 articles retrieved exhibited a significant association between vitD deficiency and an increased risk of dementia. Longitudinal studies and meta-analyses have indicated an increased risk of dementia and Alzheimer’s disease proportional to the severity of the deficit. A significant association with vascular dementia was also highlighted, with the risk increasing synergistically in the presence of hypertension. Conclusions: The evidence reviewed suggests that both vitD deficiency and insufficiency are strongly associated with increased risk of dementia, particularly Alzheimer’s disease and vascular dementia. Addressing vitD deficiency by maintaining adequate levels is proposed as a potentially effective preventive strategy against cognitive decline and dementia. Full article

Background/Objectives: Constructional apraxia (CA) is an impairment in combining simple elements into coherent spatial configurations without basic motor deficits. Although common in neurodegenerative disorders, the qualitative features of visuo-constructional errors and their role in differentiating dementia types remain unclear. This systematic review aimed to synthesize patterns of visuo-constructional errors in dementia and mild cognitive impairment (MCI), exploring distinctive qualitative features associated with different neurodegenerative conditions. Methods: A systematic literature search was conducted in PubMed, Scopus, and Web of Science for studies published between January 1990 and January 2026, following PRISMA guidelines. Studies on adults with dementia or MCI assessing drawing/copying abilities through standardized tasks and qualitative error analysis were included. Reviews, meta-analyses, case reports, non-English articles, and studies not explicitly assessing constructional apraxia were excluded. The quality of evidence was assessed using an adapted version of the Newcastle–Ottawa Scale. Results: A total of 25 studies were included, showing heterogeneous and condition-specific visuo-constructional deficits. Spatial errors and simplifications were the most common across disorders, while perseverations, rotations, and closing-in phenomena were less frequent. Alzheimer’s disease was mainly associated with spatial disorganization, omissions, and conceptual errors linked to temporo-parietal dysfunction; frontotemporal dementia with executive deficits such as perseverations and planning impairments; Lewy body and Parkinson’s disease dementias with visuospatial and attentional alterations; and Huntington’s disease with simplifications and executive dysfunction related to fronto-striatal involvement. Conclusions: No single error pattern was pathognomonic, but qualitative assessment of constructional errors may provide clinically useful information when integrated with the broader neuropsychological profile. Full article

α-Synuclein (α-Syn) is a key presynaptic protein, primarily known for its role in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, including dementia with Lewy bodies (DLB). Although much of the research has focused on the nigrostriatal dopamine (DA) pathway, there is growing recognition that the accumulation of misfolded α-Syn in the prefrontal cortex (PFC) is a critical driver of non-motor symptoms and cognitive deficits in PD and DLB. This review examines the dual role of α-Syn in the PFC circuitry, initially exploring its regulation of synaptic vesicle (SV) dynamics and recycling to maintain stable neurotransmission. We highlight its contribution to the modulation of glutamatergic (Glu) and GABAergic (γ-aminobutyric acid, GABA) synapses, which ensures the functional excitatory/inhibitory (E/I) balance of prefrontal circuits. Conversely, in PD and DLB, the transition of functional α-Syn monomers to pathological oligomers triggers a cascade of synaptic failures. We analyze how α-Syn aggregation causes pathology in dendritic spines, leads to a progressive reduction in the density of synaptic markers, and impairs cortical plasticity. Synthesizing evidence from neuroimaging studies, post-mortem human cortical samples, and animal models, this review emphasizes the PFC as a vulnerable brain region where α-Syn-mediated synaptic dysfunction translates into cognitive and emotional deficits. Deciphering these early synaptic alterations is essential for developing neuroprotective strategies that preserve cortical function in PD and DLB. Full article

Introduction: The significant impact of attention deficit/hyperactivity disorder (ADHD) on health in adult life has been widely recognized. Among the comorbidities of this disorder in later life, dementia is one of the most relevant ones. We performed a systematic review and meta-analysis to explore the impact of previous ADHD diagnosis on dementia risk. Materials and methods: We systematically searched Pubmed, Embase and Scopus for the relevant literature. Cohort and case–control studies were included in our review. Retrieved records were selected by title and abstract and then by full text reading. For quality appraisal, the Newcastle–Ottawa scale was used. A meta-analysis of hazard ratios (HRs) was performed for each type of dementia. Results: Four cohort studies and one case–control study were included, for a total of 3,703,877 and 400 participants, respectively. For all-cause dementia, the pooled HR was 2.52 (95%CI 1.51–4.22, p < 0.001), pointing out a significantly higher hazard in subjects with ADHD. For Alzheimer’s disease, vascular dementia and Lewy body dementia, no meta-analysis was performed due to the low number of available studies. Discussion and conclusions: Our results support a significant association between ADHD and risk of dementia. The results regarding specific types of dementia are more challenging to interpret and could have been influenced by sample size issues. These findings show that ADHD deserves attention in future research on cognitive disorders of the elderly; in particular, more studies are needed to reveal if a true causal relationship links ADHD and dementia. Full article

The hallmarks of allergic diseases are Type 2 immunity, including IL-4 and IL-13 production, IgE antibody generation, mast cell and basophil activation, histamine release, and eosinophil activation. There are many routes by which such mediators can influence CNS biology, including cytokine entry or signaling via brain barrier receptors; leukocyte trafficking across activated barriers; cytokine signaling via circumventricular organ sites or dural immune compartments; vagus nerve afferent signaling; mast cell degranulation; and histamine neuromodulation. Neuroinflammation is a common hallmark of many neurodegenerative diseases, but whether and to what degree allergic/type 2 immune biology may be involved depends on the specific disease stage and pathology. Here, we assess studies connecting the roles of IL-4/IL-13 signaling, IgE/mast cell activation, eosinophil-attractive chemokines, and histamines in Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, dementia with Lewy bodies, Huntington’s disease, prion disease, and tauopathy/atypical parkinsonism. Mechanisms appear most clear in the case of Parkinson’s disease, where epidemiology suggests an important role in dementia/Alzheimer’s disease, while for other neurodegenerative conditions the evidence is less compelling and may be either mechanistic or modulatory. Confounding issues include sex differences, drug exposures, comorbid conditions, socioeconomic factors, and coexisting inflammatory diseases. Finally, we suggest a strategy based on longitudinal immune phenotyping, CNS biomarkers, and pathway manipulation to assess the relationship between allergic immune signaling and neurodegeneration. 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

Psychotic symptoms, including delusions and hallucinations, frequently complicate the course of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and frontotemporal dementia (FTD). Their presence accelerates decline, worsens outcomes, and complicates management. Cognitive screening in such patients is essential yet challenging due to attentional fluctuation, impaired insight, and diagnostic overlap. Addenbrooke’s Cognitive Examination III (ACE-III) is a multidomain tool with higher sensitivity than the MMSE. Evidence indicates that ACE-III captures disorder-specific cognitive-psychotic profiles: memory impairment in AD with delusions of theft, visuospatial and attentional deficits in DLB with hallucinations, or executive dysfunction in FTD with paranoid ideation. Mini-ACE (M-ACE), a shorter derivative, is useful in acute psychiatric or advanced dementia settings. This review synthesizes evidence on ACE-III and M-ACE in psychosis-related neurodegeneration, highlights their role in differentiating from primary psychiatric psychoses, and identifies knowledge gaps, particularly in atypical AD variants, mixed dementia, and autosomal dominant AD. ACE-III emerges as a practical and informative tool, but psychosis-specific normative data and longitudinal studies are needed. Full article

Synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies, are characterized by progressive α-synuclein (α-Syn) aggregation accompanied by chronic neuroinflammatory changes. However, the mechanistic relationship between disrupted proteostasis and inflammatory signaling remains incompletely defined and may vary across disease stages and clinical subtypes. Lysophospholipids (LPLs) are bioactive lipids derived from membrane phospholipids that participate in diverse cellular processes. These functions are primarily mediated through G protein-coupled receptor (GPCR) signaling, but may also involve direct effects on membrane organization and biophysical properties. In addition to receptor-mediated pathways, the surrounding lipid environment may influence protein behavior, although its role in neurodegenerative processes remains to be fully elucidated. Within this framework, LPLs can be considered not only as signaling molecules but also as modulators of the cellular environment in which proteostasis and inflammatory responses occur. In this review, we adopt a lipid-centered perspective in which LPLs occupy an interface between lipid signaling, protein aggregation, and neuroinflammation. Rather than acting as a single initiating factor, altered lipid metabolism is likely to contribute through multiple interconnected pathways. Although current evidence is largely derived from preclinical studies, it supports a role for lipid-related mechanisms, particularly in early stages of synucleinopathy. Full article

Vascular dementia (VaD) is a type of dementia caused by cerebrovascular factors, which can arise from both ischemic cerebrovascular disease and hemorrhagic cerebrovascular disease. The incidence rate of VaD is second only to Alzheimer’s disease and dementia with Lewy bodies. Currently, there are no effective drugs specifically targeting VaD, making the discovery of new therapeutic targets of great significance. This article provides an overview of the research progress on VaD, with a focus on elucidating its pathogenesis, aiming to identify targets that play a regulatory role in the mechanism. Finally, our attention is drawn to the transcription factor E2F1. Through research, it has been found that E2F1 is involved in biological processes such as cell cycle regulation and apoptosis and plays a certain role in neurodegenerative diseases and ischemic encephalopathy. It also participates in the pathogenesis of vascular dementia, suggesting that E2F1 is a key regulatory molecule for VaD and may become a potential pharmacological therapeutic target, which warrants further in-depth research. Full article