Search Results (63)

Background and Clinical Significance: Giant sphenoid wing meningiomas are generally viewed as skull base masses that compress frontal centers and their respective pathways gradually enough to cause a dysexecutive–apathetic syndrome, which can mimic primary neurodegenerative disease. The aim of this report is to illustrate how bedside phenotyping and multimodal imaging can disclose similar clinical presentations as surgically treatable network lesions. Case Presentation: An independent, right-handed older female developed an incremental, two-year decline of her ability to perform executive functions, extreme apathy, lack of instrumental functioning, and a frontal-based gait disturbance, culminating in a first generalized seizure and a newly acquired left-sided upper extremity pyramidal sign. Standardized neuropsychological evaluation revealed a predominant frontal-based dysexecutive profile with intact core language skills, similar to behavioral-variant frontotemporal dementia (bvFTD). MRI demonstrated a large, right fronto-temporo-basal extra-axial tumor attached to the sphenoid wing with homogeneous postcontrast enhancement, significant vasogenic edema within the frontal projection pathways, and a marked midline displacement of structures with an open venous pathway. With the use of a skull-base flattening pterional craniotomy with early devascularization followed by staged internal debulking, arachnoid preserving dissection, and conservative venous preservation, the surgeon accomplished a Simpson Grade I resection. Sequential improvements in the patient’s frontal “re-awakening” were demonstrated through postoperative improvements on standardized stroke, cognitive and functional assessment scales that correlated well with persistent decompression and symmetric ventricles on follow-up images. Conclusions: This case illustrates the possibility of a non-dominant sphenoid wing meningioma resulting in a pseudo-degenerative frontal syndrome and its potential for reversal if recognized as a network lesion and treated with tailored, venous-sparing skull-base surgery. Contrast-enhanced imaging and routine frontal testing in atypical “dementia” presentations may aid in identifying additional patients with potentially surgically remediable cases. Full article

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G₄C₂ repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G₄C₂ repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD. Full article

Objective: Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome characterized by impaired motor speech planning and programming, whereas behavioral variant frontotemporal dementia (bvFTD) is characterized by deviant behavioral (e.g., personality and social) features. Clinical and anatomic characteristics of bvFTD in the context of PAOS are understudied. Methods: We identified 12 participants with PAOS and features that were consistent with bvFTD at baseline or follow-up. Eleven completed a head MRI scan. We compared clinical features and anatomical patterns of atrophy in these 11 PAOS-bvFTD participants to 11 matched PAOS participants without bvFTD and 22 age- and sex-matched healthy controls. Statistical Parametric Mapping (SPM) was applied to visualize gray matter volume across both groups compared to controls and each other. Medians and 25th and 75th percentiles were assessed in patients and across groups; Fisher’s Exact Test and Mann–Whitney U tests were applied using BlueSky software, version 10.3.1-Pro. Results: As expected, PAOS-bvFTD participants performed worse on the Frontal Behavioral Inventory (median: 33/72 vs. 10/72), 20-item behavioral assessment scale (4.5/20 vs. 1.0/20), and the Neuropsychiatry inventory (4/36 vs. 1.5/36) compared to the PAOS group (p < 0.01 for all), with no differences in other demographic, neurological, or language tests. Seven of the eleven PAOS-bvFTD participants had bvFTD features develop within three years of symptom onset. The PAOS-bvFTD and PAOS groups showed volume loss in frontal lobe regions compared to controls, with PAOS-bvFTD participants having more prefrontal volume loss than PAOS participants. Conclusions: Behavioral features consistent with bvFTD can co-occur in patients with PAOS and are related to greater atrophy of the prefrontal cortex. Full article

Sleep disturbances are increasingly recognized as early and clinically meaningful features in the pathophysiology of neurodegenerative diseases. Polysomnography (PSG), i.e., the gold standard for objectively characterizing sleep architecture, may provide non-invasive and scalable biomarkers for both early detection and differential diagnosis of dementia. This systematic review and network meta-analysis aims to synthesize existing evidence on PSG-derived sleep alterations across the neurodegenerative continuum, including subjective cognitive impairment, mild cognitive impairment, Alzheimer’s disease, frontotemporal dementia, Lewy body dementia, and Parkinson’s disease dementia, compared to healthy controls. It will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for reporting systematic reviews that include network meta-analyses, and it has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420251114418. We will include peer-reviewed studies with nocturnal PSG data from adult participants, categorized using validated diagnostic criteria, and scored according to the most recent American Academy of Sleep Medicine guidelines. Both pairwise and network meta-analyses will be conducted using standardized mean differences to quantify group-level effects. Additional analyses will explore the correlations between PSG parameters, severity of cognitive impairment, behavioral symptoms, treatments, and relevant comorbidities. Longitudinal data, where available, will be analyzed separately to evaluate prognostic value. This study will provide a comprehensive synthesis of PSG alterations across neurodegenerative disorders, offering insights into their diagnostic utility and potential as early markers for stratification in clinical trials of disease-modifying therapies. Full article

The diagnosis of behavioral variant of frontotemporal dementia (bvFTD)—a common cause of early-onset dementia—remains challenging due to a lack of determined biomarkers. 18F-fluorodeoxyglucose-positron emission tomography (FDG–PET) scan detects early glucose metabolism alterations in specific brain regions. The detection of distinct hypometabolic patterns in early stages of bvFTD has established FDG–PET as an indispensable adjunctive diagnostic tool in inconclusive cases, as well as in distinguishing between different types of dementia. Moreover, its role in the differential diagnosis of the often overlapping bvFTD and primary psychiatric disorders (PPD) is being studied by exploring disease-specific hypometabolic areas. Finally, the identification of early metabolic alterations and even earlier alterations in distinct metabolic brain networks may assist the diagnosis of presymptomatic carriers of disease-related gene mutations and lead to the development of novel biomarkers. The aim of our review is to underscore the role of FDG–PET as an approved yet promising tool that may lead to a new era in the diagnosis of bvFTD by establishing novel biomarkers and integrating AI as an assistant modality to inform diagnosis and decision-making. Full article

Dementia is a growing problem of global relevance, currently affecting over 55 million people worldwide. The number of new dementia cases is still increasing, primarily due to the aging of society. Dementia is defined as a substantial decline in cognitive function, and it is inherently associated with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, frontotemporal dementia, and vascular dementia. Of note, most patients suffering from neurodegenerative conditions, in addition to cognitive impairment, often experience various types of sleep disorders, including insomnia, rapid eye movement sleep behavior disorder, sleep-disordered breathing, and circadian rhythm disturbances. There is increasing evidence of a bidirectional interaction between sleep disturbances and mental health. Disrupted sleep may directly aggravate neuropsychiatric symptoms, like depression, anxiety, agitation, and hallucinations, and conversely, such symptoms can make sleeping more difficult. This creates a feedback loop that inevitably leads to disease progression and deterioration in quality of life. In this review, we provide an up-to-date overview of the nature and mechanisms behind sleep disorders in major neurodegenerative diseases, summarize treatment strategies for handling sleep disturbances, and discuss the clinical relevance of sleep–mental health interactions in the context of neurodegeneration-associated dementia. Neurodegeneration is a complex problem on the border between neurology and psychiatry, and it poses a challenge to the healthcare system, as it requires multidisciplinary approaches for optimal management. Understanding the connection between sleep and neuropsychiatric symptoms offers further opportunities for better symptom control, improved quality of life, and slower cognitive decline. Full article

Background and objectives: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder with autosomal dominant forms most often linked to MAPT, GRN, and C9orf72. We aimed to evaluate the prevalence of pathogenic variants in these genes in a hospital-based cohort of FTD patients assessed at a tertiary referral center in southeastern Serbia. Methods: We studied 58 consecutive patients with FTD spectrum syndromes evaluated at a tertiary referral center. All underwent standardized neurological, neuropsychological, and imaging assessments, and family history was recorded. Genetic testing included validated assays for C9orf72 repeat expansions and next-generation sequencing of MAPT and GRN. Results: Women comprised 53.45% of the cohort. The mean age was 67.88 years, with mean onset at 61.70 years. Behavioral variant FTD predominated (75.87%), while language forms were less frequent. Positive family history was present in 16 patients (27.59%). Pathogenic variants were identified in three individuals (5.17%): two unrelated carriers of the intronic MAPT mutation c.1920+16C>T and one patient with a C9orf72 expansion. No GRN variants were detected. Mutation frequency was 18.75% in familial cases, while none were found among sporadic patients (p = 0.018). Four of nine relatives were asymptomatic MAPT mutation carriers. Conclusions: This first genetic study of FTD in southeastern Serbia revealed a lower mutation frequency than in Northern and Western Europe, but similar to cohorts from Southeastern Europe. The detection of MAPT c.1920+16C>T in two unrelated families extends the geographic range of this splice-site variant and underscores the importance of systematic genetic testing and larger collaborative studies in the Balkans. Full article

Background/Objectives: Behavioral variant frontotemporal dementia (bvFTD), the most prevalent clinical subtype within the frontotemporal lobar degeneration spectrum disorders, is characterized by early and prominent changes that significantly disrupt everyday functioning. This study aims to identify the key correlates of functional status in bvFTD by investigating the relative contributions of cognitive deficits, behavioral disturbances, personality changes, and brain perfusion abnormalities. Additionally, it seeks to develop a theoretical framework to elucidate how these factors may interconnect and shape unique functional profiles. Methods: A total of 26 individuals diagnosed with bvFTD were recruited from the 2nd Neurology Clinic of “AHEPA” University Hospital in Thessaloniki, Greece, and underwent a comprehensive neuropsychological assessment to evaluate their cognitive functions. Behavioral disturbances, personality traits, and functional status were rated using informant-based measures. Regional cerebral blood flow was assessed using Single Photon Emission Computed Tomography (SPECT) imaging to evaluate brain perfusion patterns. Penalized Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was performed to identify the most robust correlates of functional impairment, followed by path analyses using structural equation modeling to explore how these factors may interrelate and contribute to functional disability. Results: The severity of negative behavioral symptoms (e.g., apathy), conscientiousness levels, and performance on neuropsychological measures of semantic verbal fluency, visual attention, visuomotor speed, and global cognition were identified as the strongest correlates of performance in activities of daily living. Neuroimaging analysis revealed hypoperfusion in the right prefrontal (Brodmann area 8) and inferior parietal (Brodmann area 40) cortices as statistically significant neural correlates of functional impairment in bvFTD. Path analyses indicated that reduced brain perfusion was associated with attentional and processing speed deficits, which were further linked to more severe negative behavioral symptoms. These behavioral disturbances were subsequently correlated with declines in global cognition and conscientiousness, which were ultimately associated with poorer daily functioning. Conclusions: Hypoperfusion in key prefrontal and parietal regions, along with the subsequent cognitive and neuropsychiatric manifestations, appears to be associated with the pronounced functional limitations observed in individuals with bvFTD, even in early stages. Understanding the key determinants of the disease can inform the development of more targeted, personalized treatment strategies aimed at mitigating functional deterioration and enhancing the quality of life for affected individuals. Full article

Background/Objectives: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that progressively impairs cognitive, neurological, and behavioral functions, severely affecting quality of life. The current diagnostic process relies on expert interpretation of extensive clinical assessments, often leading to delays that reduce the effectiveness of early interventions. Given the lack of a definitive cure, accelerating and improving diagnosis is critical to slowing disease progression. Electroencephalography (EEG), a widely used non-invasive technique, captures AD-related brain activity alterations, yet extracting meaningful features from EEG signals remains a significant challenge. This study introduces a machine learning (ML)-driven approach to enhance AD diagnosis using EEG data. Methods: EEG recordings from 36 AD patients, 23 Frontotemporal Dementia (FTD) patients, and 29 healthy individuals (HC) were analyzed. EEG signals were processed within the 0.5–45 Hz frequency range using the Welch method to compute the Power Spectral Density (PSD). From both the time-domain signals and the corresponding PSD, a total of 342 statistical and spectral features were extracted. The resulting feature set was then partitioned into training and test datasets while preserving the distribution of class labels. Feature selection was performed on the training set using Spearman and Pearson correlation analyses to identify the most informative features. To enhance classification performance, hyperparameter tuning was conducted using Bayesian optimization. Subsequently, classification was carried out using Support Vector Machines (SVMs) and k-Nearest Neighbors (k-NN) the optimized hyperparameters. Results: The SVM classifier achieved a notable accuracy of 96.01%, outperforming previously reported methods. Conclusions: These results demonstrate the potential of machine learning-based EEG analysis as an effective approach for the early diagnosis of Alzheimer’s Disease, enabling timely clinical intervention and ultimately contributing to improved patient outcomes. Full article

Tau protein plays a pivotal role in maintaining neuronal structure and function through its regulation of microtubule stability and neuronal polarity. Encoded by the MAPT gene, Tau exists in multiple isoforms due to alternative mRNA splicing, with differential expression in the central and peripheral nervous systems. In healthy neurons, tau mRNA is selectively localized and translated in axons, a process tightly regulated by untranslated regions (UTRs) and RNA-binding proteins such as HuD and FMRP. Pathologically, Tau undergoes hyperphosphorylation, misfolding, and aggregation, which contribute to neurodegeneration in a range of disorders collectively known as tauopathies. Alzheimer’s disease (AD) is the most prevalent tauopathy, where abnormal Tau accumulation in the temporal and frontal lobes correlates with cognitive decline and behavioral symptoms. Other tauopathies, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Frontotemporal Dementia with Parkinsonism (FTDP-17), and Pick’s disease, are distinguished by the predominance of specific Tau isoforms (3R or 4R), cellular distribution, and affected brain regions. Notably, astroglial tauopathies highlight the pathological role of Tau accumulation in glial cells, expanding the understanding of neurodegeneration beyond neurons. Despite advances in imaging biomarkers (e.g., Tau-PET) and molecular diagnostics, effective disease-modifying therapies for tauopathies remain elusive. Ongoing research targets Tau through immunotherapies, splicing modulators, kinase inhibitors, and antisense oligonucleotides, aiming to mitigate Tau pathology and its deleterious effects. Understanding the multifaceted roles of Tau in neuronal and glial contexts is critical for developing future therapeutic strategies against tauopathies. Full article

Intrinsically disordered proteins (IDPs), such as tau, beta-amyloid (Aβ), and alpha-synuclein (αSyn), are prone to misfolding, resulting in pathological aggregation and propagation that drive neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease (PD). Misfolded IDPs are prone to aggregate into oligomers and fibrils, exacerbating disease progression by disrupting cellular functions in the central nervous system, triggering neuroinflammation and neurodegeneration. Furthermore, aggregated IDPs exhibit prion-like behavior, acting as seeds that are released into the extracellular space, taken up by neighboring cells, and have a propagating pathology across different regions of the brain. Conventional inhibitors, such as small molecules, peptides, and antibodies, face challenges in stability and blood–brain barrier penetration, limiting their efficacy. In recent years, nanotechnology-based strategies, such as multifunctional nanoplatforms or nanoparticles, have emerged as promising tools to address these challenges. These nanoplatforms leverage tailored designs to prevent or remodel the aggregation of IDPs and reduce associated neurotoxicity. This review discusses recent advances in nanoplatforms designed to target tau, Aβ, and αSyn aggregation, with a focus on their roles in reducing neuroinflammation and neurodegeneration. We examine critical aspects of nanoplatform design, including the choice of material backbone and targeting moieties, which influence interactions with IDPs. We also highlight key mechanisms including the interaction between nanoplatforms and IDPs to inhibit their aggregation, redirect aggregation cascade towards nontoxic, off-pathway species, and disrupt fibrillar structures into soluble forms. We further outline future directions for enhancing IDP clearance, achieving spatiotemporal control, and improving cell-specific targeting. These nanomedicine strategies offer compelling paths forward for developing more effective and targeted therapies for neurodegenerative diseases. Full article

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the most common forms of dementia globally. AD is characterized by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau in the brain, leading to progressive memory loss and cognitive decline, significantly impairing daily life. In contrast, FTD is marked by selective degeneration of the frontal and/or temporal lobes, typically resulting in profound changes in personality and social behavior, speech disorders, and psychiatric symptoms. Numerous studies have found microRNAs (miRNAs)—small, non-coding RNA molecules that regulate gene expression post-transcriptionally—to be dysregulated in AD and FTD. As a result, miRNAs have emerged as promising novel biomarkers for these diseases. This review examines the current understanding of miRNAs in AD and FTD, emphasizing their potential as accessible, noninvasive biomarkers for diagnosing these prevalent neurodegenerative disorders. Full article

Dementia, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), presents critical challenges for correctional systems, particularly as global populations age. AD, affecting 60–80% of dementia cases, primarily impairs memory and cognition in individuals over 65. In contrast, FTD, rarer than AD but not uncommon in those under 65, affects the frontal and temporal brain regions, leading to deficits in social behavior, language, and impulse control, often resulting in antisocial actions and legal consequences. Behavioral variant FTD is especially associated with socially inappropriate and impulsive behaviors due to frontal lobe degeneration. The prevalence of cognitive impairment in incarcerated populations is high, exacerbated by prison environments that compound distress and limited access to specialized healthcare. Studies indicate that up to 11% of United States state prison inmates over the age of 55 exhibit cognitive impairments, often undiagnosed, resulting in punitive rather than rehabilitative responses to symptoms like disinhibition and aggression. Ethical concerns around criminal responsibility for individuals with dementia are increasingly prominent, particularly regarding their ability to comprehend and engage in legal proceedings. The growing elderly prison population necessitates reform in correctional healthcare to include early cognitive assessment, targeted intervention, and tailored post-release programs. Addressing these needs is essential to ensure appropriate treatments, alleviate healthcare demands, and support reintegration for cognitively impaired inmates. Full article

The term frontotemporal dementia (FTD) comprises a group of neurodegenerative disorders characterized by the progressive degeneration of the frontal and temporal lobes of the brain with language impairment and changes in cognitive, behavioral and executive functions, and in some cases motor manifestations. A high proportion of FTD cases are due to genetic mutations and inherited in an autosomal-dominant manner with variable penetrance depending on the implicated gene. Iron is a crucial microelement that is involved in several cellular essential functions in the whole body and plays additional specialized roles in the central nervous system (CNS) mainly through its redox-cycling properties. Such a feature may be harmful under aerobic conditions, since it may lead to the generation of highly reactive hydroxyl radicals. Dysfunctions of iron homeostasis in the CNS are indeed involved in several neurodegenerative disorders, although it is still challenging to determine whether the dyshomeostasis of this essential but harmful metal is a direct cause of neurodegeneration, a contributor factor or simply a consequence of other neurodegenerative mechanisms. Unlike many other neurodegenerative disorders, evidence of the dysfunction in brain iron homeostasis in FTD is still scarce; nonetheless, the recent literature intriguingly suggests its possible involvement. The present review aims to summarize what is currently known about the contribution of iron dyshomeostasis in FTD based on clinical, imaging, histological, biochemical and molecular studies, further suggesting new perspectives and offering new insights for future investigations on this underexplored field of research. Full article

This narrative review explores the current landscape of blood biomarkers in Frontotemporal dementia (FTD). Neurofilament light chain (NfL) may be useful in the differentiation of behavioral variant FTD from primary psychiatric disorders (PPDs) or dementia with Lewy bodies (DLB). In prodromal FTD and presymptomatic mutation carriers (GRN, MAPT, C9orf72), elevated NfL may herald pheno-conversion to full-blown dementia. Baseline NfL correlates with steeper neuroanatomical changes and cognitive, behavioral and functional decline, making NfL promising in monitoring disease progression. Phosphorylated neurofilament heavy chain (pNfH) levels have a potential limited role in the demarcation of the conversion stage to full-blown FTD. Combined NfL and pNfH measurements may allow a wider stage stratification. Total tau levels lack applicability in the framework of FTD. p-tau, on the other hand, is of potential value in the discrimination of FTD from Alzheimer’s dementia. Progranulin concentrations could serve the identification of GRN mutation carriers. Glial fibrillary acidic protein (GFAP) may assist in the differentiation of PPDs from behavioral variant FTD and the detection of GRN mutation carriers (additional research is warranted). Finally, TAR DNA-binding protein-43 (TDP-43) appears to be a promising diagnostic biomarker for FTD. Its potential in distinguishing TDP-43 pathology from other FTD-related pathologies requires further research. Full article