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51 pages, 838 KiB  
Systematic Review
Quality of Assessment Tools for Aphasia: A Systematic Review
by Francescaroberta Panuccio, Giulia Rossi, Anita Di Nuzzo, Ilaria Ruotolo, Giada Cianfriglia, Rachele Simeon, Giovanni Sellitto, Anna Berardi and Giovanni Galeoto
Brain Sci. 2025, 15(3), 271; https://doi.org/10.3390/brainsci15030271 - 3 Mar 2025
Viewed by 49
Abstract
Background/Objectives: Aphasia is a neurological condition affecting the ability to understand and/or express language fluently and accurately, and can occur following stroke, traumatic injuries, or other brain pathologies. The aim of the following study was to provide clinicians and researchers information regarding [...] Read more.
Background/Objectives: Aphasia is a neurological condition affecting the ability to understand and/or express language fluently and accurately, and can occur following stroke, traumatic injuries, or other brain pathologies. The aim of the following study was to provide clinicians and researchers information regarding the existing assessment tools to assess aphasia. Methods: For this Systematic Review, PubMed, CINAHL, Web of Science, and Scopus were searched for articles published up to August 2024. Authors independently identified eligible studies based on predefined inclusion criteria and extracted data. The study quality and risk of bias were assessed using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist. Results: Of the 1278 publications identified and screened, 238 studies fell within the inclusion criteria and were critically reviewed, and 164 assessment tools were found and divided into 8 main domains; the most used tools were the Language Screening Test (LAST), the Stroke and Aphasia Quality of Life Scale-39 (SAQOL-39), the Oxford Cognitive Screen (OCS), and the Token test. Conclusions: This review has emphasized the need for agreement among researchers as to which tool must be studied or adapted to other national contexts to develop universal norms and standards. Full article
(This article belongs to the Section Neurotechnology and Neuroimaging)
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<p>Flowchart of search and screening process.</p>
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23 pages, 1360 KiB  
Systematic Review
Executive Functions Training Improves Language Abilities in Aphasia Rehabilitation: A Systematic Review
by Laura Culicetto, Desirèe Latella, Viviana Lo Buono, Fabio Orecchio, Anna Maria Murdaca, Angelo Quartarone and Silvia Marino
J. Pers. Med. 2025, 15(3), 92; https://doi.org/10.3390/jpm15030092 - 27 Feb 2025
Viewed by 95
Abstract
Background/Objectives: In recent years, the popularity of non-verbal cognitive training for aphasia has increased. Building on evidence that language abilities engage brain areas involved in executive functions (EFs) processing, this review aims to analyze the utility of EFs training alone or combined [...] Read more.
Background/Objectives: In recent years, the popularity of non-verbal cognitive training for aphasia has increased. Building on evidence that language abilities engage brain areas involved in executive functions (EFs) processing, this review aims to analyze the utility of EFs training alone or combined with traditional rehabilitation approaches to improve language abilities in aphasia. Methods: Systematic searches were performed in four databases evaluating studies focusing on the effects of EFs training in language rehabilitation, yielding 185 studies. After reading the full text of the selected studies and applying predefined inclusion criteria, nine studies were included based on pertinence and relevance to the topic. This systematic review has been registered in the Prospective Register of Systematic Reviews (PROSPERO 2024) with the number CRD42024519087. Results: The results of the analyzed studies indicate that various EFs training methods, such as computer-assisted executive control training, Cognitive Flexibility in Aphasia Therapy (CFAT), and the Dr. Neuronowski® program, as well as the combination of transcranial direct current stimulation (tDCS) with EFs training, can lead to improvements in language abilities in people with aphasia. Additionally, EFs training often results in specific effects on treated functions like working memory (near transfer effects) and untreated ones such as spoken sentence comprehension (far transfer effects). Conclusions: Despite the heterogeneity of the treatments and the small simple size of the studies analyzed, preliminary results are promising. Future research should further explore the effectiveness and specific contribution of EFs training to improving language functions in aphasia. Full article
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<p>PRISMA flow chart.</p>
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<p>Shows the Risk of Bias (RoB 2) of studies regarding the main effective EFs training for language deficits in aphasia [<a href="#B70-jpm-15-00092" class="html-bibr">70</a>,<a href="#B71-jpm-15-00092" class="html-bibr">71</a>,<a href="#B72-jpm-15-00092" class="html-bibr">72</a>,<a href="#B73-jpm-15-00092" class="html-bibr">73</a>,<a href="#B75-jpm-15-00092" class="html-bibr">75</a>,<a href="#B76-jpm-15-00092" class="html-bibr">76</a>,<a href="#B78-jpm-15-00092" class="html-bibr">78</a>].</p>
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<p>Shows the Risk of Bias (ROBINS-E) of studies regarding the main effective EFs training for language deficits in aphasia [<a href="#B74-jpm-15-00092" class="html-bibr">74</a>,<a href="#B77-jpm-15-00092" class="html-bibr">77</a>].</p>
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24 pages, 4175 KiB  
Review
Primary Progressive Aphasias: Diagnosis and Treatment
by Genaro Gabriel Ortiz, Héctor González-Usigli, Erick R. Nava-Escobar, Javier Ramírez-Jirano, Mario Alberto Mireles-Ramírez, Maribel Orozco-Barajas, Luis E. Becerra-Solano and Víctor J. Sánchez-González
Brain Sci. 2025, 15(3), 245; https://doi.org/10.3390/brainsci15030245 - 25 Feb 2025
Viewed by 196
Abstract
Background and Objective: Primary Progressive Aphasias (PPAs) are rare neurodegenerative disorders classified within frontotemporal lobar degeneration (FTLD) and typically manifest between 45 and 70 years of age. In Mexico—and many other countries—reliable epidemiological data are lacking; however, estimates suggest that PPA accounts for [...] Read more.
Background and Objective: Primary Progressive Aphasias (PPAs) are rare neurodegenerative disorders classified within frontotemporal lobar degeneration (FTLD) and typically manifest between 45 and 70 years of age. In Mexico—and many other countries—reliable epidemiological data are lacking; however, estimates suggest that PPA accounts for 0.5–2.5% of neurodegenerative disease cases in Memory Clinics, with an incidence of approximately 1 per 100,000 and an average survival of 8 years. This review aims to provide clinicians with an overview of PPA’s epidemiology, clinical features, and classification, thereby enhancing understanding of its subtypes and distinguishing characteristics from other aphasic conditions, such as vascular aphasia. Methods: This narrative review was conducted through a literature search using databases such as PubMed and Scopus. Relevant studies addressing the epidemiology, clinical presentation, and classification of PPA were identified, selected, and synthesized to offer a broad, clinically oriented overview of the condition. This approach was chosen to inform clinical practice and highlight the need for further targeted investigations, such as future systematic reviews focusing on specific aspects like therapeutic strategies. Key Contents and Findings: (a) Epidemiology: PPA is estimated to affect 0.5–2.5% of patients with neurodegenerative diseases in Memory Clinics, with an incidence of roughly 1 per 100,000. Average survival time is around 8 years (ranging from 3 to 17 years), with a generally balanced gender ratio, though some studies indicate a predominance of men. A positive family history is observed in 20–40% of cases, with about 10% following an autosomal dominant inheritance pattern. (b) Clinical Characteristics and Classification: PPA is marked by a gradual decline in language abilities, differentiating it from vascular aphasias. Subtypes include non-fluent forms (non-fluent progressive aphasia [nfPPA] and logopenic progressive aphasia [lPPA]), fluent forms (progressive fluent aphasia [PFA] and semantic dementia [SD]), and mixed forms (progressive mixed aphasia [PMA]). The neurodegenerative process in PPA extends beyond vascular boundaries, often resulting in presentations that deviate from classical Broca’s and Wernicke’s aphasias. Common symptoms include difficulties in word finding and naming, sometimes mistaken for memory loss, and, in the case of semantic dementia, personality changes that may go unnoticed by the patient. Conclusions: PPA is a heterogeneous and complex group of neurodegenerative disorders with significant clinical variability and a profound impact on patients and their families. While current epidemiological data are limited, this review emphasizes the need for further research to better delineate disease progression and refine diagnostic and therapeutic approaches. Future systematic reviews will be essential to address specific aspects of PPA, such as treatment strategies, to further improve patient care. Full article
(This article belongs to the Section Neurodegenerative Diseases)
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<p>Characteristics of TDP-43, ubiquitination and phosphorylation process and its pathological inclusions. Created in BioRender.</p>
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<p>The main neuroimaging studies are MRI and SPECT, with predominant damage in the left lobe and bilaterally. Created in BioRender.</p>
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<p>Speech fluency criteria for the diagnosis of PPA. Created in BioRender.</p>
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<p>(<b>A</b>) Differences between agrammatism and apraxia. (<b>B</b>) Main clinical evaluations to analyze alterations in executive functions and working memory. (<b>C</b>) Differences in the evaluation of agrammatic criteria in nfPPA. Created in BioRender.</p>
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<p>(<b>A</b>) MMSE testing in patients with PPA and AD. (<b>B</b>) Differences in fluency tests. (<b>C</b>) Characteristics of switching and clustering. Created in BioRender.</p>
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<p>Different treatments in patients with PPA. Created in BioRender.</p>
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<p>Factors to classify PPA cases using different criteria [<a href="#B49-brainsci-15-00245" class="html-bibr">49</a>,<a href="#B65-brainsci-15-00245" class="html-bibr">65</a>]. Created in BioRender.</p>
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<p>Characteristics of the differential diagnosis of patients in AD and PPA. Created in BioRender. Torres, D. (2024).</p>
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10 pages, 5842 KiB  
Case Report
Frontal Variant Alzheimer’s Disease or Primary Psychiatric Disorder? A Case Report
by Siew Fai Liew and Weishan Li
Reports 2025, 8(1), 24; https://doi.org/10.3390/reports8010024 - 18 Feb 2025
Viewed by 270
Abstract
Background and Clinical Significance: In our case study, the patient experienced approximately a year-long delay in her diagnosis, where her initial diagnosis was mistakenly a primary psychiatric disorder, resulting in undue stress on her family. The aim of this case study is [...] Read more.
Background and Clinical Significance: In our case study, the patient experienced approximately a year-long delay in her diagnosis, where her initial diagnosis was mistakenly a primary psychiatric disorder, resulting in undue stress on her family. The aim of this case study is to raise awareness of frontal variant Alzheimer’s dementia (fvAD) and to increase knowledge amongst clinicians about this disorder, its management and the need for long-term follow up in specialized clinics. Case Presentation: In January 2023, a 56-year-old woman first presented with a 4-month history of worsening cognitive symptoms with considerable overlapping mood symptoms. Her Mini-Mental State Examination (MMSE) score was 20/28, whereas her Frontal Assessment Battery (FAB) score was 6/18. Upon neuropsychological evaluation, she demonstrated multidomain cognitive deficits, where impairments were most prominent in executive dysfunction, learning, memory and semantic fluency. There was evidence of progressive neurodegenerative changes, with brain MRI (April 2024) showing predominant bilateral frontal and parietal volume loss, sparing the occipital and temporal lobes. Amyloid positron emission tomography (PET) was diffusely positive. A diagnosis of fvAD (frontal variant Alzheimer’s dementia) with BPSD was made. Other differential diagnoses included a major neurocognitive disorder due to multiple etiologies (AD and dementia with Lewy bodies (DLB)), frontotemporal dementia (bvFTD), primary progressive aphasia (PPA) and the psychiatric disorder of pseudodementia secondary to a mood disorder. Conclusions: This case presented significant challenges given the atypical neuropsychological profile and the complexity of the symptom presentation with significant neuropsychiatric overlay. The preliminary research findings underscore the complexity of fvAD, warranting future research using fundamental approaches. Full article
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<p>The EEG showed intermittent slow, regional, independent results in the left and right temporal regions, as well as intermittent, generalized, slow, results which suggests bilateral temporal cortical electrophysiological dysfunction and mild diffuse encephalopathy, respectively. The overall EEG features were non-specific in nature.</p>
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<p>(<b>a</b>–<b>c</b>): MRI FLAIR sequence (from left to right): (<b>a</b>) significant symmetrical gyral thinning in frontal and parietal lobes; (<b>b</b>) significant symmetrical gyral thinning in frontal lobes, mostly sparing the occipital lobes; (<b>c</b>) reasonably preserved hippocampal volumes bilaterally.</p>
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<p>Amyloid PET scan. (<b>a</b>) Radiotracer uptake detected in bilateral frontal and parietal lobes; (<b>b</b>) radiotracer uptake detected in bilateral temporal lobes.</p>
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<p>Timeline of presentation.</p>
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10 pages, 627 KiB  
Article
Clinical and Epidemiological Characteristics of Patients with Functional Stroke Mimics: A Case–Control Study from Southern Portugal
by Miguel Domingos, Vítor Hugo Silva, Sara Schuh, Helena Correia, Pedro Palma, João Pedroso Pedro, Bruno Vila Nova, Ana Marreiros, Ana Catarina Félix and Hipólito Nzwalo
Brain Sci. 2025, 15(2), 163; https://doi.org/10.3390/brainsci15020163 - 7 Feb 2025
Viewed by 591
Abstract
Background: Patients with functional neurological disorder presenting as stroke mimics or functional stroke mimics (FSMs) pose significant diagnostic challenges. In the acute phase, especially when patients are present within the therapeutic window for acute reperfusion treatments, a misdiagnosis of FSM can lead to [...] Read more.
Background: Patients with functional neurological disorder presenting as stroke mimics or functional stroke mimics (FSMs) pose significant diagnostic challenges. In the acute phase, especially when patients are present within the therapeutic window for acute reperfusion treatments, a misdiagnosis of FSM can lead to unnecessary and costly interventions. Despite its clinical importance, the literature on the risk factors for FSM is limited. This study aims to compare the clinical and epidemiological characteristics of patients with FSM to those with confirmed acute ischemic stroke (AIS). Methods: This case–control study involved temporal matching between consecutive series of patients with FSM and controls with AIS from a single tertiary university hospital in southern Portugal. Results: A total of 188 patients were included: 64 cases (FSM) and 188 controls (AIS). The rate of stroke code activation and use of ambulance between was comparable between the two groups. The group of patients with FSM was younger (53.2 years vs. 69.5 years, p < 0.001) and had a higher proportion of females (52.4% vs. 47.6%, p = 0.001). There was no difference in terms of clinical severity at presentation. The proportion of specific signs, such as transcortical aphasia (3.1% vs. 20.9%, p = 0.014), gait abnormalities (15.6% vs. 33.9%, p = 0.004), and cranial nerve abnormalities (31.2% vs. 43.5%, p = 0.042), was lower in the FSM group compared to the AIS group. The proportion of patients on antithrombotic therapy (90.9% vs. 9.1%, p = 0.007) and antihypertensive drugs (78.5%, vs. 21.5%, p < 0.001) prior to the event was significantly higher in the AIS group. Likewise, the prevalence of cerebrovascular risk factors such as diabetes mellitus (14.3% vs. 85.7%, p = 0.005), arterial hypertension (23.8% vs. 76.2%, p = 0.001), and smoking (43.7% vs. 56.3%, p = 0.005) was lower in the FSM group compared to the AIS group. No statistically significant differences were observed in cholesterol levels or the prevalence of dyslipidemia between the two groups. Psychiatric comorbidities, including generalized anxiety disorder (71.4% vs. 28.6%, p = 0.05) and major depressive disorder (61.9% vs. 28.1%, p = 0.01), were more prevalent in the FSM group. Conclusions: Patients with FSM display different clinical and epidemiological profiles, with a higher likelihood of being younger, female, having prior psychiatric conditions, and lacking traditional cerebrovascular risk factors. Full article
(This article belongs to the Section Neurorehabilitation)
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<p>Comparison of gender and marital status distribution between patients with acute ischemic stroke and functional stroke mimics.</p>
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<p>Comparison of cerebrovascular risk factors distribution between patients with acute ischemic stroke and functional stroke mimics.</p>
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19 pages, 660 KiB  
Systematic Review
Computer- and Smart-Tablet-Based Self-Administered Treatments in Chronic Post-Stroke Aphasia: A Systematic Review
by Célia Ericson, Alisa Latysheva, Sarah-Ève Poirier and Marion Fossard
Brain Sci. 2025, 15(2), 122; https://doi.org/10.3390/brainsci15020122 - 26 Jan 2025
Viewed by 660
Abstract
Background: In current clinical practice, resources remain limited and are insufficient to address the needs of people with chronic post-stroke aphasia. To improve access to speech therapy, self-administered therapies using computers or smart tablets are increasingly recommended. In addition to enabling more intensive [...] Read more.
Background: In current clinical practice, resources remain limited and are insufficient to address the needs of people with chronic post-stroke aphasia. To improve access to speech therapy, self-administered therapies using computers or smart tablets are increasingly recommended. In addition to enabling more intensive and prolonged treatment, computer- and smart-tablet-delivered therapies can be highly enjoyable and motivating for patients. Aims: This systematic review aimed to identify computer- and smart-tablet-based self-administered treatments and analyze the proposed interventions in terms of treatment targets, effectiveness (considering specificity, generalization, transfer, and maintenance), and clinician involvement (during and/or prior self-administered therapies). Methods: Terms encompassing three main concepts (rehabilitation, self-administration, and aphasia) were used to search three electronic databases (Scopus, PubMed, and PsycINFO). Two reviewers independently screened titles and abstracts against eligibility criteria. Data extraction of included studies was completed by three reviewers. Results: Thirty-nine studies were included in this study. In terms of treatment targets, anomia is the most treated symptom in published studies (n = 24), but the existence of promising studies for other disorders means that the targets can be broadened. Therapies are effective for trained items, and gains are maintained. There is some evidence of transfer effects for treatments targeting the sentence level. Most studies offer training sessions, previous self-administered therapy, and/or observation and monitoring sessions during therapy; more rarely, self-administered therapy is supplemented with face-to-face therapy. Conclusions: This systematic review is the first to focus specifically on self-administered technology-based therapies. It provides important evidence-based information for clinical practice in self-administered therapies via computer or smart tablet. Full article
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<p>Flow diagram of the identification and selection records, adapted from the PRISMA flow diagram [<a href="#B32-brainsci-15-00122" class="html-bibr">32</a>].</p>
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<p>Summary of treatment effectiveness for targeted aphasic symptoms. Improvements are highlighted as follows: green for measures showing improvement in all groups or PWA, yellow for partial improvements (some groups or PWA), red for no improvement, and gray for unreported measures. UI, untrained items; ST, standardized tests.</p>
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13 pages, 487 KiB  
Systematic Review
The Functional Origin of Oral Word Production Deficits in the Logopenic Variant of Primary Progressive Aphasia: A Systematic Review
by Amra Hasanovic, Joël Macoir, Amélie Sanfaçon-Verret and Laura Monetta
Brain Sci. 2025, 15(2), 111; https://doi.org/10.3390/brainsci15020111 - 24 Jan 2025
Viewed by 276
Abstract
Background/Objectives: Oral word production (OWP) deficits are prominent in the logopenic variant of primary progressive aphasia (lvPPA); however, their functional origin remains unclear. Some studies suggest a lexical, post-lexical, or even a combined functional origin of these deficits. The aim of the present [...] Read more.
Background/Objectives: Oral word production (OWP) deficits are prominent in the logopenic variant of primary progressive aphasia (lvPPA); however, their functional origin remains unclear. Some studies suggest a lexical, post-lexical, or even a combined functional origin of these deficits. The aim of the present study was to synthesize and analyze the information on the functional origin of the OWP deficits in patients with lvPPA. Methods: A quantitative systematic literature review was carried out using four databases: CINAHL, PsycINFO, Linguistics and Language Behavior Abstracts, and PubMed. Fourteen studies, including a total of 243 patients with lvPPA, and reporting results on picture naming and/or word and/or pseudoword repetition, were selected. Results: The overall findings of this review highlighted that two main functional origins appear to explain the OWP deficits in lvPPA: a lexical impairment affecting lexical processing and a post-lexical impairment affecting phonological short-term memory. Interestingly, the possibility of a third functional origin, affecting the semantic processing level, was also suggested by some studies. Conclusions: We concluded that the presence of different functional origins of OWP in this population may be explained, at least partially, by the diversity of assessment tasks used in studies and the varied manipulation and control of psycholinguistic properties of words (e.g., frequency, length), as well as the various interpretations and analyses of the participants’ errors. Further studies are needed to substantiate these findings by examining all the components involved in OWP, carefully manipulating the psycholinguistic properties and qualitatively analyzing the errors made by lvPPA participants. Full article
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<p>PRISMA flow diagram for study selection.</p>
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18 pages, 1468 KiB  
Article
Eyes on the Pupil Size: Pupillary Response During Sentence Processing in Aphasia
by Christina Sen, Noelle Abbott, Niloofar Akhavan, Carolyn Baker and Tracy Love
Brain Sci. 2025, 15(2), 107; https://doi.org/10.3390/brainsci15020107 - 23 Jan 2025
Viewed by 314
Abstract
Background/Objectives: Individuals with chronic agrammatic aphasia demonstrate real-time sentence processing difficulties at the lexical and structural levels. Research using time-sensitive measures, such as priming and eye-tracking, have associated these difficulties with temporal delays in accessing semantic representations that are needed in real time [...] Read more.
Background/Objectives: Individuals with chronic agrammatic aphasia demonstrate real-time sentence processing difficulties at the lexical and structural levels. Research using time-sensitive measures, such as priming and eye-tracking, have associated these difficulties with temporal delays in accessing semantic representations that are needed in real time during sentence structure building. In this study, we examined the real-time processing effort linked to sentence processing in individuals with aphasia and neurotypical, age-matched control participants as measured through pupil reactivity (i.e., pupillometry). Specifically, we investigated whether a semantically biased lexical cue (i.e., adjective) influences the processing effort while listening to complex noncanonical sentences. Methods: In this eye-tracking while listening study (within-subjects design), participants listened to sentences that either contained biased or unbiased adjectives (e.g., venomous snake vs. voracious snake) while viewing four images, three related to nouns in the sentence and one unrelated, but a plausible match for the unbiased adjective. Pupillary responses were collected every 17 ms throughout the entire sentence. Results: While age-matched controls demonstrated increased pupil response throughout the course of the sentence, individuals with aphasia showed a plateau in pupil response early on in the sentence. Nevertheless, both controls and individuals with aphasia demonstrated reduced processing effort in the biased adjective condition. Conclusions: Individuals with aphasia are sensitive to lexical–semantic cues despite impairments in real-time lexical activation during sentence processing. Full article
(This article belongs to the Collection Collection on Neurobiology of Language)
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<p>Example of the visual world display and a sample experimental sentence.</p>
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<p>An example of the experimental procedure. Each trial would begin with a fixation cross, followed by a blank screen, and then the 2 × 2 image display. Following the onset of the visual display, sentences were presented over headphones while participant eye gaze and pupillary data were collected. At the end of each trial, participants were asked a comprehension question to ensure they were attending to the auditory information.</p>
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<p>Time windows of interest. Time Window 1 includes the whole sentence. Time Window 2 is from the beginning of the sentence until the offset of NP2.</p>
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<p>Time Window 1. Pupil responses throughout the whole sentence for AMC (blue) and IWA (red). Data are indicated by the shaded ribbons and growth curve models are indicated by the solid line.</p>
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<p>Time Window 2. Pupil responses from the beginning of the sentence to the onset of the second noun. AMC data are graphed on the left, IWA data on the right. The biased adjective condition for each group is shown in green, and the unbiased adjective condition is shown in grey. Data are indicated by the shaded ribbons and growth curve models are indicated by the solid line. Dotted lines were manually inserted to demonstrate visual differences in linear fit.</p>
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10 pages, 4613 KiB  
Case Report
Late-Onset HSV-2 Encephalitis in a Kidney Transplant Recipient: A Rare Case Report
by Danijela Zjačić Puljiz, Ivana Vrkić, Ivo Jeličić, Dijana Borić Škaro, Ivana Kristina Delić Jukić, Lučana Vicelić Čutura and Mirela Pavičić Ivelja
Life 2025, 15(2), 152; https://doi.org/10.3390/life15020152 - 22 Jan 2025
Viewed by 310
Abstract
Infections are an important cause of morbidity and mortality in renal transplant recipients. Among the viral pathogens encountered in this population, herpes simplex virus (HSV), a member of the Alphaherpesvirinae subfamily, has an important place. HSV type 2 infections in this immunosuppressed population [...] Read more.
Infections are an important cause of morbidity and mortality in renal transplant recipients. Among the viral pathogens encountered in this population, herpes simplex virus (HSV), a member of the Alphaherpesvirinae subfamily, has an important place. HSV type 2 infections in this immunosuppressed population are primarily due to viral reactivation. While HSV-2 frequently presents as genital herpes or remains asymptomatic, in rare cases, it can lead to severe neurological manifestations, such as encephalitis, particularly in the early post-transplant period with a reported mortality rate of up to 40%. We present the case of a 49-year-old male who, three years after kidney transplantation, developed acute neurological symptoms, including aphasia and disorientation. Polymerase chain reaction (PCR) analysis of cerebrospinal fluid (CSF) identified HSV-2 as the causative pathogen, enabling a swift and accurate diagnosis. The patient was promptly treated with intravenous acyclovir, adjusted for renal function, resulting in complete neurological recovery and subsequent negative follow-up CSF PCR results. This case emphasizes the vital role of PCR diagnostics as the gold standard for confirming viral encephalitis, particularly in immunosuppressed patients, where atypical presentations can complicate diagnosis. It also highlights the importance of considering HSV-2 encephalitis in the differential diagnosis even beyond the immediate post-transplant period. Early recognition and management, facilitated by the multidisciplinary approach, are critical for improving outcomes in this vulnerable patient population. Full article
(This article belongs to the Special Issue Encephalitis: From Molecular Pathophysiology to Therapy)
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<p>MRI; T2 coronal section- cortical atrophic changes.</p>
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<p>FLAIR transverse MRI scan demonstrates prominent perivascular spaces.</p>
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<p>T2-weighted transverse MRI scan reveals enlarged perivascular spaces.</p>
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12 pages, 458 KiB  
Article
The Classification and Language Description of Patients with Primary Progressive Aphasia Using the Mini Linguistic State Examination Test
by Elena Herrera, Claudia Acevedo and María González-Nosti
Geriatrics 2025, 10(1), 2; https://doi.org/10.3390/geriatrics10010002 - 26 Dec 2024
Viewed by 476
Abstract
Introduction. Primary progressive aphasia (PPA) is a clinical syndrome characterized by a progressive deterioration in language and speech. It is classified into three variants based on symptom patterns: logopenic, semantic, and non-fluent. Due to the lack of fully reliable and valid screening tests [...] Read more.
Introduction. Primary progressive aphasia (PPA) is a clinical syndrome characterized by a progressive deterioration in language and speech. It is classified into three variants based on symptom patterns: logopenic, semantic, and non-fluent. Due to the lack of fully reliable and valid screening tests for diagnosing PPA and its variants, a Spanish version of the Mini Linguistic State Examination (MLSE) has recently been introduced. Materials and methods. This study aimed to describe the language impairments in a small sample of six patients with PPA and classify them into the three variants using the decision tree and syndrome guide proposed by the MLSE authors. Results. The findings demonstrate the test’s utility in classifying some PPA variants through a qualitative analysis of patient performance and error types. The study revealed a 50% accuracy rate for the decision tree and an 83.33% accuracy rate when using the syndrome guide. Discussion. This discrepancy arises because the decision tree often classified cases as logopenic variant PPA (lvPPA) when working memory was significantly impaired. Specifically, it tended to misclassify patients with semantic, motor, or speech impairments as having lvPPA due to its reliance on the sentence repetition task for assessing working memory. Full article
(This article belongs to the Section Geriatric Psychiatry and Psychology)
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<p>Decision tree developed by Matias-Guiu et al. (2021) [<a href="#B28-geriatrics-10-00002" class="html-bibr">28</a>]. svPPA—semantic variant PPA; nfvPPA—non-fluent PPA; lvPPA—logopenic variant PPA. HC = healthy control.</p>
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12 pages, 774 KiB  
Review
Multiple Subpial Transection for the Treatment of Landau–Kleffner Syndrome—Review of the Literature
by Piotr Duda, Natalia Duda, Katarzyna Kostelecka, Filip Woliński, Joanna Góra, Michał Granat, Łukasz Bryliński, Barbara Teresińska, Robert Karpiński, Wojciech Czyżewski and Jacek Baj
J. Clin. Med. 2024, 13(24), 7580; https://doi.org/10.3390/jcm13247580 - 13 Dec 2024
Viewed by 505
Abstract
As speech-related symptoms of Landau–Kleffner syndrome (LKS) are often refractory to pharmacotherapy, and resective surgery is rarely available due to the involvement of the vital cortex, multiple subpial transection (MST) was suggested to improve patient outcome and preserve cortical functions. Here, we analyze [...] Read more.
As speech-related symptoms of Landau–Kleffner syndrome (LKS) are often refractory to pharmacotherapy, and resective surgery is rarely available due to the involvement of the vital cortex, multiple subpial transection (MST) was suggested to improve patient outcome and preserve cortical functions. Here, we analyze the reports about MST use in LKS, regarding its impact on seizures, language, behavior, EEG, cognition, and reported adverse effects. In conditions like LKS, surgery is not a popular treatment option and presumably should be considered sooner. Candidates for MST should be selected carefully, optimally with the unilateral onset of epileptic activity. Laterality can be assessed using a methohexital suppression test (MHXT), electrical intracarotid amobarbital test, or magnetoencephalography. After MST, a significant percentage of LKS patients present seizure-free status, normalization of EEG patterns, and rapid behavior improvement. Data comprising language outcomes are mixed, with improvement reported in 23.8–100% of cases, and no superiority was found in the only study comparing MST with a non-surgical group. Cognitive outcomes are not well described. The risk linked to MST is described as low, with cerebral edema and transient neurological deficits being the most common complications. MST successfully improves seizure, EEG, and behavioral outcomes in LKS patients. However, its beneficial impact on language and cognition is not well proven. It is generally a safe neurological operation. Full article
(This article belongs to the Special Issue Advances in Child Neurology)
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<p>Illustration of the subpial transection procedure. The non-transparent transector and non-transparent arrow show the process of inserting the transector into the distal end of gyrus. The semi-transparent transectorshow the process of transecting fibers, and the semi-transparent shows its direction. The figure is based on a paper by Morrell et al. [<a href="#B8-jcm-13-07580" class="html-bibr">8</a>].</p>
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<p>Flowchart illustrating the literature search. The flowchart is based on the PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers, and other sources [<a href="#B10-jcm-13-07580" class="html-bibr">10</a>], modified.</p>
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12 pages, 6688 KiB  
Case Report
Challenging Management of a Rare Complex Cerebral Arteriovenous Malformation in the Corpus Callosum and Post-Central Gyrus: A Case Study of a 41-Year-Old Female
by Corneliu Toader, Felix Mircea Brehar, Mugurel Petrinel Radoi, Razvan Adrian Covache-Busuioc, Matei Serban, Alexandru Vladimir Ciurea and Nicolaie Dobrin
J. Clin. Med. 2024, 13(24), 7494; https://doi.org/10.3390/jcm13247494 - 10 Dec 2024
Viewed by 530
Abstract
Background/Objectives: Cerebral arteriovenous malformations (AVMs) are rare but complex vascular anomalies, particularly challenging when located in eloquent regions such as the corpus callosum and post-central gyrus. This report aims to highlight the management and outcomes of a 41-year-old female patient with a hemorrhagic [...] Read more.
Background/Objectives: Cerebral arteriovenous malformations (AVMs) are rare but complex vascular anomalies, particularly challenging when located in eloquent regions such as the corpus callosum and post-central gyrus. This report aims to highlight the management and outcomes of a 41-year-old female patient with a hemorrhagic AVM in these critical areas, emphasizing the importance of early surgical intervention and advanced imaging techniques. Methods: The patient presented with a right-sided tonic–clonic seizure and expressive aphasia, prompting imaging that revealed a complex AVM with deep venous drainage and arterial supply from the anterior cerebral artery. A multidisciplinary team performed microsurgical resection via a left parasagittal fronto-parietal craniotomy. The surgical approach prioritized hematoma evacuation followed by a stepwise dissection of the AVM nidus under intraoperative monitoring. Results: Complete resection of the AVM was confirmed through postoperative angiographic and CT imaging. The patient showed stable recovery over 15 months, with no recurrence or new neurological deficits. This case demonstrates the critical role of advanced imaging, intraoperative strategies, and a multidisciplinary approach in achieving successful outcomes. Conclusions: Microsurgical resection remains the gold standard for AVMs in eloquent and deep-seated brain regions. Early diagnosis and tailored surgical interventions are crucial for managing these high-risk cases. This case underscores the importance of integrating advanced imaging, strategic surgical planning, and intraoperative monitoring to minimize complications and optimize long-term recovery. Full article
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<p>Four different MRI images from a preoperative scan provide a detailed view of a left fronto-parietal lesion. (<b>A</b>) is an axial T2-weighted view, which presents a horizontal cross-section of the brain, offering a detailed look at the lesion’s involvement in the left fronto-parietal region. (<b>B</b>) is a sagittal T2-weighted view, providing a vertical cross-section of the brain from the side, which highlights the vertical extent of the lesion and its relationship with the ventricular system. (<b>C</b>) is a coronal T2-weighted view, showing a frontal cross-section of the brain, demonstrating the lesion’s depth and impact on the surrounding cortical and subcortical structures. (<b>D</b>) is an axial diffusion-weighted imaging (DWI) view, presenting a horizontal cross-section that emphasizes the diffusion characteristics of the tissue around the lesion, revealing restricted diffusion related to the hemorrhagic event.</p>
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<p>Provides two lateral angiographic views that highlight the vascular structure of the left fronto-parietal AVM. (<b>A</b>) Arterial phase highlights the intricate network of abnormal vessels, with direct arteriovenous shunting. Feeding arteries arise predominantly from branches of the anterior cerebral artery (ACA), with abnormal venous drainage into dilated structures converging on the superior sagittal sinus. (<b>B</b>) Late arterial/early venous phase shows reduced vascular filling, indicating flow dynamics associated with the AVM. These findings correlate with the hemorrhagic event observed on preoperative MRI, providing critical insights for surgical planning.</p>
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<p>This figure presents a preoperative lateral angiographic image that illustrates the arterial phase of a left fronto-parietal AVM. The image reveals an intricate tangle of abnormal vessels typical of an AVM, with feeding arteries originating from branches of the ACA. The absence of a normal capillary bed is evident, and there is prominent arteriovenous shunting. The draining veins are directed toward the superior sagittal sinus, corresponding to the hemorrhagic lesion observed on the preoperative MRI. This angiographic view is crucial in characterizing the AVM and its hemodynamic properties prior to surgical intervention.</p>
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<p>(<b>A</b>) highlights the arterial phase, showing the absence of abnormal arterial feeders from the anterior cerebral artery, which previously supplied the AVM. (<b>B</b>) displays the venous phase, where the normalization of the venous drainage into the superior sagittal sinus is evident, with no abnormal venous structures visible. (<b>C</b>) demonstrates the delayed phase, confirming that no residual AVM or abnormal vascular connections remain postoperatively. This angiographic follow-up provides definitive evidence of successful AVM resection, with no complications or residual vascular abnormalities noted.</p>
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<p>This figure presents three axial CT images taken at the 3-month follow-up, evaluating the patient’s postoperative condition following the excision of a left fronto-parietal AVM. (<b>A</b>): Axial CT image demonstrating normal postoperative parenchymal appearance in the left fronto-parietal region, with no evidence of residual AVM, hemorrhage, or ischemic changes. (<b>B</b>): Axial CT image focusing on the soft tissue and adjacent brain structures, confirming the absence of edema or any abnormal enhancement around the surgical site. (<b>C</b>): Bone window CT image evaluating the integrity of the bone flap, showing proper placement and no signs of hardware failure, infection, or other complications.</p>
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<p>This figure presents a series of axial, coronal, and sagittal CT images, alongside a bone window, from the 12-month follow-up evaluation post-excision of a left fronto-parietal AVM. (<b>A</b>) Axial view showing the absence of residual AVM or hemorrhagic changes in the left fronto-parietal region, confirming the stability of the surgical site. (<b>B</b>) Coronal view illustrating the preserved brain structures with no signs of edema, recurrence, or new vascular anomalies. (<b>C</b>) Sagittal view highlighting the absence of mass effect or midline shift, with normal postoperative anatomy. (<b>D</b>) Bone window axial view verifying the integrity of the craniotomy site, with no complications such as bone resorption or infection.</p>
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<p>These images together confirm a favorable outcome, with no significant complications observed at the 15-month mark, supporting a good recovery trajectory for the patient. (<b>A</b>) Axial view reveals a stable postoperative site in the left fronto-parietal region, with no signs of residual AVM or recurrent hemorrhage. (<b>B</b>) Coronal view illustrates symmetrical ventricular structures and preserved parenchyma, with no evidence of new lesions or complications. (<b>C</b>) Sagittal view confirms the absence of pathological developments, with normal postoperative anatomy and no mass effect or midline shift.</p>
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49 pages, 2176 KiB  
Systematic Review
Advancing Neuropsychological Rehabilitation in Primary Progressive Aphasia Based on Principles of Cognitive Neuroscience: A Scoping Review and Systematic Analysis of the Data
by Evgenia Gkintoni and Emilia Michou
Brain Sci. 2024, 14(12), 1234; https://doi.org/10.3390/brainsci14121234 - 8 Dec 2024
Viewed by 865
Abstract
Background/Objectives: This systematic review of neuropsychological rehabilitation strategies for primary progressive aphasia will consider recent developments in cognitive neuroscience, especially neuroimaging techniques such as EEG and fMRI, to outline how these tools might be integrated into clinical practice to maximize treatment outcomes. Methods: [...] Read more.
Background/Objectives: This systematic review of neuropsychological rehabilitation strategies for primary progressive aphasia will consider recent developments in cognitive neuroscience, especially neuroimaging techniques such as EEG and fMRI, to outline how these tools might be integrated into clinical practice to maximize treatment outcomes. Methods: A systematic search of peer-reviewed literature from the last decade was performed following the PRISMA guidelines across multiple databases. A total of 63 studies were included, guided by predefined inclusion and exclusion criteria, with a focus on cognitive and language rehabilitation in PPA, interventions guided by neuroimaging, and mechanisms of neuroplasticity. Results: Integration of neuroimaging techniques contributes to the increase in the efficacy of interventions with critical information about the neural mechanisms underlying language deficits in the aphasias. Traditional rehabilitation strategies, technology-assisted interventions, and non-invasive brain stimulation techniques hold considerable promise for language improvement. Neuroimaging was also found to be necessary in subtype-specific differentiation toward tailoring therapeutic intervention. Evidence also shows that directed and sustained interventions using neuroplasticity can have long-term effects in managing the symptoms of PPA. Conclusions: The present review underlines the necessity of including cognitive neuroscience techniques within neuropsychological rehabilitation to enhance therapeutic outcomes in PPA. In addition, neuroimaging modalities such as EEG and fMRI are also of great importance in understanding the underlying neurobiology of language disturbances and guiding tailored interventions. Long-term benefits of these approaches should be evaluated, including their applicability in routine clinical practice. Full article
(This article belongs to the Section Behavioral Neuroscience)
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<p>Flowchart of PRISMA methodology.</p>
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<p>Heat map of brain regions affected by PPA variants.</p>
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<p>Trend line of intervention effectiveness in PPA rehabilitation.</p>
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<p>Venn diagram of PPA rehabilitation approaches.</p>
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Case Report
Impact of COVID-19 Pandemic-Related Restrictions for Inpatients with Aphasia and Associated Cognitive Dysfunction: Lessons Learned from Patient Detention
by Edwin Eshun, Killian Welch, Hannah Britton, Victoria Mayer, Fay Morrice, Charlotte Ogilvie, Helen Page, Jessie Pridmore and Alasdair FitzGerald
COVID 2024, 4(12), 1951-1959; https://doi.org/10.3390/covid4120137 - 4 Dec 2024
Viewed by 691
Abstract
We describe two patients with a recent stroke or traumatic brain injury associated with aphasia and cognitive impairment who required detention (under the Mental Health Act) as well as some form of restraint during their inpatient rehabilitation. Each of these episodes of care [...] Read more.
We describe two patients with a recent stroke or traumatic brain injury associated with aphasia and cognitive impairment who required detention (under the Mental Health Act) as well as some form of restraint during their inpatient rehabilitation. Each of these episodes of care occurred early into the COVID-19 pandemic and we speculate that the detention (and restraint) was attributable, at least in part, to the difficulty in comprehending COVID-19-related changes in patterns of staff interaction and the mandated social and visiting restrictions. We reflect on the impact of these restrictions on the need for detention and how these factors could have been mitigated through speech and language therapist (SLT) and broader multidisciplinary team (MDT) intervention. Full article
40 pages, 3642 KiB  
Review
The Underestimated Role of Iron in Frontotemporal Dementia: A Narrative Review
by Sara Ferretti and Isabella Zanella
Int. J. Mol. Sci. 2024, 25(23), 12987; https://doi.org/10.3390/ijms252312987 - 3 Dec 2024
Viewed by 957
Abstract
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 [...] Read more.
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 article belongs to the Section Biochemistry)
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<p>The Fenton reaction is a chemical reaction in which an important role is played by Fe<sup>2+</sup>. Once entered in the cells, redox-active Fe<sup>2+</sup> is trafficked to the sites of utilization or storage as a cytosolic labile iron pool (LIP), probably vehicled by low molecular weight molecules like citrate or by chaperone proteins (see below in the text) to avoid harmful reactions. Fe<sup>2+</sup> and hydrogen peroxide can indeed catalyze the generation of strong oxidizing species, the hydroxyl radicals OH<sup>•</sup>, which are capable of oxidizing a wide variety of organic compounds and biomolecules, like lipids, proteins and nucleic acids, ultimately causing cell death and tissue damage [<a href="#B4-ijms-25-12987" class="html-bibr">4</a>].</p>
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<p>Intestinal iron absorption (<b>left</b>) and iron handling in a generic cell (<b>right</b>). Duodenal enterocytes acquire dietary iron both as inorganic iron and heme iron. At the luminal membrane, inorganic ferric iron (Fe<sup>3+</sup>) is reduced to ferrous iron (Fe<sup>2+</sup>) by the duodenal cytochrome b/cytochrome b reductase (<span class="html-italic">DCYTB/CYBRD1</span>) and transported into the cell by divalent metal transporter 1/solute carrier family 11 member 2 (<span class="html-italic">DMT1/SLC11A2</span>). Heme iron is internalized through the heme carrier protein 1/solute carrier family 46 member 1 (<span class="html-italic">HCP1/SLC46A1</span>) and released in the cytoplasm as Fe<sup>2+</sup> by heme oxygenase 1 (<span class="html-italic">HO1/HMOX1</span>). Enterocytes store iron within ferritin or export iron at the basolateral membrane through ferroportin1/solute carrier family 40 member 1 (<span class="html-italic">FPN1/SLC40A1</span>), whose function is negatively regulated by the master regulator of iron homeostasis hepcidin (<span class="html-italic">HAMP</span>), which is mainly secreted by hepatocytes. Iron released in the extracellular space is then oxidized by hephaestin (<span class="html-italic">HEPH</span>) and loaded onto transferrin (<span class="html-italic">TF</span>), which distributes iron as Fe<sup>3+</sup> to tissues and cells through the circulation. In most cells, holo-<span class="html-italic">TF</span> interacts with the ubiquitous cell surface transferrin receptor (<span class="html-italic">TFRC</span>) and the complex is internalized by endocytosis. Within the endosomes, iron is released by acidification, reduced to Fe<sup>2+</sup> by the six-transmembrane epithelial antigen of prostate 3 (<span class="html-italic">STEAP3</span>) ferrireductase and released in the cytoplasm by the divalent metal transporter 1/solute carrier family 11 member 2 (<span class="html-italic">DMT1/SLC11A2</span>). The apo-<span class="html-italic">TF</span>/<span class="html-italic">TFRC</span> complex is recycled to the cell surface and dissociated; <span class="html-italic">TFRC</span> remains in the membrane for further cycles of iron uptake, while <span class="html-italic">TF</span> is recycled in the circulation. Cytosolic iron is then delivered to the sites of usage or stored within ferritin. Mitochondria are the main site of iron cellular usage. Iron enters mitochondria through <span class="html-italic">DMT1/SLC11A2</span>, mitoferrin 1/solute carrier family 25 member 37 (<span class="html-italic">MFN1/SLC25A37</span>) and mitoferrin 2/solute carrier family 25 member 28 (<span class="html-italic">MFN2/SLC25A28</span>), and it is mainly used for the synthesis of heme and iron sulfur clusters (ISCs). Newly synthesized heme is transferred to mitochondrial heme-containing proteins or transported to the cytosol for transfer to cytosolic heme-containing proteins through the mitochondrial heme transporter feline leukemia virus subgroup C receptor 1b (<span class="html-italic">FLVCR1b).</span> ISCs are assembled partly in the mitochondrion by the mitochondrial ISC assembly machinery and partly in the cytosol by the cytosolic ISC assembly machinery (CIA), which receives ISCs from mitochondria through the ATP binding cassette subfamily B member 7 (<span class="html-italic">ABCB7</span>) transporter. Excess mitochondrial iron is stored in mitochondrial ferritin (<span class="html-italic">FTMT</span>), while excess cytosolic iron is mainly stored in cytosolic ferritin, that may quickly release it for cellular needs through nuclear receptor coactivator 4 (<span class="html-italic">NCOA4</span>)-mediated ferritinophagy or by an autophagy-independent lysosomal pathway. Cellular iron excess may also exit cells through <span class="html-italic">FPN1/SLC40A1</span>, which is coupled with ferroxidase proteins like ceruloplasmin (<span class="html-italic">CP</span>) and <span class="html-italic">HEPH</span>.</p>
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<p>Regulation of iron homeostasis by cellular iron levels (<b>left</b>) and oxidative stress (<b>right</b>). Iron regulatory protein 1/aconitase 1 (<span class="html-italic">IRP1/ACO1</span>) and iron regulatory protein 2/iron responsive element-binding protein 2 (<span class="html-italic">IRP2/IREB2</span>) ubiquitously regulate the transcription of several iron-related genes. In conditions of low cellular iron levels, both proteins recognize and bind RNA structures named iron-responsive elements (IREs) within the 5′- or 3′-untranslated regions (UTRs) of the regulated mRNAs. In this way, the translation of ferritin heavy chain 1 (FTH1), ferritin light chain (FTL) and ferroportin1/solute carrier family 40 member 1 (FPN1/SLC40A1) mRNAs is blocked, while transferrin receptor (TFRC) and divalent metal transporter 1/solute carrier family 11 member 2 (DMT1/SLC11A2) mRNAs are stabilized and translated, thus decreasing cellular iron storage and release and increasing iron uptake. On the contrary, in iron excess conditions, both IRPs release IREs, increasing the translation of FTH1, FTL and FPN1/SLC40A1 mRNAs while decreasing the stability of TFRC and DMT1/SLC11A2 mRNAs; in this way, cellular iron storage and release are increased, while uptake is decreased. Amyloid beta precursor protein (APP) and synuclein alpha (SNCA) genes are also involved in iron homeostasis, the first being a ferroxidase and the second a ferrireductase, and they are both regulated by IRPs, like FTH1, FTL and FPN1/SLC40A1 mRNAs. Some iron-related genes are also regulated by oxidative stress through the sequestosome 1/protein 62/kelch-like ECH associated protein 1/NFE2 like bZIP transcription factor 2 (<span class="html-italic">SQSTM1/p62/KEAP1/NRF2</span>) signaling pathway. Under normal conditions, <span class="html-italic">KEAP1</span> interacts with and directs ubiquitinated <span class="html-italic">NRF2</span> to proteasomal degradation; under oxidative stress conditions, <span class="html-italic">KEAP1</span> releases <span class="html-italic">NRF2</span>, the transcription factor translocates to the nucleus and recognizes specific DNA sequences, the antioxidant responsive elements (AREs), in the promoter region of several genes involved in the antioxidant response, among which include FTH1, FTL, FPN1/SLC40A1 and SQSTM1/p62. <span class="html-italic">SQSTM1/p62</span> also binds and directs <span class="html-italic">KEAP1</span> to autophagic degradation, further activating <span class="html-italic">NRF2</span>-related antioxidant response.</p>
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<p>Iron handling in the brain. Iron entry into the brain is strictly regulated at the blood–brain barrier (BBB) by the polarized endothelial cells (ECs), which is supported by astrocytes. Iron enters ECs through the classical transferrin/transferrin receptor (<span class="html-italic">TF/TFRC</span>) endocytic pathway and is released by divalent metal transporter 1/solute carrier family 11 member 2 (<span class="html-italic">DMT1/SLC11A2</span>) in the cytosol after its reduction by six-transmembrane epithelial antigen of prostate 3 (<span class="html-italic">STEAP3</span>) within endosomes. The apo-<span class="html-italic">TF</span>/<span class="html-italic">TFRC</span> complex is then recycled to the cell surface and dissociated; <span class="html-italic">TFRC</span> remains in the membrane for further cycles of iron uptake, while <span class="html-italic">TF</span> is recycled in the circulation. Alternative routes for iron entry in ECs are the transcytosis of holo-<span class="html-italic">TF</span> from the luminal to the abluminal side of ECs or the uptake of ferritin by <span class="html-italic">TFRC</span> or T-cell immunoglobulin mucin domain 1 protein (Tim-1). Ferritin and <span class="html-italic">TF</span> may be released at the abluminal side of ECs through extracellular vesicles (EVs). In ECs, iron may be stored within the ferritin cage or released at the abluminal side through ferroportin1/solute carrier family 40 member 1 (<span class="html-italic">FPN1/SLC40A1</span>), which is coupled with ferroxidase proteins like ceruloplasmin (<span class="html-italic">CP</span>) and hephaestin (<span class="html-italic">HEPH</span>). Astrocytes and choroid plexus express and release hepcidin (<span class="html-italic">HAMP</span>), in this way controlling iron entry in the brain through its interaction with <span class="html-italic">FPN1/SLC40A1.</span> The control of iron entry is also performed by apo- and holo-<span class="html-italic">TF</span> levels in the extracellular space through the regulation of <span class="html-italic">FPN1/SLC40A1</span> stability and <span class="html-italic">HEPH</span> activity. Astrocytes, in direct contact with ECs, uptake iron through <span class="html-italic">DMT1/SLC11A2</span> and then redistribute the metal in the extracellular space through <span class="html-italic">FPN1/SLC40A1</span> coupled with <span class="html-italic">CP.</span> Iron moves in the brain extracellular space bound to citrate or ATP (released by astrocytes) or to <span class="html-italic">TF</span> (mainly secreted by oligodendrocytes and the choroid plexus). Mature oligodendrocytes acquire iron through ferritin uptake by Tim-1, store iron in ferritin and release iron through <span class="html-italic">FPN1/SLC40A1</span>. Microglial cells acquire iron through <span class="html-italic">TF/TFR</span>C endocytosis and through <span class="html-italic">DMT1/SLC11A2</span>, store the metal in the ferritin shell and release iron through <span class="html-italic">FPN1/SLC40A1</span> and secreting ferritin. Like for microglia, iron uptake is obtained through <span class="html-italic">TF/TFR</span>C endocytosis and through <span class="html-italic">DMT1/SLC11A2</span> in neurons, which store small amounts of iron in ferritin and release excess iron through <span class="html-italic">FPN1/SLC40A1</span>.</p>
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<p>Pathomechanisms of FTD that might involve iron imbalance. Iron metabolism dysfunctions may lead to mitochondrial low iron levels with the possible dysregulation of heme and iron sulfur cluster (ISC) synthesis. A paucity of ISCs and heme may lead to dysfunctions of the electron transport chain and altered mitochondrial membrane potential (Δψ). Together with oxidative phosphorylation impairment, high mitochondrial iron may lead to oxidative stress with the production of excess reactive oxygen species (ROS) that may result in mitochondrial DNA (mtDNA) damage or defects in mitochondrial morphology, fission and fusion dynamics, trafficking and quality control through the mitophagy pathway. Mitochondrial ferritin (<span class="html-italic">FTMT</span>) may buffer excess iron and protect against oxidative damage. Excess cellular iron entry or excess release from ferritin through ferritinophagy, together with mitochondrial dysfunctions, may trigger ROS production in neurons, leading to lipid peroxidation and the activation of ferroptotic cellular death. The release of damaged nuclear and mitochondrial DNA due to oxidative stress may trigger, together with neuroinflammation, the activation of stimulator of interferon genes (<span class="html-italic">STING</span>) that may exacerbate ferroptosis through the activation of ferritinophagy and further release of harmful iron. The activation of the sequestosome 1/protein 62/kelch-like ECH associated protein 1/NFE2-like bZIP transcription factor 2 (<span class="html-italic">SQSTM1/p62/KEAP1/NRF2</span>) signaling pathway, also involved in the regulation of iron-related genes, may inhibit ferroptosis. Iron dyshomeostasis can trigger microtubule-associated protein tau (<span class="html-italic">MAPT/TAU</span>) aggregation directly through the generation of ROS or through the modulation of <span class="html-italic">MAPT/TAU</span> phosphorylation. Oxidative stress and ROS production derived from iron dyshomeostasis could also affect the aggregation of further proteins observed in FTD-associated inclusions, like TAR DNA binding protein (<span class="html-italic">TARDBP/TDP43</span>), fused in Sarcoma (<span class="html-italic">FUS</span>), EWS RNA binding protein 1 (<span class="html-italic">EWSR1</span>), TATA-box binding protein associated factor 15 (<span class="html-italic">TAF15</span>), ubiquilin 2 (<span class="html-italic">UBQLN2</span>) and the dipeptide repeats (DPRs) derived from the translation of the hexanucleotide repeat region of the C9orf72 gene.</p>
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