Clinical characteristics and management of functional neurological disorders (FND) mimicking stroke in emergency settings: a functional stroke mimic cases.

Background: FNDs mimicking a stroke represent a growing challenge in the emergency department (ED). A comprehensive diagnostic approach involving clinical evaluation and neuroimaging is essential to differentiate stroke from mimics. The safety profile of thrombolysis justifies its use where FNDs cannot be ruled out. This approach highlights the need for more precise diagnostic tools and protocols to improve patient care and reduce unnecessary treatments. Distinguishing FNDs from actual cerebrovascular events is critical yet difficult, particularly under time constraints. Given the urgency and potential severity of strokes, intravenous thrombolysis is frequently administered even when FNDs cannot be definitively excluded. Methods: This retrospective study analyzed data of participants admitted to the Trieste University Hospital Stroke Unit between January 2018 and December 2022, focusing on those presenting with sudden-onset focal neurological deficits mimicking a stroke, with some presenting within the reperfusion treatment window (<4.5 h from symptoms onset). We obtained detailed clinical evaluations and neuroimaging, and administered thrombolytic therapy in selected cases. Results and discussion: We included 84 participants presenting with stroke mimics (average age of 45 yo) predominantly female (65.5%). Most common presentations: hemiparesis or hemisensory loss (75%), speech disorder (10.7%), vertigo/gait disorders (4.8%). History of psychiatric disorders was found in 32.1% of cases, and 48.8% had prior neurological disease or stroke risk factors. Advanced neuroimaging was performed in 43 cases yielding normal or non-specific results. Thrombolysis was safely administered in 31%. Patients mostly recovered within the first 24 h from admission (44.7%). We compared this FND's sample with 291 patients with mild ischemic stroke (NIHSS ≤7).

The role of parvalbumin interneuron dysfunction across neurodegenerative dementias.

Parvalbumin-positive (PV+) basket neurons are fast-spiking, non-adapting inhibitory interneurons whose oscillatory activity is essential for regulating cortical excitation/inhibition balance. Their dysfunction results in cortical hyperexcitability and gamma rhythm disruption, which have recently gained substantial traction as contributing factors as well as potential therapeutic targets for the treatment of Alzheimer's Disease (AD). Recent evidence indicates that PV+ cells are also impaired in Frontotemporal Dementia (FTD) and Dementia with Lewy bodies (DLB). However, no attempt has been made to integrate these findings into a coherent pathophysiological framework addressing the contribution of PV+ interneuron dysfunction to the generation of cortical hyperexcitability and gamma rhythm disruption in FTD and DLB. To fill this gap, we epitomized the most recent evidence on PV+ interneuron impairment in AD, FTD, and DLB, focusing on its contribution to the generation of cortical hyperexcitability and gamma oscillatory disruption and their interplay with misfolded protein accumulation, neuronal death, and clinical symptoms' onset. Our work deepens the current understanding concerning the role of PV+ interneuron dysfunction across neurodegenerative dementias, highlighting commonalities and differences among AD, FTD, and DLB, thus paving the way for identifying novel biomarkers and potential therapeutic targets for the treatment of these diseases.

Validation and convergent validity of the Boston cognitive assessment (BOCA) in an Italian population: a comparative study with the Montreal cognitive assessment (MoCA) in Alzheimer's disease spectrum.

BACKGROUND: The Boston Cognitive Assessment (BOCA) is a self-administered online test developed for cognitive screening and longitudinal monitoring of brain health in an aging population. The study aimed to validate BOCA in an Italian population and to investigate the convergent validity with the Montreal Cognitive Assessment (MOCA) in healthy ageing population and patients within the Alzheimer Disease spectrum. METHODS: BOCA was administered to 150 participants, including cognitively healthy controls (HC, n = 50), patients with mild cognitive impairment (MCI, n = 50), and dementia (DEM, n = 50). The BOCA reliability was assessed using (i) Spearman's correlation analysis between subscales; (ii) Cronbach's alpha calculation, and (iii) Principal Component Analysis. Repeated-measures ANOVA was employed to assess the impact of the sequence of test administrations between the groups. BOCA performance between HS, MCI and DEM and within different severity subgroups were compared using Kruskall Wallis test. Furthermore, a comparison was conducted between MCI patients who tested positive for amyloid and those who tested negative, utilizing Mann Whitney's U-test. RESULTS: Test scores were significantly different between patients and controls (p < 0.001) suggesting good discriminative ability. The Cronbach's alpha was 0.82 indicating a good internal consistency of the BOCA subscales and strong-to-moderate Spearman's correlation coefficients between them. BOCA total and subscores differ across different MoCA severity subgroups and demonstrated strong correlation with MoCA scores (rho = 0.790, p < 0.001). CONCLUSIONS: The Italian version of the BOCA test exhibited validity, feasibility, and accurate discrimination closely performing as MoCA.

Alpha tACS Improves Cognition and Modulates Neurotransmission in Dementia with Lewy Bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is characterized by a marked shift of electroencephalographic (EEG) power and dominant rhythm, from the α toward the θ frequency range. Transcranial alternate current stimulation (tACS) is a non-invasive brain stimulation technique that allows entrainment of cerebral oscillations at desired frequencies. OBJECTIVES: Our goal is to evaluate the effects of occipital α-tACS on cognitive functions and neurophysiological measures in patients with DLB. METHODS: We conducted a double-blind, randomized, sham-controlled, cross-over clinical trial in 14 participants with DLB. Participants were randomized to receive either α-tACS (60 minutes of 3 mA peak-to-peak stimulation at 12 Hz) or sham stimulation applied over the occipital cortex. Clinical evaluations were performed to assess visuospatial and executive functions, as well as verbal episodic memory. Neurophysiological assessments and EEG recordings were conducted at baseline and following both α-tACS and sham stimulations. RESULTS: Occipital α-tACS was safe and well-tolerated. We observed a significant enhancement in visuospatial abilities and executive functions, but no improvement in verbal episodic memory. We observed an increase in short latency afferent inhibition, a neurophysiological marker indirectly and partially dependent on cholinergic transmission, coinciding with an increase in α power and a decrease in Δ power following α-tACS stimulation, effects not seen with sham stimulation. CONCLUSIONS: This study demonstrates that occipital α-tACS is safe and enhances visuospatial and executive functions in patients with DLB. Improvements in indirect markers of cholinergic transmission and EEG changes indicate significant neurophysiological engagement. These findings justify further exploration of α-tACS as a therapeutic option for DLB patients. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Plasma p-tau181 and amyloid markers in Alzheimer's disease: A comparison between Lumipulse and SIMOA.

Aim of the project was to evaluate the technical and clinical validity of plasma Lumipulse p-tau, Aß42 and Aß40 species and their correlation with CSF core Alzheimer's Disease (AD) markers; a method comparison with SIMOA was also performed. One-hundred-thirthy-three participants, namely 55 A+T+N+ AD, 28 Neurodegenerative disorders (NDD) and 50 controls were enrolled for the study. Lumipulse technical validity showed high stability for p-tau181, Aß42, and Aß40, with higher stability of p-tau to repeated freezing thaw cycles. p-tau181 levels detected by both techniques were higher in AD compared to both NDD/controls and exhibited a similar correlation with CSF p-tau levels, whereas Aß42 levels were slightly lower in AD with both methods. In the comparison between SIMOA and Lumipulse plasma markers, both techniques exhibited similar diagnostic accuracy for AD for p-tau181 (0.87; 95 %CI 0.81-0.94, vs 0.85; 95 %CI 0.78-0.93), whereas the best performance was reached by p-tau181/ Aß42 Lumipulse ratio (ROC AUC 0.915, 95 %CI 0.86-0.97). The study thus confirmed the construct validity of both Lumipulse and SIMOA techniques for the identification of CSF AD pattern in clinical settings.

Sex Differences in the Severity and Progression of Neuropsychiatric Symptoms Across Different Dementia Types.

Background and Objectives: Dementia presents not only differing neuropsychiatric symptoms (NPS) across Alzheimer disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) but also subjective cognitive decline (SCD). This study examined sex-based variations in NPS severity and progression across these conditions. Methods: We performed a longitudinal cohort study including 1,068 participants. Hierarchical generalized linear mixed models were used to model NPS as a function of disease severity and biological sex at birth. Results: Female participants with AD exhibited NPS more frequently than male participants. In FTD, female participants had more frequent delusions, hallucinations, and depression/dysphoria, while male participants had higher instances of agitation/aggression, apathy, disinhibition, and irritability/lability. In DLB, male participants showed higher instances of depression, and female participants more frequently experienced anxiety. In SCD, female participants showed higher nighttime behaviors. The trajectory of NPS significantly differed between sexes. Discussion: These findings highlight sex-specific NPS impact in different neurodegenerative conditions.

Association of APOE genotype with blood-brain barrier permeability in neurodegenerative disorders.

Apolipoprotein E (APOE) is recognized for its role in modulating blood-brain barrier (BBB) permeability in vitro, which may have significant implications for the pathogenesis and progression of neurodegenerative disorders. However, evidence in vivo is contrasting. This study explores the impact of APOE genotypes on BBB integrity among 230 participants experiencing cognitive impairment, encompassing cases of Alzheimer's disease (AD) as well as various non-AD neurodegenerative conditions. To assess BBB integrity, we utilized cerebrospinal fluid (CSF)/serum albumin ratios and CSF/serum kappa and lambda free light chains (FLCs) as indirect markers. Our findings show a dose-dependent increase in BBB permeability in individuals carrying the APOE ε4 allele, marked by elevated CSF/serum albumin and FLCs ratios, with this trend being especially pronounced in AD patients. These results highlight the association of APOE ε4 with BBB permeability, providing valuable insights into the pathophysiology of neurodegenerative diseases.

Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features.

Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%-25% of patients with frontotemporal lobar degeneration (FTLD). Data from patients and in vitro/ex vivo pre-clinical studies indicate that anti-GluA3 hIgGs negatively affect glutamatergic neurotransmission. However, whether and how the chronic presence of anti-GluA3 hIgGs triggers synaptic dysfunctions and the appearance of FTLD-related neuropathological and behavioural signature has not been clarified yet. To address this question, we developed and characterized a pre-clinical mouse model of passive immunization with anti-GluA3 hIgGs purified from patients. In parallel, we clinically compared FTLD patients who were positive for anti-GluA3 hIgGs to negative ones. Clinical data showed that the presence of anti-GluA3 hIgGs defined a subgroup of patients with distinct clinical features. In the preclinical model, anti-GluA3 hIgGs administration led to accumulation of phospho-tau in the postsynaptic fraction and dendritic spine loss in the prefrontal cortex. Remarkably, the preclinical model exhibited behavioural disturbances that mostly reflected the deficits proper of patients positive for anti-GluA3 hIgGs. Of note, anti-GluA3 hIgGs-mediated alterations were rescued in the animal model by enhancing glutamatergic neurotransmission with a positive allosteric modulator of AMPA receptors. Overall, our study clarified the contribution of anti-GluA3 autoantibodies to central nervous system symptoms and pathology and identified a specific subgroup of FTLD patients. Our findings will be instrumental in the development of a therapeutic personalised medicine strategy for patients positive for anti-GluA3 hIgGs.

Defining the Role of Frailty in the Transition from Mild Cognitive Impairment to Dementia and in Dementia Progression.

INTRODUCTION: Neurodegenerative diseases are a growing concern in an aging global population. Frailty, often conceptualized as a state of diminished physiological reserve and increased susceptibility to stressors, emerges as a pivotal factor in this context. While frailty may be modified, it is essential to recognize its frequently irreversible nature, necessitating a careful approach when considering its role and influence in the progression from mild cognitive impairment (MCI) to dementia and within dementia progression. METHODS: A retrospective study including 1,284 participants, attending a Cognitive Disturbances and Dementia unit from January 2021 to May 2023, was conducted. Frailty was assessed using the clinical frailty scale (CFS) score. Multilevel univariate and multivariate logistic regression models were developed to determine the contributions of patient characteristics, including frailty, to disease progression. RESULTS: Frailty significantly increased with higher global clinical dementia rating (CDR) subgroups, suggesting escalating frailty burden with disease progression. Age, CFS, and mini-mental state examination (MMSE) scores were significant predictors of progression from MCI to dementia and to more severe dementia stages, even when considering the independence from variables contributing to frailty. Patients transitioning to a higher CDR group exhibited higher CFS scores. Age, education, anticholinergic burden, cumulative illness rating scale - geriatric, MMSE, and neuropsychiatric inventory scores significantly contributed to frailty. CONCLUSIONS: Frailty plays a critical role in the transition from MCI to dementia and within dementia progression. Age, cognitive impairment, and frailty were identified as significant predictors of disease progression. The CFS is a clinically applicable tool for frailty assessment. Regular frailty assessments may be valuable in early detection and management of dementia.

Diagnostic accuracy of research criteria for prodromal frontotemporal dementia.

BACKGROUND: The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls. METHODS: A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment. RESULTS: The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p < 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p < 0.001). The addition of both markers further increased the AUC to 0.90 (p < 0.001). CONCLUSIONS: The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD.

Detection of TDP-43 seeding activity in the olfactory mucosa from patients with frontotemporal dementia.

INTRODUCTION: We assessed TAR DNA-binding protein 43 (TDP-43) seeding activity and aggregates detection in olfactory mucosa of patients with frontotemporal lobar degeneration with TDP-43-immunoreactive pathology (FTLD-TDP) by TDP-43 seeding amplification assay (TDP43-SAA) and immunocytochemical analysis. METHODS: The TDP43-SAA was optimized using frontal cortex samples from 16 post mortem cases with FTLD-TDP, FTLD with tau inclusions, and controls. Subsequently, olfactory mucosa samples were collected from 17 patients with FTLD-TDP, 15 healthy controls, and three patients carrying MAPT variants. RESULTS: TDP43-SAA discriminated with 100% accuracy post mortem cases presenting or lacking TDP-43 neuropathology. TDP-43 seeding activity was detectable in the olfactory mucosa, and 82.4% of patients with FTLD-TDP tested positive, whereas 86.7% of controls tested negative (P < 0.001). Two out of three patients with MAPT mutations tested negative. In TDP43-SAA positive samples, cytoplasmatic deposits of phosphorylated TDP-43 in the olfactory neural cells were detected. DISCUSSION: TDP-43 aggregates can be detectable in olfactory mucosa, suggesting that TDP43-SAA might be useful for identifying and monitoring FTLD-TDP in living patients.

Comparing Cerebellar tDCS and Cerebellar tACS in Neurodegenerative Ataxias Using Wearable Sensors: A Randomized, Double-Blind, Sham-Controlled, Triple-Crossover Trial.

Cerebellar transcranial direct current stimulation (tDCS) represents a promising therapeutic approach for both motor and cognitive symptoms in neurodegenerative ataxias. Recently, transcranial alternating current stimulation (tACS) was also demonstrated to modulate cerebellar excitability by neuronal entrainment. To compare the effectiveness of cerebellar tDCS vs. cerebellar tACS in patients with neurodegenerative ataxia, we performed a double-blind, randomized, sham controlled, triple cross-over trial with cerebellar tDCS, cerebellar tACS or sham stimulation in twenty-six participants with neurodegenerative ataxia. Before entering the study, each participant underwent motor assessment with wearable sensors considering gait cadence (steps/minute), turn velocity (degrees/second) and turn duration (seconds), and a clinical evaluation with the scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). After each intervention, participants underwent the same clinical assessment along with cerebellar inhibition (CBI) measurement, a marker of cerebellar activity. The gait cadence, turn velocity, SARA, and ICARS significantly improved after both tDCS and tACS, compared to sham stimulation (all p<0.010). Comparable effects were observed for CBI (p<0.001). Overall, tDCS significantly outperformed tACS on clinical scales and CBI (p<0.01). A significant correlation between changes of wearable sensors parameters from baseline and changes of clinical scales and CBI scores was detected. Cerebellar tDCS and cerebellar tACS are effective in ameliorating symptoms of neurodegenerative ataxias, with the former being more beneficial than the latter. Wearable sensors may serve as rater-unbiased outcome measures in future clinical trials. ClinicalTrial.gov Identifier: NCT05621200.

Transcranial Magnetic Stimulation Across the Lifespan: Impact of Developmental and Degenerative Processes.

Transcranial magnetic stimulation (TMS) has emerged as a pivotal noninvasive technique for investigating cortical excitability and plasticity across the lifespan, offering valuable insights into neurodevelopmental and neurodegenerative processes. In this review, we explore the impact of TMS applications on our understanding of normal development, healthy aging, neurodevelopmental disorders, and adult-onset neurodegenerative diseases. By presenting key developmental milestones and age-related changes in TMS measures, we provide a foundation for understanding the maturation of neurotransmitter systems and the trajectory of cognitive functions throughout the lifespan. Building on this foundation, the paper delves into the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, and adolescent depression. Highlighting recent findings on altered neurotransmitter circuits and dysfunctional cortical plasticity, we underscore the potential of TMS as a valuable tool for unraveling underlying mechanisms and informing future therapeutic interventions. We also review the emerging role of TMS in investigating and treating the most common adult-onset neurodegenerative disorders and late-onset depression. By outlining the therapeutic applications of noninvasive brain stimulation techniques in these disorders, we discuss the growing body of evidence supporting their use as therapeutic tools for symptom management and potentially slowing disease progression. The insights gained from TMS studies have advanced our understanding of the underlying mechanisms in both healthy and disease states, ultimately informing the development of more targeted diagnostic and therapeutic strategies for a wide range of neuropsychiatric conditions.

Cortico-spinal tDCS in amyotrophic lateral sclerosis: A randomized, double-blind, sham-controlled trial followed by an open-label phase.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive disease for which no curative treatment is currently available. OBJECTIVE: This study aimed to investigate whether cortico-spinal transcranial direct current stimulation (tDCS) could mitigate symptoms in ALS patients via a randomized, double-blind, sham-controlled trial, followed by an open-label phase. METHODS: Thirty-one participants were randomized into two groups for the initial controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS), while Group 2 received cortico-spinal stimulation (real tDCS) for five days/week for two weeks (T1), with an 8-week (T2) follow-up (randomized, double-blind, sham-controlled phase). At the 24-week follow-up (T3), all participants (Groups 1 and 2) received a second treatment of anodal bilateral motor cortex and cathodal spinal stimulation (real tDCS) for five days/week for two weeks (T4). Follow-up evaluations were performed at 32-weeks (T5) and 48-weeks (T6) (open-label phase). At each time point, clinical assessment, blood sampling, and intracortical connectivity measures using transcranial magnetic stimulation (TMS) were evaluated. Additionally, we evaluated survival rates. RESULTS: Compared to sham stimulation, cortico-spinal tDCS significantly improved global strength, caregiver burden, and quality of life scores, which correlated with the restoration of intracortical connectivity measures. Serum neurofilament light levels decreased among patients who underwent real tDCS but not in those receiving sham tDCS. The number of completed 2-week tDCS treatments significantly influenced patient survival. CONCLUSIONS: Cortico-spinal tDCS may represent a promising therapeutic and rehabilitative approach for patients with ALS. Further larger-scale studies are necessary to evaluate whether tDCS could potentially impact patient survival. CLINICAL TRIAL REGISTRATION: NCT04293484.

Home-based transcranial alternating current stimulation (tACS) in Alzheimer's disease: rationale and study design.

BACKGROUND: Gamma (γ) brain oscillations are dysregulated in Alzheimer's disease (AD) and can be modulated using transcranial alternating stimulation (tACS). In the present paper, we describe the rationale and design of a study assessing safety, feasibility, clinical and biological efficacy, and predictors of outcome of a home-based intervention consisting of γ-tACS over the precuneus. METHODS: In a first phase, 60 AD patients will be randomized into two arms: ARM1, 8-week precuneus γ-tACS (frequency: 40 Hz, intensity: 2 mA, duration: 5 60-min sessions/week); and ARM2, 8-week sham tACS (same parameters as the real γ-tACS, with the current being discontinued 5 s after the beginning of the stimulation). In a second phase, all participants will receive 8-week γ-tACS (same parameters as the real γ-tACS in the first phase). The study outcomes will be collected at several timepoints throughout the study duration and include information on safety and feasibility, neuropsychological assessment, blood sampling, electroencephalography, transcranial magnetic stimulation neurotransmitter measures, and magnetic resonance imaging or amyloid positron emission tomography. RESULTS: We expect that this intervention is safe and feasible and results in the improvement of cognition, entrainment of gamma oscillations, increased functional connectivity, reduction of pathological burden, and increased cholinergic transmission. CONCLUSIONS: If our expected results are achieved, home-based interventions using γ-tACS, either alone or in combination with other therapies, may become a reality for treating AD. TRIAL REGISTRATION: PNRR-POC-2022-12376021.

Association of Choroid Plexus Volume With Serum Biomarkers, Clinical Features, and Disease Severity in Patients With Frontotemporal Lobar Degeneration Spectrum.

BACKGROUND AND OBJECTIVES: Choroid plexus (ChP) is emerging as a key brain structure in the pathophysiology of neurodegenerative disorders. In this observational study, we investigated ChP volume in a large cohort of patients with frontotemporal lobar degeneration (FTLD) spectrum to explore a possible link between ChP volume and other disease-specific biomarkers. METHODS: Participants included patients meeting clinical criteria for a probable syndrome in the FTLD spectrum. Structural brain MRI imaging, serum neurofilament light (NfL), serum phosphorylated-Tau181 (p-Tau181), and cognitive and behavioral data were collected. MRI ChP volumes were obtained from an ad-hoc segmentation model based on a Gaussian Mixture Models algorithm. RESULTS: Three-hundred and sixteen patients within FTLD spectrum were included in this study, specifically 135 patients diagnosed with behavioral variant frontotemporal dementia (bvFTD), 75 primary progressive aphasia, 46 progressive supranuclear palsy, and 60 corticobasal syndrome. In addition, 82 age-matched healthy participants were recruited as controls (HCs). ChP volume was significantly larger in patients with FTLD compared with HC, across the clinical subtype. Moreover, we found a significant difference in ChP volume between HC and patients stratified for disease-severity based on CDR plus NACC FTLD, including patients at very early stage of the disease. Interestingly, ChP volume correlated with serum NfL, cognitive/behavioral deficits, and with patterns of cortical atrophy. Finally, ChP volume seemed to discriminate HC from patients with FTLD better than other previously identified brain structure volumes. DISCUSSION: Considering the clinical, pathologic, and genetic heterogeneity of the disease, ChP could represent a potential biomarker across the FTLD spectrum, especially at the early stage of disease. Further longitudinal studies are needed to establish its role in disease onset and progression. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that choroid plexus volume, as measured on MRI scan, can assist in differentiating patients with FTLD from healthy controls and in characterizing disease severity.

Advances in the treatment and management of frontotemporal dementia.

INTRODUCTION: Frontotemporal dementia (FTD) is a complex neurodegenerative disorder, characterized by a wide range of pathological conditions associated with the buildup of proteins such as tau and TDP-43. With a strong hereditary component, FTD often results from genetic variants in three genes - MAPT, GRN, and C9orf72. AREAS COVERED: In this review, the authors explore abnormal protein accumulation in FTD and forthcoming treatments, providing a detailed analysis of new diagnostic advancements, including innovative markers. They analyze how these discoveries have influenced therapeutic strategies, particularly disease-modifying treatments, which could potentially transform FTD management. This comprehensive exploration of FTD from its molecular underpinnings to its therapeutic prospects offers a compelling overview of the current state of FTD research. EXPERT OPINION: Notable challenges in FTD management involve identifying reliable biomarkers for early diagnosis and response monitoring. Genetic forms of FTD, particularly those linked to C9orf72 and GRN, show promise, with targeted therapies resulting in substantial progress in disease-modifying strategies. The potential of neuromodulation techniques, like tDCS and rTMS, is being explored, requiring further study. Ongoing trials and multi-disciplinary care highlight the continued push toward effective FTD treatments. With increasing understanding of FTD's molecular and clinical intricacies, the hope for developing effective interventions grows.

Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist.

The Therapeutic Potential of Non-Invasive and Invasive Cerebellar Stimulation Techniques in Hereditary Ataxias.

The degenerative ataxias comprise a heterogeneous group of inherited and acquired disorders that are characterized by a progressive cerebellar syndrome, frequently in combination with one or more extracerebellar signs. Specific disease-modifying interventions are currently not available for many of these rare conditions, which underscores the necessity of finding effective symptomatic therapies. During the past five to ten years, an increasing number of randomized controlled trials have been conducted examining the potential of different non-invasive brain stimulation techniques to induce symptomatic improvement. In addition, a few smaller studies have explored deep brain stimulation (DBS) of the dentate nucleus as an invasive means to directly modulate cerebellar output, thereby aiming to alleviate ataxia severity. In this paper, we comprehensively review the clinical and neurophysiological effects of transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and dentate nucleus DBS in patients with hereditary ataxias, as well as the presumed underlying mechanisms at the cellular and network level and perspectives for future research.