The exact cause of nigral cell death in Parkinson's disease (PD) is still unknown. However, research on MPTP-induced experimental parkinsonism has significantly advanced our understanding. In this model, it is widely accepted that mitochondrial respiratory failure is the primary mechanism of cell death. Studies have shown that a toxic metabolite of MPTP inhibits Complex I and alpha-ketoglutarate dehydrogenase activities in mitochondria. Since then, many research groups have focused on mitochondrial dysfunction in PD, identifying deficiencies in Complex I or III in PD patients' brains, skeletal muscle, and platelets. There is some debate about the decline in mitochondrial function in peripheral organs. However, since α-synuclein, the main component protein of Lewy bodies, accumulates in peripheral organs, it is reasonable to consider PD a systemic disease. Additionally, mutant mitochondrial DNA with a 4,977 base pair deletion has been found in the brains of PD patients, suggesting that age-related accumulation of deleted mtDNA is accelerated in the striatum and may contribute to the pathophysiology of PD. While the cause of PD remains unknown, mitochondrial dysfunction is undoubtedly a factor in cell death in PD. In addition, the causative gene for familial PD, parkin (now PRKN), and PTEN-induced putative kinase 1 (PINK1), both gene products are also involved in mitochondrial quality control. Moreover, we have successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system. There is no doubt that mitochondrial dysfunction contributes to cell death in PD.

Monoamine oxidase catalyzes oxidative deamination of monoamine transmitters and plays a critical role in the pathogenesis of neuropsychiatric diseases. Monoamine oxidase is classified into type A and B (MAO-A, MAO-B) according to the substrate specificity and sensitivity to inhibitors. The isoenzymes are different proteins coded by different genes localized on the X-chromosome, but they have identical intron-exon organization, similar protein structure and enzymatic mechanism and are considered to be derived from the same ancestral gene. The isoform-specific transcription organization regulates expression and function of MAO-A in response to cellular signaling pathways and environmental factors. MAO-A shows distinct properties and functions: isoform-specified polymorphisms, localization in catecholamine neurons, expression during early embryonic stage, regulation of brain architecture development and mediation of death and survival of neuronal cells. MAO-A is more flexible to genetic and environmental changes than MAO-B. Defective MAO-A expression impairs embryonic brain development and causes adult abnormal mood and behavior, as shown by human male cases with MAO-A deletion. This paper presents the regulation of brain MAO-A expression epigenetically by interaction between genetic and environmental factors. Association of aberrant MAO-A expression and activity with aggression, asocial behaviors, depressive disorders, and neurodegenerative diseases is discussed. Novel therapeutic strategy for psychiatric diseases by intervention to the regulation of MAO-A expression and activity is proposed.

Aripiprazole is approved for various severe mental disorders in adults and adolescents. However, off-label prescribing is common, especially in children and adolescents (youth) in whom aripiprazole therapeutic serum level reference ranges are lacking for any disorders. The aim of the study was to evaluate the relationship between aripiprazole dose and serum concentrations and provide further knowledge on the use of aripiprazole in order to improve drug safety and effectiveness in the treatment of minors. The clinical course of youth treated with aripiprazole in the multicentre pharmacovigilance study TDM-VIGIL was systematically followed and serum concentrations measured. Sex, age, weight and comedications were analysed to identify possible effect modifiers. A preliminary therapeutic reference range was estimated for youth with schizophrenia-spectrum disorders, affective disorders and behavioural/emotional/tic disorders coded as treatment responders based on a Clinical-Global Impressions-Improvement (CGI-I) score of much or very much improved. In 93 youth (mean age = 15.2 ± 2.6, range = 7.4-18.2 years, females = 53%, CGI-Severity = 4.4 ± 1.1, responders = 64%), a positive, moderate correlation between the weight-normalized daily dose (WNDD) and aripiprazole serum concentration (=0.791, p < 0.0001) was found. The WNDD and co-medications that interact with CYP2D6 and CYP3A4 affected aripiprazole serum levels, explaining 64% of the variance. In patients within the preliminary therapeutic ranges determined by interquartile ranges (IQRs), slightly better outcomes and fewer adverse drug reactions were found versus patients within preliminary therapeutic ranges determined by the mean ± SD. The preliminary reference range for paediatric patients with schizophrenia-spectrum disorders calculated by the IQR showed an identical lower threshold (100-230 ng/ml) compared to adult schizophrenia-spectrum disorders patients (100-350 ng/ml). The preliminary therapeutic ranges for patients with affective disorders was: 60-160 ng/ml and for patients with behavioural/tic disorders 60-140 ng/ml. The therapeutic reference ranges for aripiprazole in youth estimated via the 25th and 75th IQRs may result in more clinically relevant therapeutic windows. Further studies need to confirm these results, especially in patients with affective and behavioural/tic disorder diagnoses.

TDCS is one of the most widely used non-invasive neuromodulation techniques, which changes the excitability of local cortical tissue by applying weak continuous direct current to the scalp, effectively improves the attention and concentration of ADHD children, and improves the impulse disorder of patients, but related research is still in its infancy. Based on a review of a large number of existing literatures and an analysis of the pathogenesis and principle of ADHD, this paper summarized the research on tDCS in the treatment of ADHD in recent years from the aspects of treatment mechanism, safety and stimulation parameters, and simply compared the application of tDCS with other non-traumatic neuromodulation techniques in the treatment of ADHD. The future development direction of this technology is further discussed.

In this narrative review, we address mild cognitive impairment, a frequent complication of Parkinson's disease (PD) and atypical parkinsonian disorders (APDs). Recent diagnostic criteria have blurred the lines between PD and dementia with Lewy bodies (DLB), particularly in the cognitive domain. Additionally, atypical parkinsonian syndromes like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) often present with significant cognitive decline. Even multiple system atrophy (MSA) can be associated with cognitive impairment in some cases. Several biomarkers, including imaging techniques, such brain magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET), as well as pathological proteins either of the cerebrospinal fluid (CSF), such as Tau, amyloid beta, and synuclein, or of the serum, such as neurofilament light chain (Nfl) are more and more often utilized in the early differential diagnosis of APDs. The complex interplay between these conditions and the evolving understanding of their underlying pathologies highlight the need for further research to refine diagnostic criteria, possibly incorporate the new findings from the biomarker's field into the diagnostic criteria and develop targeted therapeutic strategies.

Exposure to stress is known to affect biological aging as well as individuals' susceptibility to a wide variety of mental illnesses, such as schizophrenia. There is an established relationship between the onset of schizophrenia spectrum disorders (SSD) and biological aging. On the other hand, epigenetic modifications, such as DNA methylation (DNAm), are used as biomarkers for biological aging and were previously proven to be altered in schizophrenia. However, previous research did not consider the effect of psychosocial resilience to stress and its effect on aging in schizophrenia, which is what our study aims to address. For our pilot study, 65 schizophrenia patients were recruited and stress exposure and perception levels were assessed using the Social Readjustment Rating Scale (SRRS) and Perceived Stress Scale (PSS), respectively. Moreover, DNA was extracted from venous blood samples and 850,000 CpG loci were assessed for DNA methylation analysis. Average age of participants was 43.15 ± 13.32 years (55.4% male, 44.6% female). Linear regression plots showed significant correlation between SRRS and PSS scores as well as between biological and chronological ages (p < 0.05). The residuals from the two regression models were defined as the psychosocial resilience and DNAm age acceleration, respectively. Interestingly, DNAm age acceleration was inversely correlated with resilience to stress (p < 0.05). In conclusion, it appears that epigenetic age acceleration is associated with reduced resilience to stress in schizophrenia patients. Future studies should focus on establishing resilience effect on disease prognosis.

Alzheimer's dementia is the main cause of cognitive impairment in people over the age of 65, with Alzheimer's disease starting presumably 10-15 years before the onset of clinical symptoms. It is therefore important to recognize dementia at an early stage and identify possible predictors. The existing methods, like different parameters of ß-Amyloid and Tau quantification in cerebrospinal fluid (CSF) or the living brain by measure of PET, are invasive and expensive. Therefore, the present study investigates the predictive value of a battery of clinical, neuropsychological, and blood parameters as well as two neurophysiological methods (functional near-infrared spectroscopy [fNIRS] and vagus somatosensory evoked potentials [VSEP]) which are easy to perform, less invasive and cost-efficient, for developing cognitive impairments in the elderly.In this longitudinal, prospective study, we enrolled 604 healthy participants between 70 and 77 years of age. The participants were invited back after a mean time interval of 3 years and 11 months, and after 7 years and 8 months, and their cognitive impairments were determined.Here we show that the development of cognitive impairments after approximately 8 years can be predicted not only by previously known risk factors such as ApoE4 risk alleles, dysosmia, or poor cognitive performance at baseline but that latency prolongation in the VSEP and altered functional activation patterns measured by NIRS at baseline also provide additional predictive value.We therefore suggest that both neurophysiological parameters, VSEP and NIRS, should be included in future studies, investigating the prediction of dementia. Dementia ClinicalTrials.gov Identifier: NCT02224326.

This multicentre, prospective, single-arm study evaluated safinamide as add-on therapy to levodopa in Korean patients with Parkinson's disease (PD) with motor fluctuations with ≥ 1.5 h of "off" time daily, who took levodopa ≥ 3 times/day (n = 199). Baseline levodopa and dopamine agonist doses were maintained without escalation during the 18-week treatment period. Participants received safinamide 50 mg/day for 2 weeks and 100 mg/day thereafter. PD diaries and questionnaires (Parkinson's Disease Questionnaire, PDQ-39; Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale, MDS-UPDRS part 3 and part 4; King's Parkinson's Disease Pain Scale, KPPS; Mini-Mental State Examination, MMSE) were assessed at baseline and at week 18. Treatment-emergent adverse events (TEAEs) were recorded. Mean disease duration was 6.6 years, and mean levodopa equivalent daily dose was 721.1 mg/day. At week 18, significant improvements from baseline were seen for the co-primary endpoints, mean daily "off" time (- 1.3 ± 2.4 h, p < 0.001) and quality of life (QoL) based on PDQ-39 summary index (- 2.7 ± 10.3, p < 0.001), Moreover, significant improvements were seen in motor symptoms and motor complications (MDS-UPDRS part 3 and 4), daily "on" time without dyskinesia (all p < 0.001) and pain (KPPS; p = 0.013). TEAEs occurred in 40.2% of patients, with most being mild in severity. In conclusion, safinamide at a dosage of 100 mg/day significantly improved motor symptoms, QoL, and pain, and demonstrated a favourable safety profile without levodopa dosage escalation during the 18-week treatment period in Korean patients with PD.Trial registration number and date: NCT05312632, First Posted: April 5, 2022.

The crucial role of steroid hormones in health and diseases merits their high-throughput, accurate and affordable measurements in biological specimens. Despite advances in analytical methods, sensing and quantifying steroid hormones remains challenging. Immunoassays offer excellent sensitivity but are inherently labour-intensive, costly, and prone to false positives. Mass spectrometry (MS) has been increasingly utilised, with the main hurdle being the isobaric tendencies of similar analytes, which complicates their separation and accurate quantification. This study compares ultrahigh-performance supercritical fluid chromatography separation (UHPSFC) and ultra-high-performance liquid chromatography (UHPLC) for MS detection. It optimises the column chemistry, temperature, and pressure to provide an operational protocol for the resolution and quantification of analytes. It presents the systematic characterisation of UHPSFC-MS performance by investigating spiked blood samples using Solid-Phase Extraction (SPE) and describes the matrix effects associated with MS measurements. Although both separation methods showed adequate resolution, specificity, and retention time, UHPSFC-MS was superior for five out of seven columns tested. With added high-throughput capacities, UHPSFC-MS, thus, offers an optimal solution for the analysis of steroid hormones for research, medical chemistry, and clinical diagnostics.

Essential tremor (ET) is characterized by upper limbs action tremor, sometimes extending to other body parts. However, ET can present with additional neurological features known as "soft signs." These signs of uncertain clinical significance are not sufficient to suggest an alternative neurological diagnosis, and include, among others, questionable dystonia and subtle voluntary movement alterations, i.e., bradykinesia and related features. This study aimed to explore the prevalence and relationship between questionable dystonia and subtle bradykinesia features in ET. Forty ET patients were video-recorded during clinical examination. Five movement disorder experts reviewed the videos to identify soft motor signs, i.e., dystonia and movement alterations during finger-tapping namely, (i) bradykinesia (reduced velocity), (ii) dysrhythmia, and (iii) sequence effect. Inter-rater agreement was quantified using the Fleiss' Kappa index. Data analysis was performed using nonparametric tests. We found a fair inter-rater agreement for upper limb dystonia (Fleiss' K = 0.27). Inter-rater agreement was higher (moderate) for head dystonia (Fleiss' K = 0.49) and finger-tapping assessment (Fleiss' K = 0.45). Upper limb dystonia was identified in 70% of patients, head dystonia in 35%, and finger-tapping alterations (in variable combinations) were observed in 95% of individuals (P < 0.001 by Fisher's exact test), including subtle bradykinesia and related features. No significant concordance or correlation was found between the soft signs. Subtle bradykinesia and related features are the most easily identifiable and frequent soft signs in ET, appearing in a higher percentage of patients than subtle dystonia. These findings provide insights into the clinical and pathophysiological understanding of ET.

This study aimed to analyze the transferability of non-invasive brain stimulation (NIBS) interventions in individuals with major depressive disorder (MDD) based on the FIELD model (Function, Implementation, Ecology, Level, and Duration), encompassing function, implement, ecology, level, and duration. A systematic search of electronic databases yielded a total of 21 eligible studies, comprising 12 transcranial direct current stimulation (tDCS) and 9 transcranial magnetic stimulation (TMS) trials, involving 1029 individuals with MDD. The meta-analysis of effect sizes revealed positive transfer effects across all domains of the FIELD model, suggesting that NIBS interventions have potential efficacy in improving various facets of MDD. The subgroup analysis highlighted that bilateral dlPFC stimulation exhibited the highest effect size for transferability, indicating greater transferability for rTMS, a higher dose of stimulation, and the integration of additional interventions. Additionally, the study discusses the implications of bilateral dorsolateral prefrontal cortex (dlPFC) stimulation and the integration of complementary therapies for optimizing treatment efficacy.

Deep brain stimulation can influence the speech and voice quality in Parkinson´s disease (PD). This controlled, randomized, double-blind, cross-over clinical trial was conducted in 15 PD patients with bilateral subthalamic deep brain stimulation (DBS) to compare the effects of STN-DBS with combined subthalamic and nigral stimulation (STN + SNr-DBS) and DBS OFF on speech and voice parameters in PD patients. Speech and voice were analyzed subjectively using questionnaires (voice/pronunciation quality VAS, VHI, SHI) and objectively using audio analysis (maximum phonation time, AVQI, mean F0, intonation, syllable rate, reading time). Both stimulation conditions, STN + SNr-DBS and STN-DBS, revealed heterogeneous effects on speech and voice production with a slight beneficial effect on the voice quality of individual patients compared to DBS OFF, but not in the whole group. Small, but not significant effects were seen only in subjective voice quality on the VAS and intonation (both stimulation conditions compared to DBS OFF). No significant changes of the objective speech parameters during the audio analysis could be observed (both stimulation conditions compared to DBS OFF). There were no significant differences between STN + SNr-DBS and STN-DBS in any speech and voice domain. The beneficial effects on speech and voice production are minor in most patients compared to the motor improvements by DBS. Both STN-DBS and STN + SNr-DBS were safe, with comparable effects between both DBS modes, and represent no contraindications from the perspective of the voice specialist.

Quantitative susceptibility mapping (QSM) and transcranial sonography (TCS) offer proximal evaluations of iron load in the substantia nigra. Our prospective study aimed to investigate the relationship between QSM and TCS measurements of nigral iron content in patients with Parkinson's disease (PD). In secondary analyses, we wanted to explore the correlation of substantia nigra imaging data with clinical and laboratory findings. Eighteen magnetic resonance imaging and TCS examinations were performed in 15 PD patients at various disease stages. Susceptibility measures of substantia nigra were calculated from referenced QSM maps. Echogenicity of substantia nigra on TCS was measured planimetrically (echogenic area) and by digitized analysis (echo-intensity). Iron-related blood serum parameters were measured. Clinical assessments included the Unified PD Rating Scale and non-motor symptom scales. Substantia nigra susceptibility correlated with echogenic area (Pearson correlation, r = 0.53, p = 0.001) and echo-intensity (r = 0.78, p < 0.001). Individual asymmetry indices correlated between susceptibility and echogenic area measurements (r = 0.50, p = 0.042) and, more clearly, between susceptibility and echo-intensity measurements (r = 0.85, p < 0.001). Substantia nigra susceptibility (individual mean of bilateral measurements) correlated with serum transferrin saturation (Spearman test, r = 0.78, p < 0.001) and, by trend, with serum iron (r = 0.69, p = 0.004). Nigral echogenicity was not clearly related to serum values associated with iron metabolism. Susceptibility and echogenicity measurements were unrelated to PD duration, motor subtype, and severity of motor and non-motor symptoms. The present results support the assumption that iron accumulation is involved in the increase of nigral echogenicity in PD. Nigral echo-intensity probably reflects ferritin-bound iron, e.g. stored in microglia.

Tools for the early diagnosis of neurocognitive disorders (NCD) both accessible, fast, fun and efficient are currently needed. A digit-tracking technique (Digitrack) has been developed based on the exploration of blurred images on a tablet with the finger, related to the exploration of images during eye-tracking. The present study aimed at assessing the objective usability and the subjective User eXperience (UX) of the Digitrack by older adults according to the presence and the severity of NCD. A total of 135 patients were included in a geriatric acute care unit. Objective usability was assessed through the number of patients able to complete the Digitrack's training (3 images) and evaluation (20 images) phases. UX was measured through standard questionnaires (AttrakDiff and meCUE), and through the description of engagement behaviors following an internally developed scale which included 5 levels (interactive, constructive, active, passive and disengaged behaviors). The success rate of the device was 94.1%. The Digitrack had a very good overall attractiveness, standard hedonic and pragmatic qualities, and the emotions perceived were predominantly positive. These findings were not homogeneously observed in the whole studied population. Patients highly impaired due to NCD tended to rate the device with more neutral scores and to perceive more negative emotions. The participants mainly demonstrated active behaviors, but patients with severe major NCD were mostly passive. The study showed promising results regarding the usability and acceptability of a digit-tracking technique within older adults. Further studies should evaluate the potential of this novel methods to make a cognitive diagnosis.

Parkinson's disease is a complex neurodegenerative disorder presenting a range of motor and non-motor symptoms that greatly impact both patients and caregivers. The diverse needs arising from these symptoms make a multidisciplinary team (MDT) approach crucial for effective management. This article explores the role and benefits of MDTs in Parkinson's care, highlighting how collaborative models improve clinical outcomes and quality of life. MDTs integrate neurologists, nurse specialists, therapists, and other professionals to deliver comprehensive, patient-centered care. The inclusion of patients and caregivers fosters shared decision-making, enhancing health outcomes. However, challenges like limited controlled trials, lack of comprehensive guidelines, and under-referral remain. Innovative models, such as telehealth and community-based care, offer promising solutions, especially in underserved regions. The article advocates for further research and standardized guidelines to optimize the MDT approach for Parkinson's disease.

Behavioral disorders, with an average prevalence of 30-60% are important non-motor symptoms in amyotrophic lateral sclerosis (ALS) that have a negative impact on prognosis, management and quality of life, yet the underlying neurobiology is poorly understood. Among people with ALS, apathy, fatigue, anxiety, irritability and other behavioral symptoms are the most prominent, although less frequent than cognitive impairment. The present review explores the current understanding of behavioral changes in ALS with particular emphasis on our current knowledge about their structural and functional brain correlates, substantiating a multisystem degeneration with particular dysfunction of frontal-subcortical circuits and dysfunction of fronto-striatal, frontotemporal and other essential brain systems. The natural history of behavioral dysfunctions in ALS and their relationship to frontotemporal lobe degeneration (FTLD) are not fully understood, although they form a clinical continuum, suggesting a differential vulnerability of non-motor brain networks, ALS being considered a brain network disorder. An assessment of risks or the early detection of brain connectivity signatures before structural changes may be helpful in investigating the pathophysiological mechanisms of behavioral impairment in ALS. Treatment of both ALS and co-morbid behavioral disorders is a multidisciplinary task, but whereas no causal or disease-modifying therapies for ALS are available, symptomatic treatment of a variety of behavioral symptoms plays a pivotal role in patient care, although the management of behavioral symptoms in clinical care still remains limited.

Multiple sclerosis (MS) is a central nervous system disease involving gray and white matters. Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) could help identify potential markers of disease evolution, disability, and treatment response. This work evaluates the relationship between intracortical inhibition and facilitation, motor cortex lesions, and corticospinal tract (CST) integrity. Consecutive adult patients with progressive MS were included. Sociodemographic and clinical data were collected. MRI was acquired to assess primary motor cortex lesions (double inversion and phase-sensitive inversion recovery) and CST integrity (diffusion tensor imaging). TMS outcomes were obtained: motor evoked potentials (MEP) latency, resting motor threshold, short-interval intracortical facilitation (ICF) and inhibition. Correlation analysis was performed. Twenty-five patients completed the study (13 females, age: 55.60 ± 11.49 years, Expanded Disability Status Score: 6.00 ± 1.25). Inverse correlations were found between ICF mean and each of CST radial diffusivity (RD) (ρ =-0.56; p < 0.01), CST apparent diffusion coefficient (ADC) (ρ=-0.44; p = 0.03), and disease duration (ρ=-0.46; p = 0.02). MEP latencies were directly correlated with disability scores (ρ = 0.55; p < 0.01). High ADC/RD and low ICF have been previously reported in patients with MS. While the former could reflect structural damage of the CST, the latter could hint towards an aberrant synaptic transmission as well as a depletion of facilitatory compensatory mechanisms that helps overcoming functional decline. The findings suggest concomitant structural and functional abnormalities at later disease stages that would be accompanied with a heightened disability. The results should be interpreted with caution mainly because of the small sample size that precludes further comparisons (e.g., treated vs. untreated patients, primary vs. secondary progressive MS). The role of these outcomes as potential MS biomarkers merit to be further explored.

Patients with Parkinson disease (PD) frequently experience several behavioral symptoms, such as anxiety, apathy, irritability, agitation, impulsive control and obsessive-compulsive or REM sleep behavior disorders, which can cause severe psychosocial problems and impair quality of life. Occurring in 30-70% of PD patients, these symptoms can manifest at early stages of the disease, sometimes even before the appearance of classic motor symptoms, while others can develop later. Behavioral changes in PD show distinct patterns of brain atrophy, dopaminergic and serotonergic deterioration, altered neuronal connectivity in frontostriatal, corticolimbic, default mode and other networks due to a cascade linking molecular pathologies and deficits in multiple behavior domains. The changes suggest a multi-system neurodegenerative process in the context of a specific α-synucleinopathy inducing a variety of biochemical and functional changes, the neurobiological basis and clinical relevance of which await further elucidation. This paper is intended to review the recent literature with focus on the main behavioral disturbances in PD patients, their epidemiology, clinical features, risk factors, animal models, neuroimaging findings, pathophysiological backgrounds, and treatment options of these deleterious lesions.

Between 1878 and 1880 Camillo Golgi, professor of Histology and General Pathology at the University of Pavia, studied the termination of the nerves inside the tendons, near their muscular insertion. He defined two fundamental categories of corpuscles. The first type, which he called muscle-tendon terminal organs, was morphologically characterized by spindle structures which at one end seemed to relate to the muscle fibers while at the other end they gradually merged with the tendon bundles. Golgi discovered that these structures received from one to four myelinated nerve fibers, which lost their myelin sheath as they entered the bundle, within which they divided dichotically, ending in a large number of terminal arborizations that had the appearance of reticular intertwines. In the superficial thickness of the tendon, near the muscle, Golgi also noticed a second category of corpuscles, which he described as claviform bodies or formations similar to Pacinian bodies. In 1890 Vittorio Mazzoni precisely defined their morphological characteristics. These corpuscles were later called Golgi muscle-tendon organs and Golgi-Mazzoni corpuscles. On the basis of their position and histological appearance, Golgi also correctly hypothesized their physiological role: to be receptors of muscular tension for the muscle-tendon organs and transducers of sensitivity to touch and pressure for the Golgi-Mazzoni corpuscles.

Amyotrophic lateral sclerosis (ALS) is a fatal multi-system neurodegenerative disorder with no effective treatment or cure. Although primarily characterized by motor degeneration, cognitive dysfunction is an important non-motor symptom that has a negative impact on patient and caregiver burden. Mild cognitive deficits are present in a subgroup of non-demented patients with ALS, often preceding motor symptoms. Detailed neuropsychological assessments reveal deficits in a variety of cognitive domains, including those of verbal fluency and retrieval, language, executive function, attention and verbal memory. Mild cognitive impairment (MCI), a risk factor for developing dementia, affects between 10% and over 50% of ALS patients. Neuroimaging revealed atrophy of frontal and temporal cortices, disordered white matter Integrity, volume reduction in amygdala and thalamus, hypometabolism in the frontal and superior temporal gyrus and anterior insula. Neuronal loss in non-motor brain areas, associated with TDP-43 deposition, one of the morphological hallmarks of ALS, is linked to functional disruption of frontostriatal and frontotemporo-limbic connectivities as markers for cognitive deficits in ALS, the pathogenesis of which is still poorly understood. Early diagnosis by increased cerebrospinal fluid or serum levels of neurofilament light/heavy chain or glial fibrillary acidic protein awaits confirmation for MCI in ALS. These fluid biomarkers and early detection of brain connectivity signatures before structural changes will be helpful not only in establishing early premature diagnosis but also in clarifying the pathophysiological mechanisms of MCI in ALS, which might serve as novel targets for prohibition/delay and future adequate treatment of this debilitating disorder.