Journal of Neural Transmission最新文献

Attention-deficit/hyperactivity disorder (ADHD) is a frequently observed condition, with about 70% of individuals diagnosed with ADHD experiencing irregular sleep-wake patterns. Beyond the primary symptoms of ADHD, there is a significant overlap with sleep-related issues, indicating that disrupted sleep patterns may exacerbate ADHD symptoms. ADHD-related sleep problems can be traced to a delayed circadian rhythm and a later onset of melatonin production. Therefore, normalizing circadian rhythms has been proposed as a potential therapeutic target for psychiatric disorders. Recent animal studies have provided compelling evidence linking peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of energy metabolism, to the regulation of physiological and behavioral rhythms. In this study, we hypothesized that treating fibroblasts from ADHD patients, which exhibit disturbances in circadian rhythmicity that are replicated in peripheral fibroblasts, with rosiglitazone may restore their circadian rhythmicity to that of the controls. To this end, we used cultures of fibroblasts obtained from skin biopsy explants of ADHD patients and controls and investigated the temporal patterns of clock gene expression over a period of 24 h. We report that the administration of the PPARγ agonist, rosiglitazone significantly realigns the chronobiological patterns of ADHD patient samples and control groups by inducing phase shifts in the expression of the BMAL1, PER3, and CRY1 clock genes. Nevertheless, rosiglitazone showed limited impact on the amplitude and phase of CLOCK1, NPAS2, and PER1. No notable changes were observed in PER2 and PER3 gene expression. The data from cultured human dermal fibroblasts indicate that PPARγ-agonists may help regulate circadian molecular mechanisms. Given the shared genetic pathways between ADHD and obesity, future studies could investigate the potential of RSG as a treatment for circadian rhythm disorders, particularly in obese patients with ADHD.

In major depressive disorder (MDD), alterations in ghrelin levels and cognitive impairment coexist, yet their association has remained largely elusive. This study aimed to investigate the association between ghrelin levels and cognition in both MDD patients and healthy controls (HCs) while also exploring sex-specific differences in this correlation. A total of 155 Chinese Han subjects, including 90 first-episode drug-naive MDD patients and 65 HCs, were enrolled. Ghrelin levels were measured using ELISA kits, and neurocognitive assessments were conducted using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). MDD patients exhibited significantly higher ghrelin levels and lower cognitive scores of RBANS compared to HCs. However, there was no significant correlation between ghrelin levels and cognitive function in both MDD patients and HCs. Exploratory analyses revealed sex-specific associations between ghrelin and cognitive function, particularly in MDD patients. Females with MDD showed distinct patterns of association between ghrelin levels and cognitive domains such as attention and language, which were not observed in healthy controls or male MDD patients. The relationship between ghrelin and cognition only existed in MDD patients, not in the HCs, and there was a sex-specific difference in this association. Further research on the mechanism of ghrelin in the cognitive function of MDD should focus on sex differences.

The majority of patients with cannabis use disorder (CUD) regularly take medication. Cannabinoids influence metabolism of some commonly prescribed drugs. However, little is known about the characteristics and frequency of potential cannabis-drug (CDIs) and drug-drug interactions (DDIs) in patients with CUD. Therefore, our study aimed to determine the prevalence and characteristics of drug interactions in patients with CUD during inpatient treatment on an addiction-specific ward over a six-year-period. To this aim, medication charts were analyzed and screened for potential CDIs and DDIs. Herein, the drugs.com classification for potential CDIs and UpToDate Lexicomp program for potential DDIs were utilized. The study cohort consisted of 301 patient cases, predominantly male (85.0%), with a median age of 37 years. 89.4% (269/301) of all cases involved were taking at least one drug that could potentially interact with cannabis. Levomethadone, buprenorphine and morphine were the most common drugs involved in potentially serious CDIs. In addition, 196 DDIs were identified, of which 25.5% were classified as 'avoid combination' and 74.5% as 'consider therapy modification'. Hereby, combinations of levomethadone with other psychotropic drugs most frequently accounted for potentially severe and mild DDIs. The results of our study indicate that especially patients diagnosed with CUD also receiving opioid substitution therapy are at risk for potential drug interactions. Therefore, a clinical monitoring of vigilance and respiratory function should be applied during inpatient treatment. Routine use of interaction check tools in patients diagnosed with CUD should also be considered by healthcare providers. In addition, therapeutic drug monitoring (TDM) should be used to increase medication safety in this patient population.

Epilepsy affects 1-2% of the world population, is enigmatic in 30% of cases, and is often intractable, unresponsive to antiepileptic drugs, and accompanied by cognitive, psychiatric and behavioral problems. Tests for Autoimmune Epilepsy are not performed routinely, and limited to passive diagnosis of known autoimmune antibodies, without essential functional tests to reveal active pathogenic antibodies. We investigated two young Epilepsy patients with different Epilepsy characteristics, repeated intractable seizures, and enigmatic etiology. We suspected Autoimmune Epilepsy. We found that both patients have elevated IgG antibodies, and three types of glutamate receptor antibodies, to: AMPA-GluR3B, NMDA-NR1 and NMDA-NR2 peptides. In contrast, they lack autoantibodies to: LGI1, CASPR2, GABA-RB1, Amphiphysin, CV2, PNMA1, Ri, Yo, Hu, Recoverin, Soxi and Titin. IgG antibodies of both patients bound and killed human neural cells In vitro. Moreover, In vivo video EEG studies in naive rats revealed that patient's IgG antibodies, infused continually into rat brain, bound neural cells in the hippocampus and cortex, caused neural loss in these brain regions, and induced recurrent Generalized Tonic Clonic Seizures. We assume they can do so also in the patient's brain. This is the first model of human Autoimmune Epilepsy in rats. It can serve for discovery of patient's pathogenic antibodies, and drug development. Tests for autoimmune antibodies that bind glutamate receptor peptides, and functional diagnostic tests, are obligatory in all enigmatic intractable Epilepsy patients. Current diagnosis of Autoimmune Epilepsy is insufficient! If pathogenic antibodies are found, intractable patients must receive available, suitable and potentially life-changing immunotherapies for Autoimmune Epilepsy.

Although α-synuclein pathology is typically associated with Lewy body diseases and multiple systems atrophy, increasing evidence indicates that it also occurs in a group of lysosomal storage disorders termed sphingolipidoses caused by the incomplete degradation, and subsequent accumulation, of a class of lipids termed sphingolipids. Notably, a number of genes that cause sphingolipidoses are also risk genes for Lewy body diseases, suggesting aetiological links between these distinct disorders. In the present review, we discuss the sphingolipidoses in which α-synuclein pathology has been reported: Gaucher disease, Krabbe disease, metachromatic leukodystrophy, Tay-Sachs disease and Anderson-Fabry disease, and describe the characteristic clinical and pathological features of these disorders, in addition to the evidence suggesting α-synuclein pathology occurs in these disorders. Finally, we evaluate the pathological mechanisms that underlie these rare disorders, with particular attention to how the enzymatic deficiency, substrate accumulation, or both, could contribute to the genesis of α-synuclein pathology and the implications of this for Lewy body diseases.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by cerebellar dysfunction, a Parkinsonian syndrome with poor response to levodopa and autonomic failure. The diagnosis of MSA is particularly challenging in its early stages due to symptom overlap with other neurodegenerative Parkinson syndromes. Recent advances in neuroimaging have greatly improved the accuracy of the diagnosis in clinical routine and provided valuable insights into the pathophysiology and progression of MSA. Macrostructural MRI shows atrophy in regions such as the putamen and pontocerebellar regions, distinguishing MSA from other Parkinson syndromes. Advanced imaging techniques, including diffusion tensor imaging (DTI), free water imaging and quantitative susceptibility mapping, add further value in assessing disease progression. While dopamine transporter (DAT) imaging is the mainstay for confirmation of nigrostriatal degeneration in suspected neurodegenerative Parkinson syndromes and may enable to identify prodromal cases, cardiac sympathetic imaging with [123I]MIBG scintigraphy may be used for delineation of MSA from Parkinson's disease (PD). Positron emission tomography (PET) with the glucose analogue [¹⁸F]FDG depicts disease-specific metabolic patterns in MSA and various neurodegenerative diseases, which do not only enable a highly accurate differential diagnosis of MSA (e.g., from PD and other atypical Parkinson syndromes) but also carry important prognostic and pathophysiological information. Various other PET radiopharmaceuticals currently under investigation in MSA provide novel insights into neurotransmitter system changes, glial pathology and, most recently, α-synuclein pathology. These imaging modalities considerably expand the diagnostic and prognostic capabilities in MSA and may provide important biomarkers for tracking disease development, progression and treatment.

Multiple system atrophy (MSA), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are the most common atypical parkinsonisms. These adult-onset and lethal neurodegenerative disorders of unknown etiology are clinically characterized by varying combinations of autonomic, levodopa-poorly responsive parkinsonsm, motor, non-motor, cerebellar syndromes, behavioral, cognitive and other neuropsychiatric disorders. Although their pathological hallmarks are different-MSA α-synucleinopathy, CBD and PSP 4-repeat (4R) tauopathies-their neuropsychiatric disturbances include anxiety, depression, agitations, attention-executive dysfunctions, less often compulsive and REM sleep behavior disorders (RBD), which may contribute to disease progression and reduced quality of life (QoL) of patients and caregivers. The present paper reviews the prevalence and type of neuropsychiatric profile in these atypical parkinsonian syndromes, their neuroimaging, and pathogenic backgrounds based on extensive literature research. MSA patients show anxiety, apathy (depression), initial RBD, attentional and executive dysfunction; PSP patients present with apathy, depression, disinhibition, and to a lesser extent, anxiety and agitation; CBD patients are featured by executive and visuospatial dysfunctions, irritability, alien limb phenomena, sleep and language disorders. Neuropsychiatric disorders in these syndromes are often similar, due to disruption of prefronto-subcortical (limbic) and striato-thalamo-cortical circuitries or default mode and attention network disorder. This supports the concept that they are brain network disorders due to complex pathogenic mechanisms related to the basic proteinopathies that are still poorly understood. Psychotic symptoms, hallucinations and delusions are rare. Neuropsychiatric changes in these disorders are often premature and anticipate motor dysfunctions; their assessment and further elucidation of their pathogenesis are warranted as a basis for early diagnosis and adequate treatment of these debilitating comorbidities.

Amyotrophic Lateral Sclerosis(ALS) has traditionally been managed as a neuromuscular disorder. However, recent evidence suggests involvement of non-motor domains. This study aims to evaluate the impact of APOE and MAPT genotypes on the cognitive features of ALS. We included confirmed ALS cases from the Neurology department at Razi University Hospital, Tunisia. APOE and MAPT screening were conducted with Sanger sequencing validation, and preliminary screening for four main ALS genes was performed. Clinical phenotypes and genotypes were analyzed using appropriate tests, with healthy controls (HC) representing the Tunisian population. Two-hundred-seventy ALS patients were included, stratified as 213 spinal cases,49 with bulbar onset and 8 patients with generalized form with 140 HC. Regarding APOE, we reported high frequency of ALS cases carrier of APOE-ε4 isoform compared to controls(p < 0.0001).We found a significant association between APOE-ɛ4 and ALS onset site (p = 0.05,r = 0.33),with higher frequencies in bulbar onset patients. Cognitive signs were more frequent in ɛ4 carriers (r = 0.43,p < 0.01),and a significant link was observed between dysexecutive functions and the APOE risk allele (p = 0.0495).Concerning the MAPT haplotypes, we reported high frequency of ALS cases carrier of MAPT H1-haplotype HC (94.45% and 72.14% respectively, p < 0.001).Among ALS cases,MAPT-H1 showed a stronger positive correlation with the presence of oculomotor signs(p = 0.05,r = 0.28).As well as significant positive association between cognitive impairments(p = 0.039,r = 0.59). Our findings emphasize the correlation between APOE and MAPT genotypes and the cognitive features in our ALS patients. We also observed other interesting, though weak, significant correlations (with coefficients not exceeding 0.20),which require further validation in a larger cohort to confirm our results.

Anorexia nervosa (AN) represents an eating disorder, which features the highest rate of mortality among all psychiatric disorders. The disease prevalence is increasing steadily, and an effective cure is missing. The neurobiology of the disease is largely unknown, and only a few studies were designed to disclose specific brain areas, where altered neural transmission may occur. In AN behavioral alterations surpassing altered feeding are present, which often involve archaic behaviors finalized to the survival of the species. In fact, alterations of sleep and reward-driven behavior accompany the eating disorder, where a disruption of peripheral and central circadian rhythms occurs along with effortful behaviors, aberrant learning and mild cognitive impairment. Abnormal behavior often co-exists with a number of metabolic alterations in peripheral organs. The present article wishes to analyze the potential role of altered brain circuitry within the brainstem reticular formation during AN. In fact, this brain area contains neuronal nuclei and pathways, which are pivotal in connecting eating pattern with archaic behaviorsand autonomic activity within peripheral organs. A number of reticular nuclei releasing catecholamine and non-catecholamine neurotransmittersare evidenced in relationship with altered behavioral states and vegetative control to produce this psycho-metabolic disorder. The relevance of the reticular formation in sustaining the disorder is discussed in the light of developing effective therapeutic strategies.

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by both motor and non-motor symptoms that necessitate ongoing clinical evaluation and medication adjustments. Home-based wearable sensor monitoring offers a detailed and continuous record of patient symptoms, potentially enhancing disease management. The EmPark-PKG study aims to evaluate the effectiveness of the Parkinson's KinetoGraph (PKG), a wearable sensor device, in monitoring and tracking the progression of motor symptoms over 12 months in Emirati and non-Emirati PD patients. Fifty PD patients (32% Emirati, 68% non-Emirati) were assessed at baseline and a 12-month follow-up. Clinical evaluations included levodopa equivalent daily dosage (LEDD) and motor and non-motor assessments. Concurrently, the PKG provided metrics such as bradykinesia score (BKS) and dyskinesia score (DKS). Statistical analyses were conducted to determine changes from baseline to six months, differences between Emirati and non-Emirati groups, and correlations between PKG metrics and clinical assessments. Significant reductions in LEDD and improvements in both motor and non-motor scores were observed from baseline to six months (p < 0.05). PKG-guided medication adjustments were associated with enhanced motor and non-motor outcomes (p < 0.05). Specifically, non-Emirati patients exhibited a significant reduction in LEDD (Z = - 2.010, p = 0.044), whereas Emirati patients did not (Z = - 0.468, p = 0.640). Both groups showed significant improvements in motor scale scores and motor complication scores. Spearman correlation analysis revealed strong relationships between PKG metrics and subjective clinical assessments (p < 0.001). The EmPark-PKG study demonstrates the potential benefits of remote PKG monitoring for personalised motor symptom management in PD. PKG supports a stepped care paradigm by enabling bespoke medication titration based on objective data, facilitating tailored and effective patient care.