Rett syndrome (RTT) is a paediatric neurodevelopmental disorder spanning four developmental stages. This multi-system disorder offers a unique window to explore genotype-phenotype relationships in a disease model. However, genetic prognosticators of RTT have limited clinical value due to the disorder\'s heterogeneity on multiple levels. This case report used a precision medicine approach to better understand the clinical phenotype of RTT twins with an identical pathogenic MECP2 mutation and discordant neurodevelopmental profiles. Targeted genotyping, objective physiological monitoring of heart rate variability (HRV) parameters, and clinical severity were assessed in a RTT twin pair (5 years 7 months old) with an identical pathogenic MECP2 mutation. Longitudinal assessment of autonomic HRV parameters was conducted using the Empatica E4 wristband device, and clinical severity was assessed using the RTT-anchored Clinical Global Impression Scale (RTT-CGI) and the Multi-System Profile of Symptoms Scale (MPSS). Genotype data revealed impaired BDNF function for twin A when compared to twin B. Twin A also had poorer autonomic health than twin B, as indicated by lower autonomic metrics (autonomic inflexibility). Hospitalisation, RTT-CGI-S, and MPSS subscale scores were used as measures of clinical severity, and these were worse in twin A. Treatment using buspirone shifted twin A from an inflexible to a flexible autonomic profile. This was mirrored in the MPSS scores, which showed a reduction in autonomic and cardiac symptoms following buspirone treatment. Our findings showed that a combination of a co-occurring rs6265 BDNF polymorphism, and worse autonomic and clinical profiles led to a poorer prognosis for twin A compared to twin B. Buspirone was able to shift a rigid autonomic profile to a more flexible one for twin A and thereby prevent cardiac and autonomic symptoms from worsening. The clinical profile for twin A represents a departure from the disorder trajectory typically observed in RTT and underscores the importance of wider genotype profiling and longitudinal objective physiological monitoring alongside measures of clinical symptoms and severity when assessing genotype-phenotype relationships in RTT patients with identical pathogenic mutations. A precision medicine approach that assesses genetic and physiological risk factors can be extended to other neurodevelopmental disorders to monitor risk when genotype-phenotype relationships are not so obvious.

Rasmussen\'s encephalitis (RE) stands as a rare neurological disorder marked by progressive cerebral hemiatrophy and epilepsy resistant to medical treatment. Despite extensive study, the primary cause of RE remains elusive, while its histopathological features encompass cortical inflammation, neuronal degeneration, and gliosis. The underlying molecular mechanisms driving disease progression remain largely unexplored. In this case study, we present a patient with RE who underwent hemispherotomy and has remained seizure-free for over six months, experiencing gradual motor improvement. Furthermore, we conducted molecular analysis on the excised brain tissue, unveiling a decrease in the expression of cell-cycle-associated genes coupled with elevated levels of BDNF and TNF-α proteins. These findings suggest the potential involvement of cell cycle regulators in the progression of RE.

Cognition is a set of brain processes that allow the individual to interact with their environment. Multiple sclerosis (MS) is a chronic inflammatory disease that affects the cerebral white matter of the brain cortex and spinal cord, leading to cognitive impairment (CI) in 40-60% of the patients. Many studies have determined that CI is linked to genetic risk factors. We aimed to evaluate the association between BDNF gene rs6265 polymorphism and cognitive impairment in Mexican patients with MS by performing a case-control study. Mestizo-Mexican patients diagnosed with MS based on McDonald\'s criteria were enrolled. Cases were MS patients with CI (n = 31) while controls were MS patients without CI (n = 31). To measure cognitive functioning in MS patients, a neuropsychological screening battery for MS (NSB-MS) was used. Genotyping of the rs6265 gene variant was performed using quantitative real-time PCR (qPCR) with TaqMan probes. The results showed no statistically significant differences in sociodemographic and disease variables between case and control groups. qPCR analysis showed that there were 68% Val/Val wild-type homozygotes, 29% Val/Met polymorphic heterozygotes, and 3% Met/Met polymorphic homozygotes. The presence of BDNF gene rs6265 polymorphism showed an increased probability (3.6 times) of global cognitive impairment.

Brain-Derived Neurotrophic Factor (BDNF) has been linked to various conditions of the cardiovascular and nervous systems. Scarce data exist about the concentrations of BDNF in children and adolescents in relation with obesity and metabolic syndrome (MetS). The aim of this study was to examine the serum BDNF concentrations in adolescents with metabolic syndrome and according to their body mass index (BMI) status. This was a case-control study, assessing BDNF concentrations between adolescents with MetS (with obesity vs. normal-BMI), in relation to sex, anthropometric, metabolic and endocrine parameters. Participants included male and female adolescents, whose anthropometric and metabolic panel, as well as serum BDNF concentrations were measured. A total of 59 adolescents (obesity: 29; normal-BMI: 30) were included in the study. Increased serum BDNF concentrations were observed in MetS adolescents with obesity when compared with normal-BMI adolescents (p < 0.001). Males exhibited higher concentrations of BDNF than females (p = 0.045). The sample was further divided into four categories by sex and BMI status, with normal-BMI females exhibiting significantly lower BDNF concentrations than females and males with obesity(p = 0.005). In the entire study sample, serum BDNF concentrations correlated positively with BMI z-scores, however, this statistical significance was preserved only in the females of the sample. No statistical difference was observed between males of different BMI z-scores categories.  Conclusion: Obesity appeared as a major factor for increased serum BDNF concentrations in adolescents with MetS (vs. normal-BMI), with a higher impact on BDNF concentrations in females than males. What is Known: • The brain-derived neurotrophic factor (BDNF) is involved in metabolic syndrome in adults but data in adolescents are scarce. What is New: • Obesity (vs. normal BMI) was a major factor for increased serum BDNF in adolescents with metabolic syndrome. • Obesity had a higher impact on BDNF concentrations in females than males with metabolic syndrome.

Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinson\'s disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment began ∼8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), which represents a time point of initiating GDNF treatment later than reported in some preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemiparkinsonian rats to determine if expression of GDNF family receptor, GFR-α1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) hemilesion. Whereas GDNF expression changed minimally, GFR-α1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-α1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred, returning to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-α1 and RET expression between the striatum and SN, and cell-specific differences in GFR-α1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors thus appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. SIGNIFICANCE STATEMENT: Although preclinical evidence supports that GDNF provides neuroprotection and improves locomotor function in preclinical studies, there is uncertainty if it can alleviate motor impairment in Parkinson\'s disease patients. Using the established 6-OHDA hemiparkinsonian rat model, we determined whether expression of its cognate receptors, GFR-α1 and RET, were differentially affected between striatum and substantia nigra in a timeline study. In striatum, there was early and significant loss of RET, but a gradual, progressive loss of GFR-α1. In contrast, RET transiently increased in lesioned substantia nigra, but GFR-α1 progressively decreased only in nigrostriatal neurons and correlated with TH cell loss. Our results indicate that direct availability of GFR-α1 may be a critical element that determines GDNF efficacy following striatal delivery.

BACKGROUND: Few studies have compared serum BDNF and glycolipid profiles in patients with deficit schizophrenia (DS) and non-deficit schizophrenia (NDS). We aimed to compare BDNF and glycolipid profiles between DS and NDS patients and healthy controls, and to investigate the relationship between BDNF, glycolipid profiles in DS and NDS patients.
METHODS: A total of 591 patients with chronic schizophrenia (SZ) and 238 healthy controls participated in this study. According to Proxy for the Deficit Syndrome Scale, SZ patients were divided into DS (n = 158) and NDS (n = 273) patients. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Serum BDNF levels were measured using enzyme-linked immunosorbent assay (ELISA).
RESULTS: BDNF levels were significantly lower in SZ patients than those in healthy controls (7.81 ± 2.98 ng/ml vs. 11.96 ± 2.29 ng/ml, P < 0.01). Furthermore, BDNF levels were lower in DS group than those in NDS group (P = 0.007, OR = 0.846, 95% CI = 0.750-0.955). Lower triglyceride levels were also an independent predictor for DS patients (P = 0.007, OR = 0.846, 95% CI = 0.750-0.955). Serum BDNF levels were negatively associated with the severity of deficit syndrome in SZ patients (β = -1.151, t = -2.559, P = 0.011). In DS group, triglycerides were associated with PANSS negative subscore (β = -0.262, t = -2.994, P = 0.003) and depressive factor subscore (β = 0.282, t = 2.146, P = 0.035).
CONCLUSIONS: Serum BDNF and triglycerides may be informative biomarkers of DS in SZ patients. The differences in glycolipid metabolism patterns between DS and NDS patients indicate that deficit syndrome is an independent endophenotype of SZ patients.

Previous meta-analyses examining the continuum of Alzheimer\'s disease (AD) concluded significantly decreased peripheral brain-derived neurotrophic factor (BDNF) in AD. However, across different meta-analyses, there remain inconsistent findings on peripheral BDNF levels in individuals with mild cognitive impairment (MCI). This issue has been attributed to the highly heterogenous clinical and laboratory factors. Thus, BDNF\'s level, discriminative accuracy for identifying all-cause MCI and its subtypes, and its associations with other biomarkers and neurocognitive domains, remain largely unknown.
To address this heterogeneity, we compared a healthy control cohort (n=56, 45 female) to an MCI cohort (n=40, 28 female), to determine whether plasma BDNF, hs-CRP, and DHEA-S can differentiate healthy from MCI individuals, including two MCI subtypes (amnestic [aMCI] and non-amnestic [non-aMCI]). The associations between BDNF with other biomarkers and neurocognitive tests were examined. Adults with cerebral palsy were included as sensitivity analyses.
Compared to healthy controls, BDNF was significantly higher in all-cause MCI, aMCI, and non-aMCI. Furthermore, BDNF had good (AUC=0.84, 95% CI=0.74 to 0.95, p<0.001) and excellent discriminative accuracies (AUC=0.92, 95% CI=0.84 to 1.00, p<0.001) for all-cause MCI and non-amnestic MCI, respectively. BDNF was significantly and positively associated with plasma hs-CRP (β=0.26, 95% CI=0.02 to 0.50, p=0.038), despite attenuated association upon controlling for BMI (β=0.15, 95% CI=-0.08 to 0.38, p=0.186). Multiple inverse associations between BDNF and detailed neurocognitive tests were also detected.
These findings suggest BDNF is increased as a compensatory mechanism in preclinical dementia, supporting the neurotrophic and partially the inflammatory hypotheses of cognitive impairment.

This case series reported a group of patients with Guillain-Barré syndrome (GBS) and their plasma cytokine changes before and after immunotherapy. We aimed to understand GBS\'s pathogenesis and pathophysiology through observing the interval differences of the representative cytokines, which were the thymus and activation regulated chemokine (TARC) for T-cell chemotaxis, CD40 ligand (CD40L) for cosimulation of B and T cells, activated complement component C5/C5a, and brain-derived neurotrophic factor (BDNF) for survival and regenerative responses to nerve injuries. The fluorescence magnetic bead-based multiplexing immunoassay simultaneously quantified the five cytokines in a single sample. From June 2018 to December 2019, we enrolled five GBS patients who had completed before-after blood cytokine measurements. One patient was diagnosed with paraneoplastic GBS and excluded from the following cytokine analysis. The BDNF level decreased consistently in all the patients and made it a potential biomarker for the acute stage of GBS. Interval changes of the other four cytokines were relatively inconsistent and possibly related to interindividual differences in the immune response to GBS triggers, types of GBS variants, and classes of antiganglioside antibodies. In summary, utilizing the multiplexing immunoassay helps in understanding the complex immune mechanisms of GBS and the variation of immune responses in GBS subtypes; this method is feasible for identifying potential biomarkers of GBS.

Cholesterol is an essential constituent of cell membranes. The discovery of cholesterol-recognition amino acid consensus (CRAC) motif in proteins indicated a putative direct, non-covalent interaction between cholesterol and proteins. In the present study, we evaluated the presence of a CRAC motif and its inverted version (CARC) in the transmembrane region (TMR) of the tyrosine kinase receptor family (RTK) in several species using in silico methods. CRAC motifs were found across all species analyzed, while CARC was found only in vertebrates. The tropomyosin-related kinase B (TRKB), a member of the RTK family, through interaction with its endogenous ligand brain-derived neurotrophic factor (BDNF) is a core participant in the neuronal plasticity process and exhibits a CARC motif in its TMR. Upon identifying the conserved CARC motif in the TRKB, we performed molecular dynamics simulations of the mouse TRKB.TMR. The simulations indicated that cholesterol interaction with the TRKB CARC motif occurs mainly at the central Y433 residue. Our binding assay suggested a bell-shaped effect of cholesterol on BDNF interaction with TRKB receptors, and our results suggest that CARC/CRAC motifs may play a role in the function of the RTK family TMR.

The relationship between serum BDNF levels and cognitive dysfunction in schizophrenia (SCZ) patients comorbid with type 2 diabetes mellitus (T2DM) has not been reported. Hence, this study aimed to explore whether and how the changes of serum BDNF levels were correlated with cognitive impairment in SCZ patients comorbid with T2DM. We recruited 472 inpatients with chronic SCZ (54 T2DM and 418 non-T2DM), and 225 healthy controls. Serum BDNF levels and routine biochemical parameters were measured. Psychopathological symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS) and cognitive function was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). SCZ patients with T2DM had significantly higher serum BDNF levels than SCZ patients without T2DM (F = 11.31, p = 0.001). SCZ patients with T2DM scored higher in delayed memory than SCZ patients without T2DM (77.17 ± 18.44 vs.66.24 ± 19.51, p = 0.000), and still showed significance after controlling for confounders. Further stepwise multiple regression analysis identified serum BDNF as an independent contributor to the RBANS attention of SCZ patients with T2DM (β = 0.30, t = 2.09, p = 0.042). The increase of BDNF levels and better cognitive performance, especially delayed memory, may be related to the pathophysiological process of T2DM in chronic SCZ patients.