Pharmacokinetic evaluation of Sinisan containing vinegar-processed products in depressive rats, a comprehensive perspective of 'individual herb, herb-pair, and herbal formula'.

ETHNOPHARMACOLOGICAL RELEVANCE: As a classical formula for the treatment of depression, the clinical application of vinegar-processed products of Bupleuri Radix (Bupleurum chinense DC., BR) and Paeoniae Radix Alba (Paeonia lactiflora Pall., PRA) contained in Sinisan (SNS) is still controversial. AIM OF THE STUDY: Three levels of 'individual herb, herb-pair, and herbal formula' were employed to investigate whether and how the processing of main drugs affected the active constituents of pharmacokinetics in SNS, as well as their impacts on the hepatic CYP450 enzyme. MATERIALS AND METHODS: Rats were subjected to construct a chronic unpredictable mild stimulation (CUMS) model. A rapid and sensitive ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) analytical method was developed and validated for simultaneously quantitative evaluation of thirteen potential active compounds of SNS in depressive rat plasma, and successfully applied to a holistic comparison of pharmacokinetics. The differences in pharmacokinetic parameters based on three different forms of drug composition from BR and PRA before and after vinegar-processing were compared. Meanwhile, qRT-PCR and Western Blot were utilized to explore the metabolic activity of three isoforms of CYP450 enzyme scattered in the livers of depressive rats. RESULTS: The characteristic pharmacokinetics profiles of thirteen representative constituents in CUMS rats were influenced by vinegar-processing of BR and PRA and/or the compatibility. In detail, there were significant differences in the Cmax, AUC0-24, AUC0-∞, t1/2, and MRT0-24 of most constituents among the three different forms of drug composition from BR and PRA before and after vinegar-processing, with the most obvious changes in six constituents from the adjuvant and mediating guide drugs. And also, the pharmacokinetic parameters of seven constituents from BR and PRA in SNS containing vinegar-processed products obviously changed after compatibility. Additionally, the mRNA and protein levels of CYP1A2, CYP2E1, and CYP3A1 were observed to increase significantly with the processing of BR and PRA and the combination/formulation. CONCLUSIONS: In conclusion, SNS containing vinegar-processed products was more conducive to the absorption of most activated constituents compared to the original formula in vivo. The vinegar-processing of BR and PRA and the compatibility co-contribute to the pharmacokinetic variability of active compounds of SNS in CUMS rats, and the extent of contribution varies among drugs, which might be related to the regulation of the hepatic drug metabolizing enzymes. The finding of the investigation could help to better understand how active compounds metabolized in vivo, which might be helpful for guiding the clinical application of SNS containing vinegar-processed products.

Distinct hypothalamic involvement in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum.

BACKGROUND: Hypothalamic dysregulation plays an established role in eating abnormalities in behavioural variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS). Its contribution to cognitive and behavioural impairments, however, remains unexplored. METHODS: Correlation between hypothalamic subregion atrophy and cognitive and behavioural impairments was examined in a large sample of 211 participants (52 pure ALS, 42 mixed ALS-FTD, 59 bvFTD, and 58 age- and education- matched healthy controls). RESULTS: Graded variation in hypothalamic involvement but relative sparing of the inferior tuberal region was evident across all patient groups. Bilateral anterior inferior, anterior superior, and posterior hypothalamic subregions were selectively implicated in memory, fluency and processing speed impairments in addition to apathy and abnormal eating habits, taking into account disease duration, age, sex, total intracranial volume, and acquisition parameters (all p ≤ .001). CONCLUSIONS: These findings revealed that subdivisions of the hypothalamus are differentially affected in the ALS-FTD spectrum and contribute to canonical cognitive and behavioural disturbances beyond eating abnormalities. The anterior superior and superior tuberal subregions containing the paraventricular nucleus (housing oxytocin-producing neurons) displayed the greatest volume loss in bvFTD and ALS-FTD, and ALS, respectively. Importantly, the inferior tuberal subregion housing the arcuate nucleus (containing different groups of neuroendocrine neurons) was selectively preserved across the ALS-FTD spectrum, supporting pathophysiological findings of discrete neuropeptide expression abnormalities that may underlie the pathogenesis of autonomic and metabolic abnormalities and potentially certain cognitive and behavioural symptom manifestations, representing avenues for more refined symptomatic treatment targets.

Progress, development, and challenges in amyotrophic lateral sclerosis clinical trials.

INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) brings unique challenges to a clinical trial setting, due in part to relatively low disease prevalence coupled with a poor prognosis, in addition to the complexities linked to disease heterogeneity. As critical understanding of the disease develops, particularly in relation to clinical phenotype and the mechanisms of disease progression, so too new concepts evolve in relation to clinical trials, including the advent of precision therapy, targeted to subgroups of ALS patients. AREAS COVERED: Individualized, or precision medicine in ALS recognizes the heterogeneous nature of the disease and utilizes information such as the clinical phenotype of the disease, clinical biomarkers, and genotyping to promote a tailored approach to treatment. Separate to these considerations, the present review will discuss clinical trial design and how this can be improved to better match patient and investigator needs in ALS clinical trials. EXPERT OPINION: Precision therapy will promote a more focused treatment approach, with the goal of improving clinical outcomes for ALS patients. An increased community awareness of ALS, coupled with significant industry and philanthropic funding for ALS research, is accelerating this process.

Thalamic and Cerebellar Regional Involvement across the ALS-FTD Spectrum and the Effect of C9orf72.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of the same disease spectrum. While thalamic−cerebellar degeneration has been observed in C9orf72 expansion carriers, the exact subregions involved across the clinical phenotypes of the ALS−FTD spectrum remain unclear. Using MRIs from 58 bvFTD, 41 ALS−FTD and 52 ALS patients compared to 57 controls, we aimed to delineate thalamic and cerebellar subregional changes across the ALS−FTD spectrum and to contrast these profiles between cases with and without C9orf72 expansions. Thalamic involvement was evident across all ALS−FTD clinical phenotypes, with the laterodorsal nucleus commonly affected across all groups (values below the 2.5th control percentile). The mediodorsal nucleus was disproportionately affected in bvFTD and ALS−FTD but not in ALS. Cerebellar changes were only observed in bvFTD and ALS−FTD predominantly in the superior−posterior region. Comparison of genetic versus sporadic cases revealed significantly lower volumes exclusively in the pulvinar in C9orf72 expansion carriers compared to non-carriers, irrespective of clinical syndrome. Overall, bvFTD showed significant correlations between thalamic subregions, level of cognitive dysfunction and severity of behavioural symptoms. Notably, strong associations were evident between mediodorsal nucleus atrophy and severity of behavioural changes in C9orf72-bvFTD (r = −0.9, p < 0.0005). Our findings reveal distinct thalamic and cerebellar atrophy profiles across the ALS−FTD spectrum, with differential impacts on behaviour and cognition, and point to a unique contribution of C9orf72 expansions in the clinical profiles of these patients.

Schizotypal traits across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum: pathomechanistic insights.

BACKGROUND: Psychiatric presentations similar to that observed in primary psychiatric disorders are well described across the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum. Despite this, schizotypal personality traits associated with increased risks of clinical psychosis development and poor psychosocial outcomes have never been examined. The current study aimed to provide the first exploration of schizotypal traits and its neural underpinnings in the ALS-FTD spectrum to gain insights into a broader spectrum of psychiatric overlap with psychiatric disorders. METHODS: Schizotypal traits were assessed using the targeted Schizotypal Personality Questionnaire in 99 participants (35 behavioural variant FTD, 10 ALS-FTD and 37 ALS patients, and 17 age-, sex- and education-matched healthy controls). Voxel-based morphometry analysis of whole-brain grey matter volume was conducted. RESULTS: Relative to controls, pervasive schizotypal personality traits across positive and negative schizotypy and disorganised thought disorders were identified in behavioural variant FTD, ALS (with the exception of negative schizotypy) and ALS-FTDALS-FTD patients (all p < .013), suggesting the presence of a wide spectrum of subclinical schizotypal symptoms beyond classic psychotic symptoms. Atrophy in frontal, anterior cingulate and insular cortices, and caudate and thalamus was involved in positive schizotypy, while integrity of the cerebellum was associated with disorganised thought disorder traits. CONCLUSIONS: The frontal-striatal-limbic regions underpinning manifestation of schizotypy in the ALS-FTDALS-FTD spectrum are similar to that established in previous schizophrenia research. This finding expands the concept of a psychiatric overlap in ALS-FTD and schizophrenia, and suggests potentially common underlying mechanisms involving disruptions to frontal-striatal-limbic networks, warranting a transdiagnostic approach for future investigations.

A robust framework for characterising diffusion metrics of the median and ulnar nerves: Exploiting state-of-the-art tracking methods.

Diffusion-weighted imaging has been used to quantify peripheral nerve properties; however, traditional post-processing techniques have several limitations. Advanced neuroimaging techniques, which overcome many of these limitations, have not been applied to peripheral nerves. Here, we use state-of-the-art diffusion analysis tools to reconstruct the median and ulnar nerves and quantify their diffusion properties. Diffusion-weighted MRI scans were obtained from eight healthy adult subjects. Constrained spherical deconvolution was combined with probabilistic fibre tracking to compute track-weighted fibre orientation distribution (TW-FOD). The tensor was computed and used along with the tracks to estimate TW apparent diffusion coefficient (TW-ADC), TW fractional anisotropy (TW-FA), TW axial diffusivity (TW-AD), and TW radial diffusivity (TW-RD). Variability of TW measurements was used to estimate power size information. The population intersession mean (± SD) measurements for the median nerve were TW-FOD 1.30 (±0.17), TW-ADC 1.16 (±0.13) × 10-3  mm2 /s, TW-FA 0.60 (±0.05), TW-AD 2.05 (±0.16) × 10-3  mm2 /s, and TW-RD 0.72 (±0.12) × 10-3  mm2 /s. The corresponding measurements for the ulnar nerve were TW-FOD 1.25 (±0.14), TW-ADC 1.13 (±0.10) × 10-3  mm2 /s, TW-FA 0.56 (±0.06), TW-AD 1.93 (±0.01) × 10-3  mm2 /s, and TW-RD 0.74 (±0.12) × 10-3  mm2 /s. Based on these measurements, a sample size of 37 would be sufficient to detect a 10% difference in any of the measured TW metrics. A sample size of 20 would be large enough to detect within-subject differences as small as 2.9% (TW-AD, ulnar nerve) and between-subject differences as small as 3.8% (TW-AD, ulnar nerve).

Tackling clinical heterogeneity across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum using a transdiagnostic approach.

The disease syndromes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) display considerable clinical, genetic and pathological overlap, yet mounting evidence indicates substantial differences in progression and survival. To date, there has been limited examination of how profiles of brain atrophy might differ between clinical phenotypes. Here, we address this longstanding gap in the literature by assessing cortical and subcortical grey and white matter volumes on structural MRI in a large cohort of 209 participants. Cognitive and behavioural changes were assessed using the Addenbrooke's Cognitive Examination and the Cambridge Behavioural Inventory. Relative to 58 controls, behavioural variant FTD (n = 58) and ALS-FTD (n = 41) patients displayed extensive atrophy of frontoinsular, cingulate, temporal and motor cortices, with marked subcortical atrophy targeting the hippocampus, amygdala, thalamus and striatum, with atrophy further extended to the brainstem, pons and cerebellum in the latter group. At the other end of the spectrum, pure-ALS patients (n = 52) displayed considerable frontoparietal atrophy, including right insular and motor cortices and pons and brainstem regions. Subcortical regions included the bilateral pallidum and putamen, but to a lesser degree than in the ALS-FTD and behavioural variant FTD groups. Across the spectrum the most affected region in all three groups was the insula, and specifically the anterior part (76-90% lower than controls). Direct comparison of the patient groups revealed disproportionate temporal atrophy and widespread subcortical involvement in ALS-FTD relative to pure-ALS. In contrast, pure-ALS displayed significantly greater parietal atrophy. Both behavioural variant FTD and ALS-FTD were characterized by volume decrease in the frontal lobes relative to pure-ALS. The motor cortex and insula emerged as differentiating structures between clinical syndromes, with bilateral motor cortex atrophy more pronounced in ALS-FTD compared with pure-ALS, and greater left motor cortex and insula atrophy relative to behavioural variant FTD. Taking a transdiagnostic approach, we found significant associations between abnormal behaviour and volume loss in a predominantly frontoinsular network involving the amygdala, striatum and thalamus. Our findings demonstrate the presence of distinct atrophy profiles across the ALS-FTD spectrum, with key structures including the motor cortex and insula. Notably, our results point to subcortical involvement in the origin of behavioural disturbances, potentially accounting for the marked phenotypic variability typically observed across the spectrum.

Brainstem Correlates of Pathological Laughter and Crying Frequency in ALS.

Pseudobulbar affect is a disorder of emotional expression commonly observed in amyotrophic lateral sclerosis (ALS), presenting as episodes of involuntary laughter, or crying. The objective of the current study was to determine the association between frequency of pathological laughter and crying (PLC) episodes with clinical features, cognitive impairment, and brainstem pathology. Thirty-five sporadic ALS patients underwent neuropsychological assessment, with a subset also undergoing brain imaging. The Center for Neurological Study Lability Scale (CNS-LS) was used to screen for presence and severity of pseudobulbar affect (CNS-LS ≥ 13) and frequency of PLC episodes. Presence of pseudobulbar affect was significantly higher in bulbar onset ALS (p = 0.02). Frequency of PLC episodes was differentially associated with cognitive performance and brainstem integrity. Notably pathological laughter frequency, but not crying, showed a significant positive association with executive dysfunction on the Trail Making Test B-A (R 2 = 0.14, p = 0.04). Similarly, only pathological laughter frequency demonstrated a significant negative correlation with gray matter volume of the brainstem (R 2 = 0.46, p < 0.01), and mean fractional anisotropy of the superior cerebellar peduncles (left: R 2 = 0.44, p < 0.01; right: R 2 = 0.44, p < 0.01). Hierarchical regression indicated brainstem imaging in combination with site of symptom onset explained 73% of the variance in pathological laughter frequency in ALS. The current findings suggest emotional lability is underpinned by degeneration across distinct neural circuits, with brainstem integrity critical in the emergence of pathological laughter.

Neural mechanisms of psychosis vulnerability and perceptual abnormalities in the ALS-FTD spectrum.

OBJECTIVE: The aims of this study were to (i) explore psychotic experiences across the entire amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum from a clinical and genetic perspective, (ii) determine the rate of abnormal perceptual experiences across the five sensory modalities and (iii) explore the neurobiological factors that lead to psychosis vulnerability in ALS-FTD. METHODS: In a prospective case-controlled study design, 100 participants were enrolled including ALS (n = 37, 24% satisfied criteria for ALS-Plus), ALS-FTD (n = 11), bvFTD (n = 27) and healthy controls (n = 25). Psychotic experiences, perceptual abnormalities and psychosocial factors were determined by means of the clinical interview and carer and patient reports. Voxel-based morphometry analyses determined atrophy patterns in patients experiencing psychosis-like experiences and other perceptual abnormalities. RESULTS: The rates of psychotic experiences and abnormalities of perception in each sensory modality were high across the entire ALS-FTD continuum. The rate was highest in those with C9orf72 expansions. Rates were also high in patients with pure ALS including psychosis measured by carer-based reports (18%) and self-report measures of psychotic-like experiences (21%). In an ENTER regression model, social anxiety and ACE-III scores were the best predictors of psychosis proneness, accounting for 44% of the score variance. Psychosis-like experiences and perceptual abnormalities were associated with a predominantly frontal and temporal pattern of atrophy that extended to the cerebellum and centred on the anterior thalamus. INTERPRETATION: The model for psychosis proneness in ALS-FTD likely includes complex interactions between cognitive, social and neurobiological factors that determine vulnerability to psychosis and that may have relevance for individualised patient management.

Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.

Apathy is associated with parietal cortical-subcortical dysfunction in ALS.

Apathy is the core behavioural feature of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS). Initiation and emotional manifestations of apathy significantly affect patients and carers, particularly in terms of quality of life. As such, the primary aim of the present study was to investigate the prevalence and neural correlates of initiation, and emotional subtypes of apathy in ALS. A total of 109 participants were recruited from a specialised, tertiary referral ALS/FTD clinic. Overall rates of apathy, including cognitive, initiation and emotion subtypes as assessed by the Dimensional Apathy Scale (DAS), were examined and correlated with brain volumes, including voxel-based morphometry on high resolution MRI. Clinically significant apathy ranged between 49% (patient-rated DAS) and 64% (carer-rated DAS), with the most common apathy subtypes being initiation (84-96%) and emotional (74-75%) apathy. The results of the two-way repeated measures ANOVA revealed significant differences across the DAS executive, emotional and initiation subscales (p = .0001). Multivariate analysis using a logistic regression model showed that only initiation; (odds ratio = 3.08, p = .004) and emotional (odds ratio = 2.40, p = .008) apathy were predictive of clinically significant apathy, controlling for education and depression. Increased initiation apathy correlated with reduced grey matter within bilateral superior frontal gyrus and increased emotional apathy correlated with reduced grey matter in prefrontal cortices and right anterior cingulate, previously implicated in apathy. Additional correlations were identified including the angular gyrus (or the temporo-parietal junction), important in reward valuation and subsequent goal-directed behaviour. Taken together, results from the present series highlight the frequency and multi-dimensionality of apathy in ALS. The pathophysiological mechanisms of apathy in ALS may be critically underpinned by neurodegeneration across a distributed brain network, with key roles in task initiation, emotion, reward processing and subsequent goal-directed behaviour.

Regional callosal integrity and bilaterality of limb weakness in amyotrophic lateral sclerosis.

Background and Objectives: The corpus callosum is a site of pathological involvement in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The corpus callosum shows widespread cortical connectivity topographically distributed along its length. Initial limb weakness in ALS is typically unilateral, becoming bilateral with disease progression. The precise anatomical substrate for this spread is uncertain. The present study investigated sub-regional variations in corpus callosum integrity in ALS, and whether these reflect a relationship with the development of unilateral or bilateral limb weakness. Methods: Sporadic ALS patients were categorized into unilateral (n = 14) or bilateral (n = 25) limb weakness at the time of assessment and underwent diffusion tensor imaging. Probabilistic bundle-specific tracking was carried out using MRtrix and TractSeg to parcellate the corpus callosum into seven anatomical segments (rostrum; genu; rostral body; anterior midbody; posterior midbody; isthmus; splenium). White matter tract integrity was assessed in all segments and compared with MRI data acquired from 25 healthy controls. Results: In the combined patient group, the most prominent differences in diffusivity metrics were in the rostral body, posterior midbody and isthmus of the corpus callosum (p < 0.04). Loss of corpus callosum integrity was most prominent in the sub-group with unilateral limb weakness at the time of scanning (p < 0.05). Conclusions: Corpus callosum involvement in ALS is detectable across multiple segments, in keeping with a widespread cortical distribution of pathology. The association of unilateral limb weakness with greater loss of corpus callosum integrity informs connectivity-based hypotheses of symptom propagation in ALS.

The impact of cognitive and behavioral impairment in amyotrophic lateral sclerosis.

Introduction: A spectrum of non-motor manifestations in amyotrophic lateral sclerosis (ALS) patients has been increasingly recognized, with cognitive and behavioral impairments the most prominent. Evidence suggests that ALS overlaps on a pathological, genetic, and clinical level with frontotemporal dementia (FTD), thereby suggesting a frontotemporal spectrum disorder (ALS-FTSD). Cognitive impairment has been reported in up to 75% of ALS patients, whilst the rate of behavioral dysfunction ranges up to 50%.Areas covered: The present review explores the current understanding of cognitive and behavioral changes in ALS with a particular emphasis on its implications on prognosis and survival.Expert commentary: Further longitudinal studies are needed to clarify the evolution of cognitive impairment in ALS and how this may ultimately influence survival. Improving understanding of cognitive changes has important implications toward the capacity of patients in making critical medical decisions. There is a need to develop a universally accepted and validated cognitive assessment tool to be administered in a multidisciplinary clinic that is efficient and sensitive, as well as being integrated into the design and analysis of future ALS drug trials. In addition, revision of the ALS diagnostic criteria is critically needed that should accommodate cognitive and behavioral symptoms in addition to motor manifestations.

Cerebellar tract alterations in PLS and ALS.

The cerebellum shows neuropathological change in a number of neurodegenerative conditions where clinical involvement is not the primary feature, including amyotrophic lateral sclerosis (ALS). Whether these changes are associated with disruption to the direct cerebellar tract pathways to the motor cortex and spinal cord in ALS is uncertain. Diffusion tensor imaging was used to examine the integrity of two primary cerebellar pathways, the dentato-rubro-thalamo-cortical (DRTC) and spino-cerebellar (SC) tracts. ALS patients with an upper motor neuron (UMN)-predominant phenotype (n = 9), were matched to a group with the UMN-only condition primary lateral sclerosis (PLS, n = 10) and healthy controls (n = 17). Significant alterations across diffusion metrics in the DRTC proximal to the motor cortex were found in both patient groups. PLS patients were found to have an independent diffusion abnormality in the cerebellar region of the DRTC and SC tracts. Disruption to primary cerebellar tracts in PLS is therefore postulated, adding to other markers of its divergent pathogenesis from ALS.

Identification and Analysis of Compound Profiles of Sinisan Based on 'Individual Herb, Herb-Pair, Herbal Formula' before and after Processing Using UHPLC-Q-TOF/MS Coupled with Multiple Statistical Strategy.

Sinisan has been widely used to treat depression. However, its pharmacologically-effective constituents are largely unknown, and the pharmacological effects and clinical efficacies of Sinisan-containing processed medicinal herbs may change. To address these important issues, we developed an ultra-high performance liquid chromatography coupled with electrospray ionization tandem quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) method coupled with multiple statistical strategies to analyze the compound profiles of Sinisan, including individual herb, herb-pair, and complicated Chinese medicinal formula. As a result, 122 different constituents from individual herb, herb-pair, and complicated Chinese medicinal formula were identified totally. Through the comparison of three progressive levels, it suggests that processing herbal medicine and/or altering medicinal formula compatibility could change herbal chemical constituents, resulting in different pharmacological effects. This is also the first report that saikosaponin h/i and saikosaponin g have been identified in Sinisan.

Regional thalamic MRI as a marker of widespread cortical pathology and progressive frontotemporal involvement in amyotrophic lateral sclerosis.

BACKGROUND: The thalamus is a major neural hub, with selective connections to virtually all cortical regions of the brain. The multisystem neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) has pathogenic overlap with frontotemporal dementia, and objective in vivo markers of extra-motor pathological spread are lacking. To better consider the role of the thalamus in neurodegeneration, the present study assessed the integrity of the thalamus and its connectivity to major cortical regions of the brain in a longitudinal manner. METHODS: Diffusion-based MRI tractography was used to parcellate the thalamus into distinct regions based on structural thalamo-cortical connectivity in 20 patients with ALS, half of whom were scanned at two time points, and 31 matched controls scanned on a single occasion. RESULTS: At baseline, widespread diffusivity alterations in motor- and extramotor-associated thalamic parcellations were detectable. Longitudinal decline selectively affected thalamic regions associated with frontal and temporal lobe connectivity. Diffusivity measures were significantly correlated with clinical measures of disease burden. Progression of functional disability, as indicated by change on the ALS functional rating scale, was associated with longitudinal change in mean diffusivity of the right frontal lobe thalamic parcellation (r=0.59, p=0.05). CONCLUSIONS: Regional thalamic connectivity changes mirror the progressive frontotemporal cortical involvement associated with the motor functional decline in ALS. Longitudinal MRI thalamic parcellation has potential as a non-invasive surrogate marker of cortical dysfunction in ALS.

Profiling and analysis of multiple constituents in Baizhu Shaoyao San before and after processing by stir-frying using UHPLC/Q-TOF-MS/MS coupled with multivariate statistical analysis.

Baizhu Shaoyao San (BSS) is a famous traditional Chinese medicinal formula widely used for the treatment of painful diarrhea, intestinal inflammation, and diarrhea-predominant irritable bowel syndrome. According to clinical medication, three medicinal herbs (Atractylodis Macrocephalae Rhizoma, Paeoniae Radix Alba, and Citri Reticulatae Pericarpium) included in BSS must be processed using some specific methods of stir-frying. On the basis of the classical theories of traditional Chinese medicine, the therapeutic effects of BSS would be significantly enhanced after processing. Generally, the changes of curative effects mainly result from the variations of inside chemical basis caused by the processing procedure. To find out the corresponding changes of chemical compositions in BSS after processing and to elucidate the material basis of the changed curative effects, an optimized ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry in positive and negative ion modes coupled with multivariate statistical analyses were developed. As a result, a total of 186 compounds were ultimately identified in crude and processed BSS, in which 62 marker compounds with significant differences between crude and processed BSS were found by principal component analysis and t-test. Compared with crude BSS, the contents of 23 compounds were remarkably decreased and the contents of 39 compounds showed notable increase in processed BSS. The transformation mechanisms of some changed compounds were appropriately inferred from the results. Furthermore, compounds with extremely significant differences might strengthen the effects of the whole herbal formula.

Hot air treatment reduces postharvest decay and delays softening of cherry tomato by regulating gene expression and activities of cell wall-degrading enzymes.

BACKGROUND: Fruit softening facilitates pathogen infection and postharvest decay, leading to the reduction of shelf-life. Hot air (HA) treatment at 38 °C for 12 h is effective in reducing postharvest disease and chilling injury of tomato fruit. To explore the effect and mechanism of HA treatment on reducing postharvest decay and softening of cherry tomato, fruit at the mature green stage were treated with HA and then stored at 20 °C for 15 days. Changes in natural decay incidence, firmness, cell wall compositions, activities and gene expression of cell wall-degrading enzymes of cherry tomatoes were assessed. RESULTS: HA treatment reduced natural decay incidence, postponed the firmness decline, inhibited the respiration rate and ethylene production, and retarded pectin solubilisation and cellulose degradation of cherry tomatoes. Enzymatic activities and gene expression of pectin methylesterase, polygalacturonase, cellulase and ß-galactosidase were inhibited by HA treatment. In addition, the gene expression of LeEXP1 was reduced, while LeEXT was up-regulated after HA treatment. CONCLUSIONS: Our findings suggested that HA treatment could inhibit cell wall degradation and postpone softening of cherry tomatoes by regulating gene expression and activities of cell wall-degrading enzymes, resulting in the reduction of postharvest decay. © 2017 Society of Chemical Industry.