Treatment-resistant schizophrenia: Addressing white matter integrity, intracortical glutamate levels, clinical and cognitive profiles between early- and adult-onset patients.

Treatment-resistance in schizophrenia is 30-40%. Its neurobiology remains unclear; to explore it, we conducted a combined spectrometry/tractography/cognitive battery and psychopathological rating study on patients with treatment-resistant schizophrenia (TRS), dividing the sample into early-onset (N = 21) and adult-onset TRS (N = 20). Previous studies did not differentiate between early- (onset 13-18 years) and adult-onset (>18 years at formal diagnosis of schizophrenia) TRS. We evaluated cross-sectionally 41 TRS patients (26 male and 15 female) and 20 matched healthy controls (HCs) with psychopathological and cognitive testing prior to participating in brain imaging scanning using magnetic resonance spectroscopy and diffusion tensor imaging to determine the relationship between their symptoms and their glutamate levels and white matter integrity. TRS patients scored lower than HCs on all cognitive domains; early-onset patients performed better than adult-onset patients only on the Symbol Coding domain. TRS correlated with symptom severity, especially negative symptoms. Glutamate levels and glutamate/creatine were increased in anterior cingulate cortex. Diffusion tensor imaging showed low fractional anisotropy in TRS patients in specific white matter tracts compared to HCs (bilateral anterior thalamic radiation, cortico-spinal tract, forceps minor, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, and right uncinate fasciculus). We identified specific magnetic resonance spectroscopy and diffusion tensor imaging alterations in TRS patients. Adult-onset TRS differed little from early-onset TRS on most measures; this points to alterations being present since the outset of schizophrenia and may constitute a biological signature of treatment-resistance.

Matrone M ，Kotzalidis GD ，Romano A ，Bozzao A ，Cuomo I ，Valente F ，Gabaglio C ，Lombardozzi G ，Trovini G ，Amici E ，Perrini F ，De Persis S ，Iasevoli F ，De Filippis S ，de Bartolomeis A ... -  《-》

White matter microstructural organizations in patients with severe treatment-resistant schizophrenia: A diffusion tensor imaging study.

Previous diffusion tensor imaging (DTI) studies have reported white matter alterations in patients with schizophrenia. Notably, one third of this population does not respond to first-line antipsychotics and is thus referred to as treatment-resistant schizophrenia (TRS). Despite potentially distinct neural bases between TRS and non-TRS, few studies have compared white matter integrity between these groups. In order to reflect clinical picture of TRS, we enrolled TRS patients who had severe symptoms. According to the consensus criteria for TRS. TRS was defined by severe positive symptomatology despite optimal antipsychotic treatment. Fractional anisotropy (FA), an index of white matter integrity, was examined by DTI and analyzed with tract-based spatial statistics in 24 TRS patients (mean PANSS = 108.9), 28 non-TRS patients (mean PANSS = 50.0), and 27 healthy controls (HCs) for group comparison. Additionally, correlation analyses were conducted between FA values and symptomatology. The TRS group had lower FA values in multiple tracts (cerebral peduncle, corona radiata, corpus callosum, external and internal capsules, posterior thalamic radiation, sagittal stratum, superior longitudinal fasciculus, tapetum, and uncinate fasciculus) compared to the HC group as well as the non-TRS group (p < .05; family-wise error-corrected), while no differences were found between the non-TRS and HC groups. In the TRS group, FA values in most of the tracts (other than the left anterior limb of internal capsule, left cerebral peduncle, and right uncinate fasciculus) were negatively correlated with the Positive and Negative Syndrome Scale total scores, and negative and general symptom scores. No such relationships were found in the non-TRS group. The identified white matter integrity deficits may reflect the pathophysiology of TRS.

Ochi R ，Noda Y ，Tsuchimoto S ，Tarumi R ，Honda S ，Matsushita K ，Tsugawa S ，Plitman E ，Masuda F ，Ogyu K ，Wada M ，Miyazaki T ，Fujii S ，Chakravarty MM ，Graff-Guerrero A ，Uchida H ，Mimura M ，Nakajima S ... -  《-》

Abnormal white matter microstructure in drug-naive first episode schizophrenia patients before and after eight weeks of antipsychotic treatment.

Abnormal white matter integrity has been reported among first episode schizophrenia patients. However, findings on whether it can be reversed by short-term antipsychotic medications are inconsistent. Diffusion tensor imaging (DTI) was obtained from 55 drug-naive first episode schizophrenia patients and 61 healthy controls, and was repeated among 25 patients and 31 controls after 8 weeks during which patients were medicated with antipsychotics. White matter integrity is measured using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). These measures showing a group difference by Tract-based spatial statistics (TBSS) at baseline were extracted for longitudinal comparisons. At baseline, patients exhibited lower FA, higher MD and higher RD versus controls in forceps, left superior longitudinal fasciculus, inferior fronto-occipital fasciculus, left corticospinal tract, left uncinate fasciculus, left anterior thalamic radiation, and bilateral inferior longitudinal fasciculi. FA values of schizophrenia patients correlated with their negative symptoms (r=-0.412, P=0.002), working memory (r=0.377, P=0.005) and visual learning (r=0.281, P=0.038). The longitudinal changes in DTI indices in these tracts did not differ between patients and controls. However, among the patients the longitudinal changes in FA values in left superior longitudinal fasciculus correlated with the change of positive symptoms (r=-0.560, p=0.004), and the change of processing speed (r=0.469, p=0.018). White matter deficits were validated in the present study by a relatively large sample of medication naïve and first episode schizophrenia patients. They could be associated with negative symptoms and cognitive impairment, whereas improvement in white matter integrity of left superior longitudinal fasciculus correlated with improvement in psychosis and processing speed. Further examination of treatment-related changes in white matter integrity may provide clues to the mechanism of antipsychotic response and provide a biomarker for clinical studies.

Zeng B ，Ardekani BA ，Tang Y ，Zhang T ，Zhao S ，Cui H ，Fan X ，Zhuo K ，Li C ，Xu Y ，Goff DC ，Wang J ... -  《-》

Analysis of white matter characteristics with tract-based spatial statistics according to diffusion tensor imaging in early Parkinson's disease.

To analyze the microstructure of brain white matter according to diffusion tensor imaging (DTI) based on tract-based spatial statistics (TBSS) in early Parkinson's disease (PD). A total of 31 age- and sex-matched early PD patients and 22 healthy volunteers were recruited in the present study. DTI was performed, and the data analyzed with fsl4.0 software. The fractional anisotropy (FA) was compared between both groups with an independent t test, and the differential area was analyzed. White matter fiber tracts with significant difference in FA between the two groups were selected, and their FAs were measured. Pearson's correlation analysis was employed to analyze the unified Parkinson's disease rating scale (UPDRS) score and its association with FA of different tracts. When compared with healthy volunteers, early PD patients had reduced FA in the following areas: bilateral anterior corona radiate, upper corona radiate, fasciculus arcuatus, crus anterius capsulae internae, crus posterius capsulae internae, capsula externa, posterior thalamic radiation, optic radiation, sagittal layer (including fasciculus arcuatus and inferior fronto-occipital fasciculus), crura fornicis, stria terminalis, fornix, genu, body and pad of corpus callosum, left unciform fasciculus, right cingulate bundle, right medipeduncle, and arcuate fibers in the bilateral frontal, temporal, and occipital lobes (P < 0.05). When compared with healthy volunteers, early PD patients showed abnormal FA of fasciculus in the white matter mainly in following areas: bilateral crus anterius capsulae internae, bilateral capsula externa, right anterior corona radiate, body and pad of bilateral corpus callosum, and left sagittal layer (including fasciculi longitudinalis inferior and fasciculus occipitofrontalis inferior) (P < 0.05). In addition, in early PD patients, the UPDRS score and movement score had no relationship with the FA of different fasciculi in the white matter (P > 0.05). There is wide alteration of white matter microstructure in early PD patients, which is characterized by disruption of projection fibers in the descending pathway, limbic system-related fasciculi, corpus callosum, thalamus after radiation, posterior thalamic radiation, Gratiolet's bundle and other fasciculi in the white matter.

Li XR ，Ren YD ，Cao B ，Huang XL ... -  《-》

N-methyl-D-aspartate Receptor Antibody and White Matter Deficits in Schizophrenia Treatment-Resistance.

Insufficient or lack of response to antipsychotic medications in some patients with schizophrenia is a major challenge in psychiatry, but the underlying mechanisms remain unclear. Two seemingly unrelated observations, cerebral white matter and N-methyl-D-aspartate receptor (NMDAR) hypofunction, have been linked to treatment-resistant schizophrenia (TRS). As NMDARs are critical to axonal myelination and signal transduction, we hypothesized that NMDAR antibody (Ab), when present in schizophrenia, may impair NMDAR functions and white matter microstructures, contributing to TRS. In this study, 50 patients with TRS, 45 patients with nontreatment-resistant schizophrenia (NTRS), 53 patients with schizophrenia at treatment initiation schizophrenia (TIS), and 90 healthy controls were enrolled. Serum NMDAR Ab levels and white matter diffusion tensor imaging fractional anisotropy (FA) were assessed. The white matter specificity effects by NMDAR Ab were assessed by comparing with effects on cortical and subcortical gray matter. Serum NMDAR Ab levels of the TRS were significantly higher than those of the NTRS (P = .035). In patients with TRS, higher NMDAR Ab levels were significantly associated with reduced whole-brain average FA (r = -.37; P = .026), with the strongest effect at the genu of corpus callosum (r = -.50; P = .0021, significant after correction for multiple comparisons). Conversely, there was no significant correlation between whole-brain or regional cortical thickness or any subcortical gray matter structural volume and NMDAR Ab levels in TRS. Our finding highlights a potential NMDAR mechanism on white matter microstructure impairment in schizophrenia that may contribute to their treatment resistance to antipsychotic medications.

Tong J ，Zhou Y ，Huang J ，Zhang P ，Fan F ，Chen S ，Tian B ，Cui Y ，Tian L ，Tan S ，Wang Z ，Feng W ，Yang F ，Hare S ，Goldwaser EL ，Bruce HA ，Kvarta M ，Chen S ，Kochunov P ，Tan Y ，Hong LE ... -  《-》