Molecular Pathological Examination Research Articles

Clinical efficacy and safety of mTOR inhibitor in patients with advanced unresectable epithelioid hemangioendothelioma (EHE).

e23540 Background: Epithelioidhemangioendothelioma is a rare vascular soft tissue sarcoma, 90% of which contains WWTR1-CAMTA1 fusion gene. Studies have shown that mTOR inhibitors may have a certain effect on EHE patients. Methods: A retrospective analysis of the efficacy and safety of mTOR inhibitor everolimus in the treatment of advanced unresectable epithelioidhemangioendothelioma in our hospital in the past one year. Patients with advanced epithelioidhemangioendothelioma (EHE) confirmed by consultation in the pathological center received this regimen, everolimus 10mg, once a day orally for 28 days, every 4 weeks as a treatment cycle until the disease progressed or showed intolerable toxicity. Results: There were 3 females and 5 males, and their average age was 41.8 years old. All of them were unresectable with liver, lung, and shoulder primary lesions, and lungs, liver, pleura and bone metastasis. Ki67 is from 2% to 10%. 3 patients who received molecular pathological examination were all identified the WWTR1-CAMTA1 fusion gene, and one of them also had EWSR1 chromosome translocation. Previous antineoplastic treatments included gemcitabine, cisplatin, albumin paclitaxel, epirubicin, dacarbazine chemotherapy, anlotinib targeting, and toripalimab immune therapy. 5 patients were treated with first-line drugs, 2 cases with second-line and 1 case with third-line. In terms of overall efficacy, 1 case was not evaluated, 2 cases lost follow-up due to poor tolerance and economic factors, 2 cases were included in the clinical trails after reaching tumor control for 3 months, and the other 3 cases achieved tumor remission with a median PFS of 11.0 months, and the best curative effect was SDa. Severe oral mucositis can greatly affect the medication experience of patients, which can be relieved after symptomatic medication, or when interstitial pneumonia and hemogram decrease significantly, we can consider the oral administration of everolimus 5mg. Conclusions: At present, there is no standard treatment for EHE, we can roughly see the efficacy of mTOR inhibitor everolimus in some EHE patients, mainly disease stability. Emphasis on side effect management, improve tolerance, and systematic treatment of EHE needs to be further explored.

Molecular pathological analysis through the ages

Molecular pathological examinations of tumor samples encompass awide range of diagnostic analyses. Especially in recent years, numerous new biomarkers have come to the forefront-the analysis of which is crucial for therapy decisions. Within the field of molecular pathology, the demands of next generation sequencing (NGS)-based requirements have experienced massive growth in recent years. To meet this demand, methods are constantly being adapted and further developed. The following sections aim to illuminate how this trend arises and which analyses are gaining importance. The article provides an overview of the essential nucleic acid-based analysis techniques in the field of massive parallel sequencing. Terms such as DNA- and RNA-based techniques, as well as the associated analysis methods, are described, particularly with regard to their use in routine molecular pathological diagnostics. The breadth of genomic sequencing has been steadily growing in recent years, particularly due to the increasing relevance of personalized medicine, along with the rising approvals of targeted therapeutics. This necessitates, among other things, the analysis of new biomarkers. The diagnostics as part of interdisciplinary molecular tumor boards (MTB) are now based on large gene panels (> 1 megabase). Furthermore, through the "Modellvorhaben Genomsequenzierung" §64e, whole exome or whole genome sequencing has been made available for oncological patients. Given these developments, it is evident that future analyses will require the integration of additional omics fields, such as whole transcriptome analysis, epigenomics, and proteomics. The challenges of personalized medicine along with the necessity of simultaneously assessing numerous new biomarkers require the implementation and execution of new techniques in molecular pathology whose complexity is steadily increasing.

Application of ultrasonic cavitation combined with rapid pathological tissue processing method of novel environmental protection reagents in pathological diagnosis.

To investigate the effect of pretreatment of tumor biopsy specimens using fixed, dehydrated and transparent three-in-one composite environmental protection reagent ultrasound tissue rapid processing technique on subsequent detection. From April 2020 to October 2020, a total of 100 cases including breast, stomach and lung tissues were submitted to our diagnosis, and 3 specimens were collected from each specimen and divided into the control group (traditional biopsy tissue processing method), experimental group 1 (3.7% neutral buffered formaldehyde fixation, compound environmental protection reagent rapid ultrasound tissue processing technique, processing temperature 48 °C, time 20 minutes/time, twice, wax immersion temperature 62 °C, time 25 minutes) and experimental group 2 (3.7% neutral buffered formaldehyde fixation, compound environmental protection reagent rapid ultrasound tissue processing technique, processing temperature 50 °C, time 15 min/time, twice, Wax dipping temperature 64 °C, time 20 minutes). The effects of different treatments on hematoxylin eosin section, immunohistochemistry (IHC) and molecular pathological examination were analyzed. The detection results of hematoxylin eosin, fluorescence in situ hybridization and IHC against human epidermal growth factor receptor 2 and epidermal growth factor receptor gene mutation in the experimental group were completely consistent with those in the control group. There was no significant difference in the results between experiment 1 and experiment 2 groups. The rapid processing technique of ultrasound tissue with compound environmental protection reagent can be applied to the rapid detection of tumor biopsy specimens, and different processing temperatures and durations have no significant effect on the accuracy of HE staining, IHC, fluorescence in situ hybridization and gene mutation detection.

Description, molecular identification and pathological lesions of Huffmanela persica sp. nov. (Nematoda: Trichosomoididae: Huffmanelinae) from the daggertooth pike conger Muraenesox cinereus

BackgroundThe genus Huffmanela Moravec, 1987 (Nematoda, Trichosomoididae, Huffmanelinae), represents a group of nematodes that infect both marine and freshwater fish, and the main gross feature of infection with different species of the genus is the presence of noticeable dark spots or tracks within the parasitized tissues. The purpose of this study was to describe morphologically and morphometrically the eggs of a new marine species of Huffmanela (Huffmanela persica sp. nov.), which was found in the form of black spots in the ovary and the tunica serosa of the stomach of the daggertooth pike conger (Muraenesox cinereus). The new species differs from Huffmanela hamo, another species reported from musculature of this host in Japan, in egg metrics, eggshell features and targeted organ. Molecular identification and pathological examination of the lesions caused by the new species are also reported.MethodsNematode eggs with varying degrees of development were separated from the infected tissues (ovary and tunica serosa of stomach) and investigated using light and scanning electron microscopy. Different species-specific markers (small subunit ribosomal DNA, 18S; large subunit ribosomal DNA, 28S; internal transcribed spacer, ITS) were used for molecular identification and phylogenetic study of the new species. Infected tissues were fixed in buffered formalin for pathological investigations.ResultsThe fully developed eggs of H. persica sp. nov. are distinguished from those previously described from this host on the basis of their measurements (size, 54–68 × 31–43 µm; polar plugs, 6.4–9.7 × 8.4–12 µm; shell thickness, 3.5–6.1 µm) and a delicate but ornate uterine layer (UL) covering the entire eggshell including the polar plugs. Histopathological examination revealed a fibro-granulomatous inflammation in the ovary and the serosal layer of the stomach of infected fish. Maximum-likelihood (ML) phylogenetic analysis recovered a sister relationship between the new species of marine origin and Huffmanela species previously collected from freshwater hosts.ConclusionsThe present study is the first to report the molecular characterization and phylogenetic position of a teleost-associated marine species of the genus Huffmanela. A comprehensive list of nominal and innominate populations of Huffmanela is also provided.Graphical abstract

Molecular pathological analysis in routine diagnostic

Molecular pathological examinations in the context of diagnostic analyses of tumour samples cover a broad spectrum of techniques for routine diagnostics. Especially in the last few years, there has been an increase in a large number of new biomarkers, the investigation of which is of great importance for therapy decision but also for accurate diagnosis. At the same time, the available amount of tissue is getting more and more limited due to different reasons: 1. The change in surgical procedure from large resections to tiny little biopsies; 2. The increasing number of markers which has to be tested on this limited material, e. g. by immunohistochemical stainings.

Cutaneous metastasis of cecum cancer with MSI-high and BRAFV600E mutation: a case report

BackgroundCutaneous metastases of colorectal cancer (CRC) are rare, occurring in 0.7% to 5% of cancer patients. Furthermore, the molecular subtypes of cutaneous metastasis of CRC are unclear. Here, we present a rare case of cutaneous metastasis of high-frequency microsatellite instability (MSI-high)/BRAFV600E-mutant cecum cancer.Case presentationA 77-year-old woman presented at the outpatient clinic with a subcutaneous mass on her left back. An excisional biopsy was performed and metastatic cutaneous adenocarcinoma was diagnosed. A computed tomography scan of the thorax and abdomen showed thickening of the cecum wall, the presence of pericolic lymph nodes, multiple masses in the liver, and a single nodule in the right lung. Right colectomy with D2 lymphadenectomy and functional end-to-end anastomosis was performed because of the almost-complete intestinal obstruction. The expression of KRAS wild type, BRAFV600E mutation, and MSI-high was detected in the cecum cancer using molecular pathological examination. She received chemotherapy with XELOX + BEV regimen (capecitabine + oxaliplatin + bevacizumab). After four administrations, a computed tomography scan showed reduction of distant metastases, which suggested partial response.ConclusionsWe encountered a rare case of cutaneous metastasis of MSI-high and BRAFV600E-mutant cecum cancer. In the future, it will be necessary to accumulate more cases to identify clinical features and more effective treatments for CRCs with cutaneous metastasis.

Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB) Immunohistochemistry in Pheochromocytoma, Head and Neck Paraganglioma, Thoraco-Abdomino-Pelvic Paragangliomas: Is It a Good Idea to Use in Routine Work?

Background:In this study, we aimed to detect Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB) frequency in paragangliomas and pheochromocytomas (PPGL) with immunohistochemistry; compare with Pheochromacytoma of the Adrenal Gland Scaled Score (PASS) classification and analyse the differences between pheochromocytoma (Pheo), head-neck paragangliomas (HNPGL) and thoraco-abdominal-pelvic paraganglioma (TAPPGL) sub-groups. Methods:A total 114 PPGL cases (73 HNPGL, 15 TAPPGL and 27 Pheo belonging to 112 cases) are included. Immunohistochemically, SDHB and Ki-67 are investigated and malignancy risks are determined by PASS classification. Results are assessed statistically with chi-square test and p <0,01 is considered significant.Results:SDHB mutations are observed in 20 of 114 (17.54 %) PPGL cases, 3 (11,12%) of which is Pheo, 12 (16,44) is HNPGL, and 5 (35,71%) is TAPPGL (P <0,02). While 15/82 (18,29%) cases with SDHB mutations do not have a malignancy potential according to PASS classification, 5/32 (15,63%) cases has (p=0,73). TAPPGL, HNPGL and Pheo sub-groups have a significant difference between SDHB expression (p <0,02), malignancy potential according to PASS classification (p <0,0001) and Ki-67 proliferation index (p <0,0001). Conclusion:To identify patients for molecular pathological examination, routine application of SDHB immunohistochemistry to PPGL tumors are suggested especially in HNPGLs.

Giant congenital nodular melanoma in a newborn: a case report and literature review

BackgroundMalignant melanoma (MM) arises predominantly after adolescence and is uncommon in children. Congenital MM in newborns is even rarer with a dearth of published literature; as a consequence, there is no uniform standard for the pathogenesis and treatment for neonatal malignant melanoma. Herein we report a case of giant congenital nodular MM in a newborn, including its clinical, imaging, pathological and molecular pathological features. This case is the largest giant congenital primary nodular malignant melanoma in utero in neonates currently reported in China.Case presentationA female neonatal patient was found to have a 2.97 cm× 1.82 cm×1.50 cm mass with a clear boundary at the right acromion in color Doppler ultrasound examination at 24 weeks of gestation. The mass increased to 3.0 cm×5.0 cm×9.0 cm at birth, and local ulceration was seen. MRI demonstrated that the mass was located on the right shoulder and underarm in a lobulated appearance, and surrounded the right scapula which was deformed. Clinical stage:IV(AJCC 8th Edition (2017)). α-Fetoprofein (AFP) by hematological examination: 1210ng/ml, NSE: 21.28ng/ml, LDH: 842U/L. The patient underwent surgical resection of the tumor, and was pathologically diagnosed as neonatal congenital malignant melanoma; immunohistochemistry (IHC): S-100 (+), HMB45 (+), Melan A (+), and Tyrosinase (+). Molecular pathological examination for BRAF V600E showed no mutations (Quantitative Real-time PCR, qPCR); And so were NRAS, C-kit (exons 9,11,13,14,17,18), and TERT (promoter locus, C228T and C250T) (Sanger sequencing). Non-surgical therapies were not carried out after the surgical resection of the tumor. After 6 months of follow-up, the child developed normally, and color Doppler ultrasound showed no obvious tumor growth or abnormality in the original tumor site.ConclusionsIt is extremely rare to see giant congenital primary nodular MM in utero in neonates. The pathogenesis, treatment and prognosis of congenital MM need further research. The diagnosis mainly depends on histopathology and immunohistochemistry, and it needs to be differentiated from malignant lymphoma and primitive neuroectodermal tumor. The current treatment strategy for MM relies on the surgical excision of the mass. Research directed at molecular detection for genetic mutations would contribute to targeted therapy and better prognosis.

Molecular pathology of tuberculosis : Status, methodology, and limits

In the diagnosis of mycobacterioses, microbiological examination with culture and antibiogram, possibly in combination with molecular biological testing of the fresh material, still represents the gold standard. However, these methods are not available for formalin-fixed paraffin-embedded (FFPE) material or other fixed samples. For this reason, the first step in pathology is to attempt microscopic pathogen detection (ZN/Fite/rhodamine-auramine). Subsequently, molecular pathological examination for the detection of mycobacterial gene sequences should also be considered mandatory today. Although this has clear limits due to the material, it is nevertheless well suited, if carried out correctly, to detect amycobacterial infection or make it unlikely. Anegative result may favor an alternative diagnosis but does not completely rule out mycobacteriosis.For the therapy of tuberculosis or nontuberculous mycobacterial (NTM) disease, the reliable detection of the species and the determination of resistance is of utmost importance. With regard to therapy, the clinician cannot afford to make afalse diagnosis. In case of doubt, arebiopsy for sampling native material, particularly for microbiological testing, should be discussed.

Diagnostic principles of thyroid tumors in pathology : Relevant changes due to the current WHO classification

The current edition of the WHO classification of thyroid tumors (2017) contains anumber of very relevant changes with considerable consequences for the diagnostic assessment of thyroid specimens. This applies to both the histomorphological examination of surgical specimens and the preoperative fine needle biopsy (FNB). In addition, molecular pathological examinations are becoming increasingly important in the diagnosis of thyroid tumors. Changes affect practically all areas of thyroid tumor diagnostics. Some of these changes have far-reaching consequences that justify acomprehensive commentary and query of the knowledge acquired in the form of this CME article.

Clinical complete regression after local radiotherapy combined with chemotherapy for stage IV rectal cancer: A case report.

Colorectal cancer is the fourth most common type of cancer worldwide with about 0.8 million new cases annually. Improving patient survival remains a challenge for clinicians. Observation waiting method provides improved quality of life compared with direct surgery. This case report suggested that colorectal cancer patients could choose active observation waiting method for treatment. A 59-year-old male patient, with rectal bleeding and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, was admitted to the hospital due to increased fecal blood volume. The electronic colonoscopy revealed multiple polyps in colon and rectum, whereas the pathological biopsy indicated poorly differentiated rectal adenocarcinoma. The clinical stage was defined as T3N2M1a according to the TNM classification of the American Joint Committee on Cancer (AJCC) staging manual (version 8). In addition, positron emission tomography/computed tomography (PET/CT) examination showed non-regional lymph node metastasis (subclavian). Subsequently, the expression of PD-L1 (-), NRAS (-), KRAS (-), HRAS (-), BRAF (-) (-, negative) and the microsatellite stability (MSS) were detected in the rectal cancer lesion using molecular pathological examination. Patients with primary rectal cancer and pelvic lymph node metastasis were treated with three-dimensional conformal radiotherapy (3D-CRT; dose, 60 Gy/30 Fr) and XELOX chemotherapy (200 mg oxaliplatin at day 1 plus 1.5 g capecitabine twice a day from day 1-14 for a total of 5 cycles). PET/CT scan revealed that the metabolism levels of the lesion returned to normal. In addition, the routine re-examination showed progressive improvement of tumor lesions. Until recently, the carcinoembryonic antigen (CEA) level of the male patient has been within normal range. The observation waiting method rather than the direct sequential surgical resection of the primary lesion in patients with advanced rectal cancer who achieved complete clinical remission (CCR) may provide a novel treatment method for rectal cancer. Thus, overall survival (OS) and quality of survival (QoS) differences between the two strategies need to be further verified by multicenter clinical trials.

Fatal interstitial\xa0lung disease associated with Crizotinib pathologically confirmed by percutaneous lung biopsy in a patient with ROS1-rearranged advanced non-small-cell lung cancer: a case report

BackgroundCrizotinib is a multi-target inhibitor approved for the treatment of advanced non-small-cell lung cancer patients with a ROS1 rearrangement. However, interstitial lung disease is a rare but severe and fatal side effect of crizotinib that should lead to immediate discontinuation of the drug. Unfortunately, the pathophysiology, molecular mechanism and risk factors for crizotinib-induced interstitial lung disease remain poorly understood.Case presentationWe first identified and reported interstitial lung disease induced de novo by crizotinib in a 47-year-old female patient who was diagnosed with advanced lung adenocarcinoma with a ROS1 rearrangement in a malignant pleural effusion. Subsequent next-generation sequencing analysis revealed both ROS1 rearrangement and an EGFR exon 19 deletion mutation in lung biopsy specimens, which were histologically confirmed to be interstitial lung disease. Although crizotinib treatment was ceased immediately and a shock treatment with high-dose methylprednisolone as well as other necessary treatment procedures was applied to reverse the interstitial lung disease process, the patient died.ConclusionsThe present case indicates that while treating non-small-cell lung cancer patients with crizotinib, it is important to constantly monitor any newly emerging respiratory symptoms and unexplained imaging changes, which may suggest an adverse effect related to drug-induced interstitial lung disease or even lethality. Histopathology and molecular pathological examination of lung biopsy specimens may help clinicians understand the development mechanism and exclude other causes.

Colorectal Cancers: An Update on Their Molecular Pathology.

Colorectal cancers (CRCs) are the third leading cause of cancer-related mortality worldwide. Rather than being a single, uniform disease type, accumulating evidence suggests that CRCs comprise a group of molecularly heterogeneous diseases that are characterized by a range of genomic and epigenomic alterations. This heterogeneity slows the development of molecular-targeted therapy as a form of precision medicine. Recent data regarding comprehensive molecular characterizations and molecular pathological examinations of CRCs have increased our understanding of the genomic and epigenomic landscapes of CRCs, which has enabled CRCs to be reclassified into biologically and clinically meaningful subtypes. The increased knowledge of the molecular pathological epidemiology of CRCs has permitted their evolution from a vaguely understood, heterogeneous group of diseases with variable clinical courses to characteristic molecular subtypes, a development that will allow the implementation of personalized therapies and better management of patients with CRC. This review provides a perspective regarding recent developments in our knowledge of the molecular and epidemiological landscapes of CRCs, including results of comprehensive molecular characterizations obtained from high-throughput analyses and the latest developments regarding their molecular pathologies, immunological biomarkers, and associated gut microbiome. Advances in our understanding of potential personalized therapies for molecularly specific subtypes are also reviewed.

P1.02-040 Heterogeneity of the EGFR / KRAS Gene Mutation in Multifocal Lung Adenocarcinoma and the Clinical Significance

Significant advances on EGFR-targeted therapy have allowed increasing availability of therapeutic options for non-small cell lung cancers. For multifocal lung adenocarcinoma patients in clinic, the EGFR gene mutation is generally examined only on the largest tumor or the one containing the most tumor cells, which could omit the tumors harboring the EGFR mutation and thus loss of opportunity for the tyrosine kinase inhibitors therapy. A total of 58 cases of multifocal lung adenocarcinoma, including 129 intrapulmonary tumors resected surgically, was recruited for this study. The genome DNA samples were prepared from formalin-fixed and paraffin-embedded tumor tissues. The EGFR / KRAS mutational status of each tumor was examined by Sanger’s DNA sequencing. The targeted hotspot mutations in EGFR gene included p.G719S/C/A (exon 18), p.T790M (exon 20), p.S768I (exon 20), p.L858R (exon 21), p.L861Q (exon 21) and deletions in exon 19. The hotspot mutations in KRAS gene were within codon 12 including p.G12C/V/S/R/D/A. In this group of 58 patients with multifocal lung adenocarcinoma, 38 patients were found EGFR or KRAS mutations in their tumors. Among them, the EGFR mutations were detected in 59 tumors derived from 34 cases; while the KRAS mutations were detected in 7 tumors from 5 cases. One patient (Case 30) was identified EGFR (exon 18, p.G719A) or KRAS (p.G12A or p.G12C) mutation in her 3 tumors, respectively. It is noteworthy that there were 21 (36.2%) in the 58 cases showing the mutational heterogeneity among the multiple intrapulmonary tumors derived from one individual, and that 6 tumors harbored 2 different types of EGFR mutation. However, none of the specimens investigated contained both EGFR and KRAS mutations within a same tumor. Comparing data from the present study along with the molecular pathological diagnosis records from the Department of Pathology, among the 58 cases enrolled, 30 cases accepted routine molecular pathological examination to check the EGFR / KRAS mutation, and 28 cases did not. However, 37 out of 66 tumors from the 30 cases were tested -- only 5 patients had all their tumors examined; whereas in the rest total 92 tumors unchecked, 42 EGFR sensitive mutations were identified in this study. Current finding suggests that the EGFR and KRAS mutational heterogeneity is widely existed in multifocal lung adenocarcinomas. Therefore, reliable and exhaustive examination for EGFR/KRAS mutation should be executed in the every tumor, to provide more individualized therapy choices for the patients.

HPV infection in oral, pharyngeal and laryngeal papillomas

HPV infections play a major role in the pathogenesis of squamous cell carcinomas of the head and neck. Regarding benign papillomas, the role of HPV is still uncertain. To clarify this issue, 100 exophytic papillomas of the oral cavity, pharynx and larynx were subjected to histopathological and molecular pathological examination. Excision biopsies were taken from 62 male and 38 female patients with an age range of 18 to 87 years. Biopsies were tested for p16 expression by immunohistochemistry and analyzed for HPV subtypes 6/11 (low-risk), 16/18 and 31/33/53 (high-risk) by chromogenic in situ hybridization. HPV infections were verified molecularly in 34 % of biopsies; in all cases with the low-risk HPV subtypes 6/11. Only one case showed infection with both 6/11 and 31/33/53 subtypes, but not subtype 16/18; whereas expression of p16 was found in 67 %. The rate of positive molecular verification of HPV infection (in situ hybridization) was highest in the laryngeal lesions with 61.1 %, followed by the oral cavity with 52.9 %, and lowest in pharyngeal lesions (21.5 %). Recurrent papillomas were seen in 18 cases (18 %), of which 14 were molecularly positive for HPV (in situ hybridization). A correlation between inflammatory infiltration and HPV infection could be verified in 82 %. Our data demonstrate an important role of HPV infection for the development of benign papillomas of the head and neck region. Furthermore, there is a positive correlation between HPV infection and recurrent papillomas. Therefore, a molecular morphological HPV analysis of papillomas could provide important prognostic data.

Dopamine reduction in the substantia nigra of Parkinson's disease patients confirmed by in vivo magnetic resonance spectroscopic imaging.

ObjectivesMetabolic changes in the substantia nigra of patients with Parkinson's disease were previously investigated in different molecular-pathological examinations. The aim of our study was the in vivo measurement of these alterations using three-dimensional magnetic resonance spectroscopic imaging.Methods21 patients with Parkinson's disease and 24 controls were examined using magnetic resonance spectroscopic imaging at 3 Tesla. The spectra of rostral and caudal substantia nigra regions were analyzed using LCModel. For spectral fitting, an adjusted basis data set with pathology-specific metabolites and macromolecules was used to better reproduce the in vivo spectra. To assess differences between both groups more accurately, especially in metabolites at lower concentrations, group-averaged spectra were evaluated in addition to the analysis of individual data.ResultsWe found significantly decreased N-acetylaspartate, choline, creatine, myo-inositol, glutathione and dopamine concentrations in patients with Parkinson's disease compared to controls, whereas glutamine+glutamate, γ-aminobutyric acid, and homovanillic acid were slightly increased. According to anatomical features, clear differences in the biochemical profiles were found between rostral and caudal substantia nigra voxels in both groups.ConclusionsReduced N-acetylaspartate and dopamine concentrations result from progressive degeneration of dopamine-producing neurons within the substantia nigra pars compacta. Decreased creatine levels can be interpreted as impaired energy metabolism due to mitochondrial dysfunction. Lower glutathione concentrations might be a cause or consequence of oxidative stress. Furthermore, slightly increased glutamine+glutamate and γ-aminobutyric acid levels are expected based on post mortem data in Parkinson's disease. To the best of our knowledge, this is the first non-invasive confirmation of these metabolic changes.