Diagnostic Performance of Cortical Lesions and the Central Vein Sign in Multiple Sclerosis.

Importance: Multiple sclerosis (MS) misdiagnosis remains an important issue in clinical practice. Objective: To quantify the performance of cortical lesions (CLs) and central vein sign (CVS) in distinguishing MS from other conditions showing brain lesions on magnetic resonance imaging (MRI). Design, Setting, and Participants: This was a retrospective, cross-sectional multicenter study, with clinical and MRI data acquired between January 2010 and May 2020. Centralized MRI analysis was conducted between July 2020 and December 2022 by 2 raters blinded to participants' diagnosis. Participants were recruited from 14 European centers and from a multicenter pan-European cohort. Eligible participants had a diagnosis of MS, clinically isolated syndrome (CIS), or non-MS conditions; availability of a brain 3-T MRI scan with at least 1 sequence suitable for CL and CVS assessment; presence of T2-hyperintense white matter lesions (WMLs). A total of 1051 individuals were included with either MS/CIS (n = 599; 386 [64.4%] female; mean [SD] age, 41.5 [12.3] years) or non-MS conditions (including other neuroinflammatory disorders, cerebrovascular disease, migraine, and incidental WMLs in healthy control individuals; n = 452; 302 [66.8%] female; mean [SD] age, 49.2 [14.5] years). Five individuals were excluded due to missing clinical or demographic information (n = 3) or unclear diagnosis (n = 2). Exposures: MS/CIS vs non-MS conditions. Main Outcomes and Measures: Area under the receiver operating characteristic curves (AUCs) were used to explore the diagnostic performance of CLs and the CVS in isolation and in combination; sensitivity, specificity, and accuracy were calculated for various cutoffs. The diagnostic importance of CLs and CVS compared to conventional MRI features (ie, presence of infratentorial, periventricular, and juxtacortical WMLs) was ranked with a random forest model. Results: The presence of CLs and the previously proposed 40% CVS rule had a sensitivity, specificity, and accuracy for MS of 59.0% (95% CI, 55.1-62.8), 93.6% (95% CI, 91.4-95.6), and 73.9% (95% CI, 71.6-76.3) and 78.7% (95% CI, 75.5-82.0), 86.0% (95% CI, 82.1-89.5), and 81.5% (95% CI, 78.9-83.7), respectively. The diagnostic performance of the CVS (AUC, 0.89 [95% CI, 0.86-0.91]) was superior to that of CLs (AUC, 0.77 [95% CI, 0.75-0.80]; P < .001), and was increased when combining the 2 imaging markers (AUC, 0.92 [95% CI, 0.90-0.94]; P = .04); in the random forest model, both CVS and CLs outperformed the presence of infratentorial, periventricular, and juxtacortical WMLs in supporting MS differential diagnosis. Conclusions and Relevance: The findings in this study suggest that CVS and CLs may be valuable tools to increase the accuracy of MS diagnosis.

Automatic covariance pattern analysis outperforms visual reading of 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in variant progressive supranuclear palsy.

BACKGROUND: To date, studies on positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) in progressive supranuclear palsy (PSP) usually included PSP cohorts overrepresenting patients with Richardson's syndrome (PSP-RS). OBJECTIVES: To evaluate FDG-PET in a patient sample representing the broad phenotypic PSP spectrum typically encountered in routine clinical practice. METHODS: This retrospective, multicenter study included 41 PSP patients, 21 (51%) with RS and 20 (49%) with non-RS variants of PSP (vPSP), and 46 age-matched healthy controls. Two state-of-the art methods for the interpretation of FDG-PET were compared: visual analysis supported by voxel-based statistical testing (five readers) and automatic covariance pattern analysis using a predefined PSP-related pattern. RESULTS: Sensitivity and specificity of the majority visual read for the detection of PSP in the whole cohort were 74% and 72%, respectively. The percentage of false-negative cases was 10% in the PSP-RS subsample and 43% in the vPSP subsample. Automatic covariance pattern analysis provided sensitivity and specificity of 93% and 83% in the whole cohort. The percentage of false-negative cases was 0% in the PSP-RS subsample and 15% in the vPSP subsample. CONCLUSIONS: Visual interpretation of FDG-PET supported by voxel-based testing provides good accuracy for the detection of PSP-RS, but only fair sensitivity for vPSP. Automatic covariance pattern analysis outperforms visual interpretation in the detection of PSP-RS, provides clinically useful sensitivity for vPSP, and reduces the rate of false-positive findings. Thus, pattern expression analysis is clinically useful to complement visual reading and voxel-based testing of FDG-PET in suspected PSP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Brain MRI in Progressive Supranuclear Palsy with Richardson's Syndrome and Variant Phenotypes.

BACKGROUND: Brain magnetic resonance imaging (MRI) is used to support the diagnosis of progressive supranuclear palsy (PSP). However, the value of visual descriptive, manual planimetric, automatic volumetric MRI markers and fully automatic categorization is unclear, particularly regarding PSP predominance types other than Richardson's syndrome (RS). OBJECTIVES: To compare different visual reading strategies and automatic classification of T1-weighted MRI for detection of PSP in a typical clinical cohort including PSP-RS and (non-RS) variant PSP (vPSP) patients. METHODS: Forty-one patients (21 RS, 20 vPSP) and 46 healthy controls were included. Three readers using three strategies performed MRI analysis: exclusively visual reading using descriptive signs (hummingbird, morning-glory, Mickey-Mouse), visual reading supported by manual planimetry measures, and visual reading supported by automatic volumetry. Fully automatic classification was performed using a pre-trained support vector machine (SVM) on the results of atlas-based volumetry. RESULTS: All tested methods achieved higher specificity than sensitivity. Limited sensitivity was driven to large extent by false negative vPSP cases. Support by automatic volumetry resulted in the highest accuracy (75.1% ± 3.5%) among the visual strategies, but performed not better than the midbrain area (75.9%), the best single planimetric measure. Automatic classification by SVM clearly outperformed all other methods (accuracy, 87.4%), representing the only method to provide clinically useful sensitivity also in vPSP (70.0%). CONCLUSIONS: Fully automatic classification of volumetric MRI measures using machine learning methods outperforms visual MRI analysis without and with planimetry or volumetry support, particularly regarding diagnosis of vPSP, suggesting the use in settings with a broad phenotypic PSP spectrum. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Whole-Brain Magnetic Resonance Spectroscopy Reveals Distinct Alterations in Neurometabolic Profile in Progressive Supranuclear Palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized by supranuclear gaze palsy, early postural instability, and a frontal dysexecutive syndrome. Contrary to normal brain magnetic resonance imaging in Parkinson's disease (PD), PSP shows specific cerebral atrophy patterns and alterations, but these findings are not present in every patient, and it is still unclear if these signs are also detectable in early disease stages. OBJECTIVE: The aim of the present study was to analyze the metabolic profile of patients with clinically diagnosed PSP in comparison with matched healthy volunteers and PD patients using whole-brain magnetic resonance spectroscopic imaging (wbMRSI). METHODS: Thirty-nine healthy controls (HCs), 29 PD, and 22 PSP patients underwent wbMRSI. PSP and PD patients were matched for age and handedness with HCs. Clinical characterization was performed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, PSP rating scale, and DemTect (test for cognitive assessment). RESULTS: In PSP patients a significant reduction in N-acetyl-aspartate (NAA) was detected in all brain lobes. Fractional volume of the cerebrospinal fluid significantly increased in PSP patients compared to PD and healthy volunteers. CONCLUSIONS: In PSP much more neuronal degeneration and cerebral atrophy have been detected compared with PD. The most relevant alteration is the decrease in NAA in all lobes of the brain, which also showed a partial correlation with clinical symptoms. However, more studies are needed to confirm the additional value of wbMRSI in clinical practice. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Adoptive Allogeneic T-Cell Therapy Improves the Clinical Outcome of JC Virus Granule Cell Neuronopathy: A Case Report.

OBJECTIVES: JC virus granule cell neuronopathy is a potentially fatal otherwise highly disabling disease without an approved therapeutic option. This case report presents the positive record to T-cell therapy in JC virus granule cell neuronopathy. METHODS: The patient represented with subacute cerebellar symptoms. Diagnosis of JC virus granule cell neuronopathy was made because of infratentorially accentuated brain volume atrophy shown by brain MRI and the detection of JC virus DNA in the CSF. RESULTS: Six doses of virus-specific T cells were administered. Within 12 months after therapy initiation, the patient showed clear clinical benefit with improvement of symptoms, and JC viral DNA load significantly declined. DISCUSSION: We present the case report of a positive response to T-cell therapy in JC virus granule cell neuronopathy, leading to an improvement of symptoms.

Bifrontal electroconvulsive therapy leads to improvement of cerebral glucose hypometabolism in frontotemporal dementia with comorbid psychotic depression - a case report.

BACKGROUND: Differentiating depression and dementia in elderly patients represents a major clinical challenge for psychiatrists. Pharmacological and non-pharmacological treatment options for both conditions are often used cautiously due to fear of adverse effects. If a clinically indicated therapy is not initiated due to fear of adverse effects, the quality of life of affected patients may significantly be reduced. CASE PRESENTATION: Here, we describe the case of a 65-year-old woman who presented to the department of psychiatry of a university hospital with depressed mood, pronounced anxiety, and nihilistic thoughts. While several pharmacological treatments remained without clinical response, further behavioral observation in conjunction with 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) revealed the diagnosis of frontotemporal dementia (FTD). To counter the pharmacological treatment resistance of psychotic depression, we decided to perform electroconvulsive therapy (ECT). Remarkably, ten sessions of ECT yielded an almost complete remission of depressive symptoms. In addition, the patient's delusional ideas disappeared. A follow-up 18F-FDG PET/CT after the ECT series still showed a frontally and parieto-temporally accentuated hypometabolism, albeit with a clear regression compared to the previous image. The follow-up 18F-FDG PET/CT thus corroborated the diagnosis of FTD, while on the other hand it demonstrated the success of ECT. CONCLUSIONS: In this case, ECT was a beneficial treatment option for depressive symptoms in FTD. Also, 18F-FDG PET/CT should be discussed as a valuable tool in differentiating depression and dementia and as an indicator of treatment response.

Feasibility of flow-related enhancement brain perfusion MRI.

PURPOSE: Brain perfusion imaging is of enormous importance for various neurological diseases. Fast gradient-echo sequences offering flow-related enhancement (FREE) could present a basis to generate perfusion-weighted maps. In this study, we obtained perfusion-weighted maps without contrast media by a previously described postprocessing algorithm from the field of functional lung MRI. At first, the perfusion signal was analyzed in fast low-angle shot (FLASH) and balanced steady-state free precession (bSSFP) sequences. Secondly, perfusion maps were compared to pseudo-continuous arterial spin labeling (pCASL) MRI in a healthy cohort. Thirdly, the feasibility of the new technique was demonstrated in a small selected group of patients with metastases and acute stroke. METHODS: One participant was examined with bSSFP and FLASH sequences at 1.5T and 3T, different flip angles and slice thicknesses. Twenty-five volunteers had bSSFP imaging and pCASL MRI. Three patients with cerebral metastases and one with acute ischemic stroke had bSSFP imaging and were compared to T1 post-contrast images and CT perfusion. Frequency analyses, SNR and perfusion contrast were compared at different flip angles and slice thicknesses. Regional correlations and Sorensen-Dice overlap were calculated in the healthy cohort. Dice overlap of the pathologies in the patient cohort were calculated. RESULTS: The bSSFP sequence presented detectable perfusion signal within brain vessel and parenchyma together with superior SNR compared to FLASH. Perfusion contrast and its corticomedullary differentiation increased with flip angle. Mean regional correlation was 0.36 and highly significant between FREE maps and pCASL and grey and white matter Dice match were 72% and 60% in the healthy cohort. Pathologies presented good overlap between FREE perfusion-weighted and T1 post-contrast images. CONCLUSION: The feasibility of FREE brain perfusion imaging has been shown in a healthy cohort and selected patient cases with brain metastases and acute stroke. The study demonstrates a new approach for non-contrast brain perfusion imaging.

The potential role of diffusion weighted imaging in the diagnosis of early carotid and vertebral artery dissection.

PURPOSE: To investigate the role of the diffusion weighted imaging (DWI) in the acute dissection of internal carotid artery (ICA) and vertebral artery (VA) and assessing the length of intramural hematoma (IMH), caused by dissection. METHODS: We analyzed 28 patients presenting with a dissection of the ICA and/or VA with respect to the presence of high signal intensity areas on DWI suggestive of dissection and 20 control subjects without arterial dissection, some with and some without atherosclerotic lesions. ICA or VA dissection was defined by clinical and imaging, computed tomography angiography (CTA), MR angiography (MRA), and digital subtraction angiography (DSA) findings. The length of DWI hyperintensity was compared to length of the occlusion or stenosis on the angiographic examination. RESULTS: In 28 patients, 30 dissected arteries were analyzed. Time intervals from the onset of the first clinical symptoms to the radiological evaluation ranged from 1.5 h to 42 days. In 28 (93%) of the dissections, a high signal intensity of the affected artery was present on DWI. The measurement of the dissection length on DWI compared to DSA showed a mean deviation of 2.7 mm and a standard deviation of 3.7 mm. CONCLUSION: DWI is a highly sensitive and valuable pulse sequence for the detection of dissected cervical arteries even in the first hours after symptom onset. In contrast to CTA and MRA, DWI can be a potential tool for a reliable measurement of the dissection length.

Cerebral Microstructural Alterations in Patients With Early Parkinson's Disease Detected With Quantitative Magnetic Resonance Measurements.

Objective: Parkinson's disease (PD) is the second most common neurodegenerative disease in the elderly. In early stages of PD, patients typically display normal brain magnet resonance imaging (MRI) in routine screening. Advanced imaging approaches are necessary to discriminate early PD patients from healthy controls. In this study, microstructural changes in relevant brain regions of early PD patients were investigated by using quantitative MRI methods. Methods: Cerebral MRI at 3T was performed on 20 PD patients in early stages and 20 age and sex matched healthy controls. Brain relative proton density, T1, T2, and T2' relaxation times were measured in 14 regions of interest (ROIs) in each hemisphere and compared between patients and controls to estimate PD related alterations. Results: In comparison to matched healthy controls, the PD patients revealed decreased relative proton density in contralateral prefrontal subcortical area, upper and lower pons, in ipsilateral globus pallidus, and bilaterally in splenium corporis callosi, caudate nucleus, putamen, thalamus, and mesencephalon. The T1 relaxation time was increased in contralateral prefrontal subcortical area and centrum semiovale, putamen, nucleus caudatus and mesencephalon, whereas T2 relaxation time was elevated in upper pons bilaterally and in centrum semiovale ipsilaterally. T2' relaxation time did not show significant changes. Conclusion: Early Parkinson's disease is associated with a distinct profile of brain microstructural changes which may relate to clinical symptoms. The quantitative MR method used in this study may be useful in early diagnosis of Parkinson's disease. Limitations of this study include a small sample size and manual selection of the ROIs. Atlas-based or statistical mapping methods would be an alternative for an objective evaluation. More studies are necessary to validate the measurement methods for clinical use in diagnostics of early Parkinson's disease.

Alterations of Striato-Thalamic Metabolism in Normal Aging Human Brain-An MR Metabolic Imaging Study.

Aging effects on striato-thalamic metabolism in healthy human brains were studied in vivo using short-TE whole brain 1H-MR spectroscopic imaging (wbMRSI) on eighty healthy subjects aged evenly between 20 to 70 years at 3T. Relative concentrations of N-acetyl-aspartate (NAA), choline, total creatine (tCr), myo-inositol (mI), glutamate, and glutamine in bilateral caudate nucleus, putamen, pallidum, and thalamus were determined using signal normalization relative to brain tissue water. Linear regression analysis was used to analyze the age-dependence of the metabolite concentrations. The metabolite concentrations revealed spatial inhomogeneity across brain regions and metabolites. With age, NAA decreased significantly in bilateral caudate nucleus and putamen, left pallidum, and left thalamus, tCr decreased in left putamen and bilateral pallidum, mI increased in bilateral caudate nucleus and right thalamus, and spectral linewidth increased in left putamen and right thalamus. In conclusion, normal aging of striato-thalamic metabolism in healthy human is associated with regional specific decreases of NAA and tCr and increases of mI, which may reflect the individual role of each brain structure within brain functionality.

An unusual presentation of Huntington's disease.

We describe the case of a 59-year-old woman who exhibited psychotic symptoms, cognitive dysfunction, and restlessness. While the clinical picture and 18F-FDG PET/CT suggested the presence of a tauopathy, especially frontotemporal dementia or progressive supranuclear palsy, genetic testing eventually revealed Huntington's disease.

Allogeneic BK Virus-Specific T-Cell Treatment in 2 Patients With Progressive Multifocal Leukoencephalopathy.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating opportunistic infection of the brain caused by the ubiquitously distributed JC polyomavirus. There are no established treatment options to stop or slow down disease progression. In 2018, a case series of 3 patients suggested the efficacy of allogeneic BK virus-specific T-cell (BKV-CTL) transplantation. METHODS: Two patients, a bilaterally lung transplanted patient on continuous immunosuppressive medication since 17 years and a patient with dermatomyositis treated with glucocorticosteroids, developed definite PML according to AAN diagnostic criteria. We transplanted both patients with allogeneic BKV-CTL from partially human leukocyte antigen (HLA) compatible donors. Donor T cells had directly been produced from leukapheresis by the CliniMACS IFN-γ cytokine capture system. In contrast to the previous series, we identified suitable donors by HLA typing in a preexamined registry and administered 1 log level less cells. RESULTS: Both patients' symptoms improved significantly within weeks. During the follow-up, a decrease in viral load in the CSF and a regression of the brain MRI changes occurred. The transfer seemed to induce endogenous BK and JC virus-specific T cells in the host. CONCLUSIONS: We demonstrate that this optimized allogeneic BKV-CTL treatment paradigm represents a promising, innovative therapeutic option for PML and should be investigated in larger, controlled clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with PML, allogeneic transplant of BKV-CTL improved symptoms, reduced MRI changes, and decreased viral load.

Clinical, Radiological, and Laboratory Features of Spinal Cord Involvement in Primary Sjögren's Syndrome.

OBJECTIVE: To identify radiological and laboratory hallmarks in patients with primary Sjögren's syndrome (pSS) presenting with spinal cord involvement. METHODS: Clinical and laboratory routine parameters were analyzed in a retrospective multicenter case series of four patients who developed myelitis associated with pSS. Serological and cerebrospinal fluid (CSF) measurements of pSS associated anti-SSA(Ro)-antibodies were initiated, and CSF neurofilament light chain (NFL) levels were assessed. NFL values were compared with results from 15 sex- and age-matched healthy controls. Radiological assessment was performed using multi-sequence spinal cord magnetic resonance imaging. RESULTS: Three of the four patients initially developed neurological signs suggestive of myelitis and were subsequently diagnosed with pSS. All patients presented a longitudinal spinal T2-hyperintense lesion in the cervical spinal cord, whereas only two patients showed pleocytosis and oligoclonal bands in the CSF. Median (range) CSF-NFL levels were significantly elevated in patients compared to controls (6672 pg/mL (621-50000) vs. 585 pg/mL (357-729), p = 0.009). One patient showed sustained, highly increased NFL levels (50000 pg/mL) in the initial assessment when radiological signs of axonal injury were still absent. Anti-SSA(Ro)-antibodies were found in the serum of three patients, while two patients additionally presented intrathecal anti-SSA(Ro)-antibody production. Elevated CSF-NFL levels and intrathecal synthesis of anti-SSA(Ro)-antibodies were associated with a relapsing and treatment-resistant disease course. CONCLUSION: Inflammatory spinal cord lesions associated with pSS are a rare but serious disease leading to severe disability. NFL and anti-SSA(Ro)-antibodies in CSF might serve as prognostic biomarkers and should be routinely assessed in patients with pSS.

Brain Morphological Alterations Are Detected in Early-Stage Parkinson's Disease with MRI Morphometry.

BACKGROUND AND PURPOSE: To detect brain morphological alterations in patients with early Parkinson's disease (PD) by using magnetic resonance imaging (MRI) morphometry under radiological diagnostic conditions. METHODS: T1-weighted brain images of 18 early PD patients and 18 age-sex-matched healthy controls (HCs) were analyzed with free software Computational Anatomy Toolbox (CAT12). Regional cortical thickness (rCTh) in 68 atlas-defined regions-of-interest (ROIs) and subcortical gray matter volume (SGMV) in 14 atlas-defined ROIs were determined and compared between patients and HCs by paired comparison using both ROI-wise and voxel-wise analyses. False-discovery rate (FDR) was used multiple comparison correction. Possible correlations between brain morphological changes in patients and clinical observations were also analyzed. RESULTS: Comparing to the HCs, the ROI-wise analysis revealed rCTh thinning significantly in left medial orbitofrontal (P = .001), by trend (P < .05 but not significant after FDR correction) in four other ROIs located in frontal and temporal lobes, and a volume decreasing trend in left pallidum of the PD patients, while the voxel-wise analysis revealed one cluster with rCTh thinning trend located between left insula and superior temporal region of the patients. In addition, the patients showed more distinct rCTh thinning in ipsilateral hemisphere and SGMV deceasing trends in contralateral hemisphere in respect of the symptom-onset body side. CONCLUSION: Brain morphological alterations in early PD patients are evident despite of their inconspicuous findings in standard MRI. Quantitative morphological measurements with CAT12 may be an applicable add-on tool for clinical diagnosis of early PD. These results have to be verified in future studies with larger patient samples.