Combining semi-quantitative rating and automated brain volumetry in MRI evaluation of patients with probable behavioural variant of fronto-temporal dementia: an added value for clinical practise?

PURPOSE: To evaluate the diagnostic value of combined semiquantitative and quantitative assessment of brain atrophy in the diagnostic workup of the behavioural-variant of frontotemporal dementia (bvFTD). METHODS: Three neuroradiologists defined brain atrophy grading and identified atrophy pattern suggestive of bvFTD on 3D-T1 brain MRI of 112 subjects using a semiquantitative rating scale (Kipps'). A quantitative atrophy assessment was performed using two different automated software (Quantib® ND and Icometrix®). A combined semiquantitative and quantitative assessment of brain atrophy was made to evaluate the improvement in brain atrophy grading to identify probable bvFTD patients. RESULTS: Observers' performances in the diagnosis of bvFTD were very good for Observer 1 (k value = 0.881) and 2 (k value = 0.867), substantial for Observer 3 (k value = 0.741). Semiquantitative atrophy grading of all the observers showed a moderate and a poor correlation with the volume values calculated by Icometrix® and by Quantib® ND, respectively. For the definition of neuroradiological signs presumptive of bvFTD, the use of Icometrix® software improved the diagnostic accuracy for Observer 1 resulting in an AUC of 0.974, and for Observer 3 resulting in a AUC of 0.971 (p-value < 0.001). The use of Quantib® ND software improved the diagnostic accuracy for Observer 1 resulting in an AUC of 0.974, and for Observer 3 resulting in a AUC of 0.977 (p-value < 0.001). No improvement was observed for Observer 2. CONCLUSION: Combining semiquantitative and quantitative brain imaging evaluation allows to reduce discrepancies in the neuroradiological diagnostic workup of bvFTD by different readers.

Diagnostic efficacy and safety of gadoteridol compared to gadobutrol and gadoteric acid in a large sample of CNS MRI studies at 1.5T.

PURPOSE: To evaluate safety and diagnostic accuracy of gadoteridol vs. other macrocyclic gadolinium-based contrast agents (GBCAs) in a large cohort of consecutive and non-selected patients referred for CE-MRI of the CNS. MATERIAL AND METHODS: Between November 2017 and March 2018, we prospectively enrolled a consecutive cohort of patients referred for neuroradiological CE-MRI (1.5T MRI). Image quality and adverse events were assessed. Diagnostic performance was determined for a subgroup of patients with truth standard findings available. Comparison was made between patients receiving gadoteridol and patients receiving other macrocyclic GBCAs. Inter-reader agreement (kappa) between two expert neuroradiologists was calculated for the diagnosis of malignancy. RESULTS: Overall, 460 patients (220M/240F; mean age 54±16 years) were enrolled of which 230 received gadoteridol (Group 1) and 230 either gadoteric acid or gadobutrol [n=83 (36.1%) and n=147 (63.9%), respectively; Group 2]. Image quality was rated as good or excellent in both groups. The sensitivity, specificity and diagnostic accuracy for determination of malignancy was 88.2%, 96.5% and 95.4%, respectively, for Group 1 and 93.7%, 97.4% and 96.9%, respectively, for Group 2, with no significant differences between groups (P>0.75) for any determination. Inter-reader agreement for the identification of malignancy was excellent [K=0.877 (95%CI: 0.758-0.995) and K=0.818 (95%CI: 0.663-0.972) for groups 1 and 2, respectively; P=0.0913]. Adverse events occurred in 5 of 460 (1.09%) patients overall, with no significant difference (P=0.972) between groups. CONCLUSION: Gadoteridol was safe and guaranteed good image quality without significant differences when compared to gadobutrol and gadoteric acid in a wide range of CNS pathologies.

The role of CE-MRA of the supraortic vessels in the detection of associated intracranial pathology.

BACKGROUND: Contrast-enhanced magnetic resonance angiography (CE-MRA) has become a very popular imaging technique in the evaluation of the extracranial vessels pathology, while it is not commonly used to rule out intracranial vascular pathology. On the contrary, 3D time of flight MRA (TOF-MRA) has a solid role in the study of intracranial arterial vessels disease. MATERIALS AND METHODS: One hundred and eight patients were consecutively included in the study. All patients were submitted to a 3 Tesla 3D CE-MRA imaging to rule out extracranial vessels pathology. A comparison was made with a 3D-TOF sequence acquired at the same time in the assessment of intracranial vessels diseases such as steno-occlusion, dissection, and aneurysms. RESULTS: With regard to steno-occlusive disease, Spearman's rank correlation coefficient was of 0.56 for stenosis detection and of 0.57 for occlusive disease detection. The two techniques shared similar results in the evaluation of anterior circulation, while 3D-TOF found higher grades of stenosis for posterior circulation. With regard to dissection, Spearman's rank correlation coefficient was of 0.7. 3D-TOF depicted more intramural hematoma (Spearman's rank = 0.46), while CE-MRA showed more pseudo-aneurysms (Spearman's rank = 0.56). Both the technique equally evaluated the presence of intracranial aneurysms (Spearman's rank = 1). CONCLUSION: CE-MRA can be considered a reliable tool to rule out intracranial pathology associated to supraortic steno-occlusive disease, also allowing time reduction. In the suspicion of dissection a T1-weighted sequence has to be added to detect the presence of a subacute vessel wall hematoma.

Allogeneic hematopoietic stem cell transplantation for neuromyelitis optica.

Neuromyelitis optica is a rare neurological autoimmune disorder characterized by a poor prognosis. Immunosuppression can halt disease progression, but some patients are refractory to multiple treatments, experiencing frequent relapses with accumulating disability. Here we report on durable clinical remissions after allogeneic hematopoietic stem cell transplantation in 2 patients suffering from severe forms of the disease. Immunological data evidenced disappearance of the pathogenic antibodies and regeneration of a naive immune system of donor origin. These findings correlated with evident clinical and radiological improvement in both patients, warranting extended clinical trials to investigate this promising therapeutic option.

Real-word application of the AT(N) classification and disease-modifying treatment eligibility in a hospital-based cohort.

BACKGROUND AND OBJECTIVES: The AT(N) classification system stratifies patients based on biomarker profiles, including amyloid-beta deposition (A), tau pathology (T), and neurodegeneration (N). This study aims to apply the AT(N) classification to a hospital-based cohort of patients with cognitive decline and/or dementia, within and outside the Alzheimer's disease (AD) continuum, to enhance our understanding of the multidimensional aspects of AD and related disorders. Furthermore, we wish to investigate how many cases from our cohort would be eligible for the available disease modifying treatments, such as aducanemab and lecanemab. METHODS: We conducted a retrospective evaluation of 429 patients referred to the Memory Center of IRCCS San Raffaele Hospital in Milan. Patients underwent clinical/neuropsychological assessments, lumbar puncture, structural brain imaging, and positron emission tomography (FDG-PET). Patients were stratified according to AT(N) classification, group comparisons were performed and the number of eligible cases for anti-ß amyloid monoclonal antibodies was calculated. RESULTS: Sociodemographic and clinical features were similar across groups. The most represented group was A + T + N + accounting for 38% of cases, followed by A + T - N + (21%) and A - T - N + (20%). Although the clinical presentation was similar, the A + T + N + group showed more severe cognitive impairment in memory, language, attention, executive, and visuospatial functions compared to other AT(N) groups. Notably, T + patients demonstrated greater memory complaints compared to T - cases. FDG-PET outperformed MRI and CT in distinguishing A + from A - patients. Although 61% of the observed cases were A + , only 17% of them were eligible for amyloid-targeting treatments. DISCUSSION: The AT(N) classification is applicable in a real-world clinical setting. The classification system provided insights into clinical management and treatment strategies. Low cognitive performance and specific regional FDG-PET hypometabolism at diagnosis are highly suggestive for A + T + or A - T + profiles. This work provides also a realistic picture of the proportion of AD patients eligible for disease modifying treatments emphasizing the need for early detection.

Imaging characterization of an adult H3 K27M-altered diffuse midline glioma of the medulla oblongata with a confounding steroid response.

We report an uncommon, infratentorial localization of adult H3 K27M-altered diffuse midline glioma arising in a particularly rare site (medulla oblongata). In addition to this unusual presentation, the lesion exhibited a substantial contrast enhancement and size decrease after dexamethasone, generating diagnostic dilemmas. Histology, molecular details, advanced Magnetic Resonance imaging features and differential diagnoses are here described and discussed, as well as common misconceptions about steroid-sensitive mass lesions, and practical difficulties for clinicians involved in the process of making diagnosis.

Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study.

Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18-55 years, disease duration 2-20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients.

Amyloid-Related Imaging Abnormalities and ß-Amyloid-Targeting Antibodies: A Systematic Review.

IMPORTANCE: After more than a decade of research and development of clinical trials testing anti-ß-amyloid monoclonal antibodies (mAbs), extensive experience has been gained regarding the effects of these treatments in patients with Alzheimer disease (AD). On the verge of an expected large-scale introduction in the clinical setting after the recent US Food and Drug Administration approval of aducanumab, shared knowledge regarding amyloid-related imaging abnormalities (ARIAs) is of paramount importance. OBJECTIVE: To summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti-ß-amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment. EVIDENCE REVIEW: In this systematic review, a literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence-Based Medicine. FINDINGS: Twenty-two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid-attenuated inversion recovery and T2-weighted sequences were termed ARIA-E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA-H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA-E incidence was further associated with treatment dose, affecting the 55% of ApoE ε4 carriers in the high-dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3% of ARIA-E cases at higher treatment doses across RCTs, whereas ARIA-H cases were generally asymptomatic. Most ARIA-E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA-E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6% across RCTs. CONCLUSIONS AND RELEVANCE: Evidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid-modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real-world clinical settings.

Breakthrough Invasive Fungal Infections in Allogeneic Hematopoietic Stem Cell Transplantation.

Despite the recent introduction of mold-active antifungal prophylaxis (MAP), breakthrough invasive fungal infections (b-IFI) still represent a possible complication and a cause of morbidity and mortality in hematological patients and allogeneic hematopoietic stem-cell transplantation recipients (HSCT). Data on incidence and type of b-IFI are limited, although they are mainly caused by non-fumigatus Aspergillus and non-Aspergillus molds and seem to depend on specific antifungal prophylaxis and patients' characteristics. Herein, we described the clinical presentation and management of two cases of rare b-IFI which recently occurred at our institution in patients undergoing HSCT and receiving MAP. The management of b-IFI is challenging due to the lack of data from prospective trials and high mortality rates. A thorough analysis of risk factors, ongoing antifungal prophylaxis, predisposing conditions and local epidemiology should drive the choice of antifungal treatments. Early broad-spectrum preemptive therapy with a lipid formulation of amphotericin-B, in combination with a different mold-active azole plus/minus terbinafine, is advisable. The therapy would cover against rare azole-susceptible and -resistant fungal strains, as well as atypical sites of infections. An aggressive diagnostic work-up is recommended for species identification and subsequent targeted therapy.