Magnetic susceptibility as a 1-year predictor of outcome in familial cerebral cavernous malformations: a pilot study.

OBJECTIVES: To test whether quantitative susceptibility mapping (QSM) of cerebral cavernous malformations (CCMs) assessed at baseline may predict the presence or absence of haemorrhagic signs at 1-year follow-up. METHODS: Familial CCM patients were enrolled in the longitudinal multicentre study Treat-CCM. The 3-T MRI scan allowed performing a semi-automatic segmentation of CCMs and computing the maximum susceptibility in each segmented CCM (QSMmax) at baseline. CCMs were classified as haemorrhagic and non-haemorrhagic at baseline and then subclassified according to the 1-year (t1) evolution. Between-group differences were tested, and the diagnostic accuracy of QSMmax in predicting the presence or absence of haemorrhagic signs in CCMs was calculated with ROC analyses. RESULTS: Thirty-three patients were included in the analysis, and a total of 1126 CCMs were segmented. QSMmax was higher in haemorrhagic CCMs than in non-haemorrhagic CCMs (p < 0.001). In haemorrhagic CCMs at baseline, the accuracy of QSMmax in differentiating CCMs that were still haemorrhagic from CCMs that recovered from haemorrhage at t1 calculated as area under the curve (AUC) was 0.78 with sensitivity 62.69%, specificity 82.35%, positive predictive value (PPV) 93.3% and negative predictive value (NPV) 35.9% (QSMmax cut-off ≥ 1462.95 ppb). In non-haemorrhagic CCMs at baseline, AUC was 0.91 in differentiating CCMs that bled at t1 from stable CCMs with sensitivity 100%, specificity 81.9%, PPV 5.1%, and NPV 100% (QSMmax cut-off ≥ 776.29 ppb). CONCLUSIONS: The QSMmax in CCMs at baseline showed high accuracy in predicting the presence or absence of haemorrhagic signs at 1-year follow-up. Further effort is required to test the role of QSM in follow-up assessment and therapeutic trials in multicentre CCM studies. KEY POINTS: • QSM in semi-automatically segmented CCM was feasible. • The maximum magnetic susceptibility in a single CCM at baseline may predict the presence or absence of haemorrhagic signs at 1-year follow-up. • Multicentric studies are needed to enforce the role of QSM in predicting the CCMs' haemorrhagic evolution in patients affected by familial and sporadic forms.

Quantitative susceptibility mapping of the normal-appearing white matter as a potential new marker of disability progression in multiple sclerosis.

OBJECTIVES: To investigate the normal-appearing white matter (NAWM) susceptibility in a cohort of newly diagnosed multiple sclerosis (MS) patients and to evaluate possible correlations between NAWM susceptibility and disability progression. METHODS: Fifty-nine patients with a diagnosis of MS (n = 53) or clinically isolated syndrome (CIS) (n = 6) were recruited and followed up. All participants underwent neurological examination, blood sampling for serum neurofilament light chain (sNfL) level assessment, lumbar puncture for the quantification of cerebrospinal fluid (CSF) ß-amyloid1-42 (Aß) levels, and brain MRI. T2-weighted scans were used to quantify white matter (WM) lesion loads. For each scan, we derived the NAWM volume fraction and the WM lesion volume fraction. Quantitative susceptibility mapping (QSM) of the NAWM was calculated using the susceptibility tensor imaging (STI) suite. Susceptibility maps were computed with the STAR algorithm. RESULTS: Primary progressive patients (n = 9) showed a higher mean susceptibility value in the NAWM than relapsing-remitting (n = 44) and CIS (n = 6) (p = 0.01 and p = 0.02). Patients with a higher susceptibility in the NAWM showed increased sNfL concentration (ρ = 0.38, p = 0.004) and lower CSF Aß levels (ρ = -0.34, p = 0.009). Mean NAWM susceptibility turned out to be a predictor of the expanded disability status scale (EDSS) worsening at follow-up (ß = 0.41, t = 2.66, p = 0.01) and of the MS severity scale (MSSS) (ß = 0.38, t = 2.43, p = 0.019). CONCLUSIONS: QSM in the NAWM seems to predict the EDSS increment over time. This finding might provide evidence on the role of QSM in identifying patients with an increased risk of early disability progression. KEY POINTS: • NAWM-QSM is higher in PPMS patients than in RRMS. • NAWM-QSM seems to be a predictor of EDSS worsening over time. • Patients with higher NAWM-QSM show increased sNfL concentration and lower CSF Aß levels.

Amyotrophic lateral sclerosis phenotypes significantly differ in terms of magnetic susceptibility properties of the precentral cortex.

OBJECTIVES: The aim of our study was to investigate whether the magnetic susceptibility varies according to the amyotrophic lateral sclerosis (ALS) phenotypes based on the predominance of upper motor neuron (UMN)/lower motor neuron (LMN) impairment. METHODS: We retrospectively collected imaging and clinical data of 47 ALS patients (12 with UMN predominance (UMN-ALS), 16 with LMN predominance (LMN-ALS), and 19 with no clinically defined predominance (Np-ALS)). We further enrolled 23 healthy controls (HC) and 15 ALS mimics (ALS-Mim). These participants underwent brain 3-T magnetic resonance imaging (3-T MRI) with T1-weighted and gradient-echo multi-echo sequences. Automatic segmentation and quantitative susceptibility mapping (QSM) were performed. The skewness of the susceptibility values in the precentral cortex (SuscSKEW) was automatically computed, compared among the groups, and correlated to the clinical variables. RESULTS: The Kruskal-Wallis test showed significant differences in terms of SuscSKEW among groups (χ2(3) = 24.2, p < 0.001), and pairwise tests showed that SuscSKEW was higher in UMN-ALS compared to those in LMN-ALS (p < 0.001), HC (p < 0.001), Np-ALS (p = 0.012), and ALS-Mim (p < 0.001). SuscSKEW was highly correlated with the Penn UMN score (Spearman's rho 0.612, p < 0.001). CONCLUSION: This study demonstrates that the clinical ALS phenotypes based on UMN/LMN sign predominance significantly differ in terms of magnetic susceptibility properties of the precentral cortex. Combined MRI-histopathology investigations are strongly encouraged to confirm whether this evidence is due to iron overload in UMN-ALS, unlike in LMN-ALS. KEY POINTS: • Magnetic susceptibility in the precentral cortex reflects the prevalence of UMN/LMN impairment in the clinical ALS phenotypes. • The degree of UMN/LMN impairment might be well described by the automatically derived measure of SuscSKEW in the precentral cortex. • Increased SuscSKEW in the precentral cortex is more relevant in UMN-ALS patients compared to those in Np-ALS and LMN-ALS patients.

Banks of the Superior Temporal Sulcus in Alzheimer's Disease: A Pilot Quantitative Susceptibility Mapping Study.

BACKGROUND: Brain iron homeostasis is disrupted in neurodegeneration and areas of iron overload partially overlap with regions of amyloid and tau burden in Alzheimer's disease (AD). Previous studies demonstrated alterations in brain iron accumulation in AD using quantitative susceptibility mapping (QSM). OBJECTIVE: Here, we investigate brain alterations of QSM values in AD and non-AD patients as compared to healthy controls (HC) in the superior temporal sulcus and its banks (BANKSSTS), one of the top AD-affected regions. METHODS: Thirty-four patients who underwent brain MRI including a multi-echo gradient-echo sequence were subdivided into AD (n = 19) and non-AD (n = 15) groups according to their clinical profile, CSF (Aß42/40) and/or amyloid-PET status. Ten HC were also included. QSM values were extracted from left and right BANKSSTS and compared among groups. Correlation and binomial regression analyses between QSM values and CSF-AD biomarkers were conducted. RESULTS: QSM in left BANKSSTS was significantly different among groups (p = 0.003, H = 11.40), being higher in AD. QSM values in left BANKSSTS were correlated with Aß42 (rho -0.55, p = 0.005), Aß42/40 (rho -0.66, p < 0.001), pTau (rho 0.63, p < 0.001), tTau (rho 0.56, p = 0.005), tTau/Aß42 (rho 0.68, p < 0.001) and pTau/Aß42 (rho 0.71, p < 0.001). No correlations between QSM values and amyloid-PET SUVR in the left BANKSSTS were found. QSM values in left BANKSSTS showed good accuracy in discriminating AD (AUC = 0.80, CI95 % [0.66-0.93]). Higher QSM values were independent predictors of Aß42 (B = 0.63, p = 0.032), Aß42/40 (B = 0.81, p = 0.028), pTau (B = 0.96, p = 0.046), tTau (B = 0.55, p = 0.027), and tTau/Aß42 (B = 1.13, p = 0.042) positivity. CONCLUSION: Our preliminary data support the potential role of increased QSM values in the left BANKSSTS as an auxiliary imaging biomarker in AD diagnosis.

Unravelling the Association Between Amyloid-PET and Cerebrospinal Fluid Biomarkers in the Alzheimer's Disease Spectrum: Who Really Deserves an A+?

BACKGROUND: Association between cerebrospinal fluid (CSF)-amyloid-ß (Aß)42 and amyloid-PET measures is inconstant across the Alzheimer's disease (AD) spectrum. However, they are considered interchangeable, along with Aß42/40 ratio, for defining 'Alzheimer's Disease pathologic change' (A+). OBJECTIVE: Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients. METHODS: We included 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aß42 within a 365-days interval. Thresholds used for dichotomization were: Aß42 < 640 pg/mL (Aß42+); pTau > 61 pg/mL (pTau+); and Aß42/40 < 0.069 (ADratio+). Amyloid-PET scans were visually assessed and processed by four pipelines (SPMCL, SPMAAL, FSGM, FSWC). RESULTS: Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rho = 0.93-0.99). The most significant findings were: pTau positive correlation with SPMCL SUVR (rho = 0.56, p = 0.0063) and Aß42/40 negative correlation with SPMCL and SPMAAL SUVRs (rho = -0.56, p = 0.0058; rho = -0.52, p = 0.0117 respectively). No correlations between CSF-Aß42 and global SUVRs were observed. In subregion analysis, both pTau and Aß42/40 values significantly correlated with cingulate SUVRs from any pipeline (R2 = 0.55-0.59, p < 0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aß42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aß42 or using Aß42/40, instead of Aß42 alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids. CONCLUSION: We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aß42/40 and secondarily pTau rather than Aß42 levels.

Association of Superficial White Matter Alterations with Cerebrospinal Fluid Biomarkers and Cognitive Decline in Neurodegenerative Dementia.

BACKGROUND: Superficial white matter (SWM) alterations correlated with cognitive decline have been described in Alzheimer's disease (AD). OBJECTIVE: The study aims to extend the investigation of the SWM alterations to AD and non-AD neurodegenerative dementia (ND) and explore the relationship with cerebrospinal fluid (CSF) biomarkers and clinical data. METHODS: From a database of 323 suspected dementia cases, we retrospectively recruited 55 ND with abnormal amyloid-ß42 (AD) and 38 ND with normal amyloid-ß42 (non-AD) and collected clinical data, CSF biomarkers, and magnetic resonance images. Ten healthy controls (HC) were recruited for imaging and Mini-Mental State Examination (MMSE). Diffusion tensor imaging (DTI) measurements were performed in the lobar SWM regions and Kruskal Wallis tests were used for among-group comparison. Spearman's correlation tests were performed between DTI measures, CSF biomarkers, and clinical data. RESULTS: AD and non-AD showed significant differences in the DTI measures across the SWM compared to HC. Significant differences between AD and non-AD were detected in the left parietal lobe. DTI measures correlated with amyloid-ß42 and MMSE diffusely in the SWM, less extensively with total-tau and phosphorylated tau, and with disease duration in the parietal lobe bilaterally. CONCLUSION: Widespread SWM alterations occur in both AD and non-AD ND and AD shows appreciably more severe alterations in the parietal SWM. Notably, the alterations in the SWM are strongly linked not only to the cognitive decline but also to the diagnostic CSF biomarkers. Further studies are encouraged to evaluate the DTI measures in the SWM as in vivo non-invasive biomarkers in the preclinical phase.

Iron deposition in Parkinsonisms: A Quantitative Susceptibility Mapping study in the deep grey matter.

PURPOSE: The aim of the study is to quantify the susceptibility in deep grey nuclei that are affected by pathological processes related to iron accumulation in patients with Parkinson's disease and primary atypical parkinsonisms such as Progressive Supranuclear Palsy, Multiple System Atrophy and Cortico-Basal Degeneration, in order to assist the differential diagnosis among parkinsonian syndromes. METHODS: We enrolled 49 patients with Parkinson's disease and 26 patients with primary atypical parkinsonisms. Automatic segmentation of putamen, globus pallidus, caudate nucleus and thalamus and manual segmentation of red nuclei and substantia nigra were performed, and region of interest-based Quantitative Susceptibility Mapping analysis were performed. Statistical comparisons of the mean susceptibility values in the segmented brain regions were performed among primary atypical parkinsonisms and Parkinson's disease. RESULTS: Susceptibility values in red nuclei were increased in Progressive Supranuclear Palsy patients compared to parkinsonian phenotype Multiple System Atrophy (p = 0.004), and Parkinson's disease patients (p = 0.006). Susceptibility in thalamus was decreased in Cortico-Basal Degeneration patients compared to Parkinson's disease (p = 0.006), Multiple System Atrophy with cerebellar phenotype (p = 0.031) and parkinsonian phenotype (p = 0.001) patients, and in Progressive Supranuclear Palsy patients compared to Multiple System Atrophy with parkinsonian phenotype patients (p = 0.012). CONCLUSIONS: Quantitative Susceptibility Mapping allows the depiction and quantification of different patterns of iron deposition in the deep gray nuclei occurring in primary atypical parkinsonisms and Parkinson's disease and it may help as a non-invasive tool in the differential diagnosis between parkinsonian syndromes.