Association between enlarged perivascular spaces and cerebrospinal fluid aquaporin-4 and tau levels: report from a memory clinic.

Background: Perivascular spaces (PVS) are fluid-filled compartments that dilate in response to many different conditions. A high burden of enlarged PVS (EPVS) in the centrum semiovale (CSO) has been linked to neurodegeneration. Moreover, an increase in cerebrospinal fluid (CSF) levels of aquaporin-4 (AQP4), a water channel expressed on PVS-bounding astrocytes, has been described in patients with neurodegenerative dementia. Our aim was to investigate the relationship between neurodegenerative diseases and two putative glymphatic system biomarkers: AQP4 and EPVS. Methods: We included 70 individuals, 54 patients with neurodegenerative diseases and 16 subjects with non-degenerative conditions. EPVS were visually quantified on MRI-scans applying Paradise's scale. All subjects underwent lumbar puncture for the measurement of AQP4 levels in the cerebrospinal fluid (CSF). CSF levels of amyloid-ß-1-42, phosphorylated and total tau (tTau) were also measured. Linear regression analyses were adjusted for age, sex, education and disease duration, after excluding outliers. Results: Cerebrospinal fluid (CSF)-AQP4 levels were independent predictors of total (ß = 0.28, standard error [SE] = 0.08, p = 0.001), basal ganglia (ß = 0.20, SE = 0.08, p = 0.009) and centrum semiovale EPVS (ß = 0.37, SE = 0.12, p = 0.003). tTau levels predicted CSO-EPVS (ß = 0.30, SE = 0.15, p = 0.046). Moreover, increased levels of AQP4 were strongly associated with higher levels of tTau in the CSF (ß = 0.35, SE = 0.13, p = 0.008). Conclusion: We provide evidence that CSO-EPVS and CSF-AQP4 might be clinically meaningful biomarkers of glymphatic dysfunction and associated neurodegeneration.

Amyotrophic lateral sclerosis with upper motor neuron predominance: diagnostic accuracy of qualitative and quantitative susceptibility metrics in the precentral gyrus.

OBJECTIVE: The study aims at comparing the diagnostic accuracy of qualitative and quantitative assessment of the susceptibility in the precentral gyrus in detecting amyotrophic lateral sclerosis (ALS) with predominance of upper motor neuron (UMN) impairment. METHODS: We retrospectively collected clinical and 3T MRI data of 47 ALS patients, of whom 12 with UMN predominance (UMN-ALS). We further enrolled 23 healthy controls (HC) and 15 ALS Mimics (ALS-Mim). The Motor Cortex Susceptibility (MCS) score was qualitatively assessed on the susceptibility-weighted images (SWI) and automatic metrics were extracted from the quantitative susceptibility mapping (QSM) in the precentral gyrus. MCS scores and QSM-based metrics were tested for correlation, and ROC analyses. RESULTS: The correlation of MCS score and susceptibility skewness was significant (Rho = 0.55, p < 0.001). The susceptibility SD showed an AUC of 0.809 with a specificity and positive predictive value of 100% in differentiating ALS and ALS Mim versus HC, significantly higher than MCS (Z = -3.384, p-value = 0.00071). The susceptibility skewness value of -0.017 showed specificity of 92.3% and predictive positive value of 91.7% in differentiating UMN-ALS versus ALS mimics, even if the performance was not significantly better than MCS (Z = 0.81, p = 0.21). CONCLUSION: The MCS and susceptibility skewness of the precentral gyrus show high diagnostic accuracy in differentiating UMN-ALS from ALS-mimics subjects. The quantitative assessment might be preferred being an automatic measure unbiased by the reader. CLINICAL RELEVANCE STATEMENT: The clinical diagnostic evaluation of ALS patients might benefit from the qualitative and/or quantitative assessment of the susceptibility in the precentral gyrus as imaging marker of upper motor neuron predominance. KEY POINTS: • Amyotrophic lateral sclerosis diagnostic work-up lacks biomarkers able to identify upper motor neuron involvement. • Susceptibility-weighted imaging/quantitative susceptibility mapping-based measures showed good diagnostic accuracy in discriminating amyotrophic lateral sclerosis with predominant upper motor neuron impairment from patients with suspected motor neuron disorder. • Susceptibility-weighted imaging/quantitative susceptibility mapping-based assessment of the magnetic susceptibility provides a diagnostic marker for amyotrophic lateral sclerosis with upper motor neuron predominance.

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.

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.

Quantitative MRI Harmonization to Maximize Clinical Impact: The RIN-Neuroimaging Network.

Neuroimaging studies often lack reproducibility, one of the cardinal features of the scientific method. Multisite collaboration initiatives increase sample size and limit methodological flexibility, therefore providing the foundation for increased statistical power and generalizable results. However, multisite collaborative initiatives are inherently limited by hardware, software, and pulse and sequence design heterogeneities of both clinical and preclinical MRI scanners and the lack of benchmark for acquisition protocols, data analysis, and data sharing. We present the overarching vision that yielded to the constitution of RIN-Neuroimaging Network, a national consortium dedicated to identifying disease and subject-specific in-vivo neuroimaging biomarkers of diverse neurological and neuropsychiatric conditions. This ambitious goal needs efforts toward increasing the diagnostic and prognostic power of advanced MRI data. To this aim, 23 Italian Scientific Institutes of Hospitalization and Care (IRCCS), with technological and clinical specialization in the neurological and neuroimaging field, have gathered together. Each IRCCS is equipped with high- or ultra-high field MRI scanners (i.e., ≥3T) for clinical or preclinical research or has established expertise in MRI data analysis and infrastructure. The actions of this Network were defined across several work packages (WP). A clinical work package (WP1) defined the guidelines for a minimum standard clinical qualitative MRI assessment for the main neurological diseases. Two neuroimaging technical work packages (WP2 and WP3, for clinical and preclinical scanners) established Standard Operative Procedures for quality controls on phantoms as well as advanced harmonized quantitative MRI protocols for studying the brain of healthy human participants and wild type mice. Under FAIR principles, a web-based e-infrastructure to store and share data across sites was also implemented (WP4). Finally, the RIN translated all these efforts into a large-scale multimodal data collection in patients and animal models with dementia (i.e., case study). The RIN-Neuroimaging Network can maximize the impact of public investments in research and clinical practice acquiring data across institutes and pathologies with high-quality and highly-consistent acquisition protocols, optimizing the analysis pipeline and data sharing procedures.

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.

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.

A susceptibility-weighted imaging qualitative score of the motor cortex may be a useful tool for distinguishing clinical phenotypes in amyotrophic lateral sclerosis.

OBJECTIVES: To distinguish amyotrophic lateral sclerosis (ALS) and its subtypes from ALS mimics and healthy controls based on the assessment of iron-related hypointensity of the primary motor cortex in susceptibility-weighted imaging (SWI). METHODS: We enrolled 64 patients who had undergone magnetic resonance imaging studies with clinical suspicions of ALS. The ALS group included 48 patients; the ALS-mimicking disorder group had 16 patients. The ALS group was divided into three subgroups according to the prevalence of upper motor neuron (UMN) or lower motor neuron (LMN) impairment, with 12 subjects in the UMN-predominant ALS group (UMN-ALS), 16 in the LMN-predominant ALS group (LMN-ALS), and 20 with no prevalent impairment (C-ALS). The Motor Cortex Susceptibility (MCS) score was defined according to the hypointensity of the primary motor cortex in the SWI sequence. Its diagnostic accuracy in differentiating groups was evaluated. RESULTS: The MCS was higher in the ALS group than in the healthy control and ALS-mimicking disorder groups (p < 0.001). Among ALS subgroups, the MCS was significantly higher in the UMN-ALS group than in the healthy control (p < 0.001), ALS-mimicking disorder (p = 0.002), and LMN-ALS groups (p = 0.002) and higher in the C-ALS group than in the healthy control group (p = 0.019). An MCS value ≥ 2 showed specificity and a positive predictive value of 100% in the detection of both UMN-ALS and C-ALS patients. CONCLUSIONS: The assessment of MCS in the SWI sequence could be a useful tool in supporting diagnosis in patients suspicious for ALS with prevalent signs of UMN impairment or with no prevalence signs of UMN or LMN impairment. KEY POINTS: • The hypointensity of the primary motor cortex in susceptibility-weighted imaging could support the diagnosis of ALS. • Our new qualitative score called MCS shows high specificity and positive predictive value in differentiating ALS patients with upper motor neuron impairment from patients with ALS-mimicking disorders and healthy controls.

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.

Cortical thinning trajectories across disease stages and cognitive impairment in amyotrophic lateral sclerosis.

BACKGROUND: Cortical neuron degenerative process underlying upper motor neuron involvement in amyotrophic lateral sclerosis (ALS) spreads to extra-motor regions as disease progresses. This is associated with cognitive and behavioural worsening in more severe disease stages. However, the clinical variability of ALS patients might reflect different cortical involvement in extra-motor areas. OBJECTIVES: To investigate cortical thinning across disease stages in ALS patients accounting for their cognitive/behavioural impairment. METHODS: Thirty-six ALS patients (17 with cognitive/behavioural impairment, ALSimp) and 26 healthy controls underwent structural 3T magnetic resonance imaging. Cortical thickness was measured with a region-wise approach. The King's Clinical Staging System was used to determine disease stages. The Jonckheere-Terpstra test tested for trends in cortical thinning and cognitive involvement across disease stages. RESULTS: Significant trends toward cortical atrophy across disease stages were found in bilateral frontal and cingular cortex, left temporal gyrus and right occipital gyrus of ALS patients, consistently with cognitive impairment in phonemic fluency, language, verbal episodic memory and social cognition. Sub-group analyses revealed that ALSimp had specific thinning in the right fronto-temporal insular cortex related to more pronounced cognitive involvement. CONCLUSION: Looking at ALS patients irrespective of their cognitive phenotype, motor and extra-motor cortical involvement is consistent with neuropathological studies of disease dissemination. Segregating patients according to their cognitive status, a distinctive trajectory of cortical thinning emerged for ALSimp patients, suggesting a specific course distinct to that of the classic ALS phenotype.

Toward a marker of upper motor neuron impairment in amyotrophic lateral sclerosis: A fully automatic investigation of the magnetic susceptibility in the precentral cortex.

PURPOSE: Diagnostic work-up in motor neuron disease (MND) needs a quantitative biomarker of upper motor neuron (UMN) impairment. We investigated the susceptibility properties of the precentral cortex in a cohort of patients affected by Amyotrophic lateral sclerosis (ALS) to obtain a useful biomarker of UMN impairment in a fully automatic paradigm. MATERIALS AND METHODS: We retrospectively collected imaging and clinical data of 42 ALS patients who had undergone brain 3 T MRI including tridimensional T1-weighted and spoiled gradient-echo multi-echo T2-weighted images. We further acquired images from 23 healthy control (HC) volunteers. The precentral cortex was automatically segmented and the cortical thickness calculated. Histogram metrics (mean, median, standard deviation, skewness, kurtosis) derived from the quantitative susceptibility map (QSM) were extracted from the automatically segmented precentral cortex. Multivariate regression analyses were performed to identify the variables predicting the disease status (ALS vs HC), the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and the UMN score. RESULTS: A decreased cortical thickness (B = 9.40; Wald's test = 7.43; p = 0.006) and increased susceptibility skewness (B = -3.08; Wald's test = 4.36; p = 0.037) independently predicted ALS in a logistic regression model (χ2(3, N = 65) = 22.07, p < 0.001. No predictors of ALSFRS-R were identified. An increased susceptibility skewness (ß = 0.55; t = 4.23; p < 0.001) and longer disease duration (ß = 0.35; t = 2.67; p = 0.011) independently predicted a higher UMN score in a linear regression model (R2 = 0.32; p < 0.001). CONCLUSION: The susceptibility skewness might be an unbiased quantitative biomarker of UMN impairment in ALS patients.

Distortion of the cortical motor map in patients with Unverricht-Lundborg disease: A combined TMS-MRI study.

OBJECTIVE: To assess functional organization of the motor cortex in patients with Unverricht-Lundborg disease (EPM1A) using a combined neurophysiologic and imaging approach. METHODS: EPM1A patients underwent transcranial magnetic stimulation (TMS)-based cortical mapping of the motor hand area. Moreover, they performed neuroimaging studies to assess functional magnetic resonance imaging (fMRI) activation maps related to motor hand task and cortical thickness (CTH) on T1-weighted 3D images. RESULTS: The hand cortical representation was different in EPM1A patients from that of the control subjects both in TMS and in fMRI brain mapping, characterized by a posterior dislocation and a mild reduction in the activation of motor areas. CTH analysis revealed a thinning of both precentral and paracentral areas in the patients. CONCLUSIONS: We hypothesize that the altered cortical motor map reflects a functional reorganization of the residual cortical neuronal pool of the sensorimotor hand areas driven by plastic reorganization and/or pathophysiological mechanisms. SIGNIFICANCE: Both pathophysiological process and plastic changes may represent two sides of the same phenomenon in the EPM1A patients; structural and functional brain mapping may help to identify functional reorganization of the cortical motor system.

Low CSF ß-amyloid levels predict early regional grey matter atrophy in multiple sclerosis.

BACKGROUND AND PURPOSE: Grey matter (GM) atrophy is present from the earliest stages of multiple sclerosis (MS) and occurs largely in a nonrandom manner. However, the biological mechanisms underlying the progression of regional atrophy are still unclear. Aim of this study is to investigate whether amyloid pathology might be involved in determining the pattern of GM atrophy over time. METHODS: Forty-six subjects were recruited: 31 newly diagnosed relapsing-remitting (RR-) MS patients and 15 age- and sex-matched healthy controls (HC). Aß levels were determined in CSF samples from all subjects. All participants underwent brain magnetic resonance imaging (MRI) at baseline, and 23 out of 31 patients at one year follow-up. T1-weighted scans were segmented using the Geodesic Information Flows software. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses. RESULTS: CSF Aß concentration was the best predictor of global GM loss over time after age (ß = 0.403; p = 0.024), in particular in the left precuneus (p = 0.045), in the left middle cingulate gyrus (p = 0.009), in the left precentral gyrus (p = 0.021) and in the right angular gyrus (p = 0.029). CONCLUSIONS: CSF Aß levels seem to be crucial in MS early brain volume loss as GM atrophy manifests in regions particularly vulnerable to early Aß deposition.

Effects of in-utero exposure to chemotherapy on fetal brain growth.

OBJECTIVE: Children exposed to chemotherapy in the prenatal period demonstrate normal neurocognitive development at 3 years but concerns regarding fetal brain growth remain high considering its vulnerability to external stimuli. Our aim was to evaluate the impact of in-utero chemotherapy exposure on brain growth and its effects on neurodevelopmental outcome. METHODS: The protocol was approved by the local ethics committee. Brain regional volumes at term postmenstrual age were measured by MRI in children exposed to in-utero chemotherapy and compared with normal MRI controls. Brain segmentation was performed by Advanced Normalization Tools (ANTs)-based transformations of the Neonatal Brain Atlas (ALBERT). Neurodevelopmental assessment (Bayley-III scales) was performed at 18 months corrected age in both exposed infants and in a group of healthy controls. Multiple linear regressions and false discovery rate correction for multiple comparisons were performed. RESULTS: Twenty-one newborns prenatally exposed to chemotherapy (epirubicin administered in 81% of mothers) were enrolled in the study: the mean gestational age was 36.4±2.4 weeks and the mean birthweight was 2,753±622 g. Brain MRI was performed at mean postmenstrual age of 41.1±1.4 weeks. No statistically significant differences were identified between the children exposed to chemotherapy and controls in both the total (398±55 cm3 vs 427±56 cm3, respectively) and regional brain volumes. Exposed children showed normal Bayley-III scores (cognitive 110.2±14.5, language 99.1±11.3, and motor 102.6±7.3), and no significant correlation was identified between the brain volumes and neurodevelopmental outcome. CONCLUSION: Prenatal exposure to anthracycline/cyclophosphamide-based chemotherapy does not impact fetal brain growth, thus supporting the idea that oncological treatment in pregnant women seems to be feasible and safe for the fetus.

Cortical correlates of behavioural change in amyotrophic lateral sclerosis.

BACKGROUND: Behavioural changes in amyotrophic lateral sclerosis (ALS) are heterogeneous. The study aim was to identify the behavioural profiles of non-demented patients with ALS and their neuroimaging correlates and to elucidate if they are comparable to those reported in studies of the behavioural-variant of frontotemporal dementia (bvFTD). METHODS: Behavioural changes of 102 non-demented patients with ALS were assessed through the Frontal Behavioural Inventory (FBI), a 24-item scale assessing different behavioural modifications, mainly chosen from the core clinical features of FTD. Principal component analysis (PCA) was used to detect distinct clusters of behavioural changes based on FBI subscores. The cortical thinning related to each behavioural profile was analysed in 29 patients with ALS. Cronbach's α was used to test the reliability of bvFTD-related FBI clustering in our cohort. RESULTS: Sixty patients with ALS had FBI score≥1. PCA identified three phenotypic clusters loading on disinhibited/hostile, dysexecutive and apathetic FBI subscores. Imaging analyses revealed that the thinning of bilateral orbitofrontal cortex was related to apathy, the right frontotemporal and cingular cortex to the disinhibited/hostile profile and the left precuneus cortex to the dysexecutive behaviours. The bvFTD-associated aggressive profile reliably applied to our cohort. CONCLUSIONS: In non-demented patients with ALS, different behavioural profiles could be identified. The right frontotemporal and cingular cortex thinning was the hallmark of the behavioural profile mostly overlapping that described in bvFTD. Our findings provide the unbiased identification of determinants relevant for a novel stratification of patients with ALS based on their behavioural impairment, which might be useful as proxy of cognitive decline.

Cortical markers of cognitive syndromes in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) can be associated with a spectrum of cognitive and behavioural symptoms, but the related patterns of focal cortical atrophy in non-demented ALS patients remain largely unknown. We enrolled 48 non-demented ALS patients and 26 healthy controls for a comprehensive neuropsychological assessment and a magnetic resonance exam. Behavioural and cognitive impairment was defined on the basis of a data-driven multi-domain approach in 21 ALS patients. Averaged cortical thickness of 74 bilateral brain regions was used as a measure of cortical atrophy. Cortical thinning in a fronto-parietal network, suggesting a disease-specific pattern of neurodegeneration, was present in all patients, independent of cognitive and behavioural status. Between-group and correlational analyses revealed that inferior frontal, temporal, cingular and insular thinning are markers for cognitive and behavioural deficits, with language impairment mainly related to left temporal pole and insular involvement. These specific correlates support the concept of a spectrum of deficits, with an overlap between the ALS cognitive phenotypes and the syndromes of frontotemporal dementia.

Cortical thickness, stance control, and arithmetic skill: An exploratory study in premanifest Huntington disease.

BACKGROUND: Huntington disease (HD) is an inherited neurodegenerative disorder most commonly manifesting in adulthood. Identification of biomarkers tracking neurodegeneration before the onset of motor symptoms is important for future interventional studies. Our study aimed to contribute in the phenotypic characterization of the premanifest HD phase. METHODS: 28 premanifest subjects (preHD), 25 age-matched controls, and 12 manifest HD patients were enrolled for the study. The participants underwent a multimodal protocol including cognitive evaluations, arithmetic ability test, posturography, composite cerebellar functional test (CCFS), and brain 3T-MRI. PreHD were divided at the group median for predicted years to expected onset into "far-from-onset" (>15 years, PreHD-far), and "close-to-onset" (≤15 years, preHD-close). Basal ganglia volumes and cortical thickness were computed using FreeSurfer. RESULTS: PreHD-close showed significantly lower scores than controls in Symbol Digit Modalities Test (p = 0.017), Arithmetic subtraction task (p = 0.04), and MMSE (p < 0.006). At posturography, preHD-close showed increased sway velocity (<0.04) and distance (p < 0.02) compared to controls. PreHD-close had reduced striatum and globus pallidus volumes and left occipital cortical thinning compared to controls. Compared to PreHD far-from-onset, PreHD-close showed bilateral cortical thinning in occipital and parahippocampal regions, inversely correlating with burden score and prognostic index for HD. CCFS only differed between controls and manifest HD. PreHD far-from-onset did not show significant differences in comparison with controls. CONCLUSIONS: We confirmed that quantitative brain MRI represents a valid biomarker of neurodegeneration in preHD. Posturography and Arithmentic tests seem promising tools for detecting early changes in premanifest HD, but need to be further confirmed in large cohorts.