Alessandro Meani

Brain network connectivity assessed using graph theory in frontotemporal dementia.

Objective: To investigate whether brain functional network connectivity is disrupted in patients with the behavioral variant of frontotemporal dementia (bvFTD). Methods: Graph theoretical analysis was applied to resting state functional MRI data from 18 patients with probable bvFTD and 50 healthy individuals. Functional connectivity between 90 cortical and subcortical brain regions was estimated using bivariate correlation analysis and thresholded to construct a set of undirected graphs. Correlations between network properties and cognitive variables were tested. Results: Global topologic organization of the functional brain network in bvFTD was significantly disrupted as indicated by reduced mean network degree, clustering coefficient, and global efficiency and increased characteristic path length and assortativity relative to normal subjects. Compared to controls, bvFTD data showed retention of major “hub” regions in the medial parietal, temporal, and occipital lobes, but cortical hubs were not noted in the frontal lobes. Medial and dorsal frontal regions, left caudate nucleus, left insular cortices, and some regions of the temporal, parietal, and occipital lobes showed decreased nodal centrality. BvFTD patients showed the greatest decrease in inter-regional connectivity between the frontal and occipital regions, and the insular cortices and occipital, temporal, subcortical, and frontal regions. In bvFTD, altered global network properties correlated with executive dysfunction. Conclusions: Global and local functional networks are altered in bvFTD, suggesting a loss of efficiency in information exchange between both distant and close brain areas. Altered brain regions are located in structures that are closely associated with neuropathologic changes in bvFTD. Aberrant topology of the functional brain networks in bvFTD appears to underlie cognitive deficits in these patients.

Functional MR Imaging Correlates of Neuropsychological Impairment in Primary-Progressive Multiple Sclerosis

BACKGROUND AND PURPOSE: Cognitive deficits affect ≤30% of patients with PPMS. We investigated the functional correlates of cognitive network dysfunction in patients with PPMS and their correlation with the extent of structural MR imaging damage. MATERIALS AND METHODS: From 16 right-handed patients with PPMS and 17 matched controls, structural and fMRIs (during the performance of the 2-back task) were acquired. Neuropsychological tests exploring memory, attention, and frontal lobe cognitive domains were administered. T2 LL, NBV, and CC areas were measured. RESULTS: Six patients with PPMS were CI. Structural MR imaging measures did not differ between patients who were CI and those who were CP. Compared with patients who were CI, patients who were CP had increased activations of the left caudate nucleus, PFC, and inferior parietal lobule. Compared with controls and patients who were CP, patients who were CI had increased activations of the SII, cerebellum, and insula. Compared with controls, they also had increased activations of the right precentral gyrus and a reduced recruitment of the left PFC. In patients with PPMS, a decreased composite cognitive score correlated with increased activity of the cerebellum, insula, and SII, as well as decreased PFC activity. T2 LL correlated with decreased PFC recruitment and increased SII recruitment. CONCLUSIONS: In PPMS, an increased recruitment of cognitive-related networks might represent a functional reserve with the potential to limit the severity of cognitive impairment. The accumulation of T2 lesions and the consequent exhaustion of frontal lobe plasticity might contribute to cognitive impairment in PPMS.

Persistent 7-tesla phase rim predicts poor outcome in new multiple sclerosis patient lesions

BACKGROUND In some active multiple sclerosis (MS) lesions, a strong immune reaction at the lesion edge may contain growth and thereby isolate the lesion from the surrounding parenchyma. Our previous studies suggest that this process involves opening of the blood-brain barrier in capillaries at the lesion edge, seen on MRI as centripetal contrast enhancement and a colocalized phase rim. We hypothesized that using these features to characterize early lesion evolution will allow in vivo tracking of tissue degeneration and/or repair, thus improving the evaluation of potential therapies for chronic active lesions. METHODS Centripetally and centrifugally enhancing lesions were studied in 17 patients with MS using 7-tesla MRI. High-resolution, susceptibility-weighted, T1-weighted (before/after gadolinium), and dynamic contrast-enhanced scans were acquired at baseline and months 1, 3, 6, and 12. For each lesion, time evolution of the phase rim, lesion volume, and T1 hypointensity were assessed. In autopsies of 3 progressive MS cases, the histopathology of the phase rim was determined. RESULTS In centripetal lesions, a phase rim colocalized with initial contrast enhancement. In 12 of 22, this phase rim persisted after enhancement resolved. Compared with centripetal lesions with transient rim, those with persistent rim had less volume shrinkage and became more T1 hypointense between months 3 and 12. No centrifugal lesions developed phase rims at any time point. Pathologically, persistent rims corresponded to an iron-laden inflammatory myeloid cell population at the edge of chronic demyelinated lesions. CONCLUSION In early lesion evolution, a persistent phase rim in lesions that shrink least and become more T1 hypointense over time suggests that the rim might mark failure of early lesion repair and/or irreversible tissue damage. In later stages of MS, phase rim lesions continue to smolder, exerting detrimental effects on affected brain tissue. TRIAL REGISTRATION NCT00001248. FUNDING The Intramural Research Program of NINDS supported this study.

Differential Cerebellar Functional Interactions during an Interference Task across Multiple Sclerosis Phenotypes

PURPOSE To determine whether modification of the connections between cerebellar and prefrontal areas might vary among multiple sclerosis (MS) phenotypes and might be associated with cognitive failure. MATERIALS AND METHODS Approval of the institutional review boards and written informed consent were obtained from each participant. Stroop-related functional magnetic resonance (MR) imaging activations and effective connectivity abnormalities between the right cerebellum and any other brain regions were assessed by using a psychophysiologic interaction (PPI) analysis from 17 patients with relapsing-remitting (RR), 17 with benign, and 23 with secondary progressive (SP) MS and 18 healthy control subjects (P < .05, corrected at cluster level). Correlations with disease duration, T2 lesion volume, brain volume, and response times (RTs) during the incongruent condition were estimated (P < .001, uncorrected). RESULTS Activation and PPI analyses showed that, compared with the other groups, RR MS group had abnormal recruitment of regions of the left frontoparietal lobes, whereas compared with RR MS group, SP MS group had abnormal recruitment of the cingulum or precuneus. Benign MS group had increased activation of the right prefrontal cortex, and increased interaction between these regions and the right cerebellum. In healthy controls, RTs inversely correlated with activity of right cerebellum and several frontoparietal regions. In MS, RTs inversely correlated with bilateral cerebellar activity and directly correlated with right precuneus activity. In MS, disease duration inversely correlated with right cerebellar activity and directly correlated with left inferior frontal gyrus and right precuneus activity. Higher T2 lesion volume and lower brain volumes were related to activity in these areas. CONCLUSION Patients with MS who have various clinical phenotypes experience different abnormalities in activation and effective connectivity between the right cerebellum and frontoparietal areas, which contribute to inefficient cortical reorganization, with increasing cognitive load. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120216/-/DC1.

Leptomeningeal gadolinium enhancement across the spectrum of chronic neuroinflammatory diseases

Objective: To assess the prevalence and the specificity of leptomeningeal enhancement (LME) on postcontrast T2–fluid-attenuated inversion recovery (FLAIR) MRI in multiple sclerosis (MS) compared to a variety of inflammatory and noninflammatory neurologic conditions assessed in 2 academic research hospitals. Methods: On 3T postcontrast T2-FLAIR images, the presence of focal gadolinium enhancement was evaluated in the leptomeningeal compartment in 254 people with non-MS neurologic conditions or neurotropic viral infections. Based on their clinical diagnosis, patients were grouped as follows: (1) other-than-MS inflammatory neurologic diseases; (2) noninflammatory neurologic diseases; (3) human T-lymphotropic virus (HTLV)–infected; (4) HIV-infected; (5) healthy volunteers. Results: LME was detected in 56/254 non-MS cases (22%) vs 74/299 (25%) of MS cases. LME was nearly 4-fold more frequent in non-MS inflammatory neurologic conditions (18/51 cases, 35%) than in noninflammatory neurologic conditions (3/38, 8%) and healthy volunteers (5/66, 8%). The highest prevalence of LME was detected in HTLV infection (17/38 cases, 45%), particularly in the setting of HTLV-associated myelopathy (14/25 cases, 56%). LME also frequently occurred in HIV infection (13/61 cases, 21%). Unlike in MS, LME is not associated with lower brain and cortical volumes in non-MS inflammatory neurologic conditions, including HTLV and HIV infection. Conclusions: Despite its relevance to MS pathogenesis and cortical pathology, LME is not specific to MS, occurring frequently in non-MS inflammatory neurologic conditions and especially in those patients with HTLV-associated myelopathy. Overall, this strengthens the notion that LME localizes inflammation-related focal disruption of the blood–meninges barrier and associated scarring.

Abnormal adaptation over time of motor network recruitment in multiple sclerosis patients with fatigue

Objectives: Using functional magnetic resonance imaging (fMRI) during a motor task, we investigated the functional correlates of central fatigue in multiple sclerosis (MS), and adaptation of motor network recruitment during a prolonged effort. Methods: Motor fMRI was obtained from 79 MS patients (50 fatigued (F), 29 non-fatigued (nF)) and 26 matched healthy controls (HC). Cognitive and physical fatigue were rated using the Modified Fatigue Impact Scale (MFIS). Results: Compared to HC and nF patients, F-MS patients experienced reduced activations of the left middle temporal gyrus, left supplementary motor area (SMA), bilateral superior frontal gyrus, left postcentral gyrus and basal ganglia regions. They also showed increased activation of the right middle frontal gyrus (MFG). Time-modulation analysis showed a reduced activity of the SMA and right precentral gyrus, and increased activity of the basal ganglia in HC. Such a trend was impaired in F-MS patients. In MS patients, increased MFG activity was related to MFIS scores. Physical MFIS score was related to a reduced recruitment of the right thalamus and SMA. Conclusions: Abnormalities and impaired timing of activation between different areas of the motor and executive networks occur in F-MS patients. The dysfunction of critical cortical areas contributes to the occurrence of central fatigue.

Brain plasticity in Parkinson’s disease with freezing of gait induced by action observation training

Gait disorders represent a therapeutic challenge in Parkinson’s disease (PD). This study investigated the efficacy of 4-week action observation training (AOT) on disease severity, freezing of gait and motor abilities in PD, and evaluated treatment-related brain functional changes. 25 PD patients with freezing of gait were randomized into two groups: AOT (action observation combined with practicing the observed actions) and “Landscape” (same physical training combined with landscape-videos observation). At baseline and 4-week, patients underwent clinical evaluation and fMRI. Clinical assessment was repeated at 8-week. At 4-week, both groups showed reduced freezing of gait severity, improved walking speed and quality of life. Moreover, AOT was associated with reduced motor disability and improved balance. AOT group showed a sustained positive effect on motor disability, walking speed, balance and quality of life at 8-week, with a trend toward a persisting reduced freezing of gait severity. At 4-week vs. baseline, AOT group showed increased recruitment of fronto-parietal areas during fMRI tasks, while the Landscape group showed a reduced fMRI activity of the left postcentral and inferior parietal gyri and right rolandic operculum and supramarginal gyrus. In AOT group, functional brain changes were associated with clinical improvements at 4-week and predicted clinical evolution at 8-week. AOT has a more lasting effect in improving motor function, gait and quality of life in PD patients relative to physical therapy alone. AOT-related performance gains are associated with an increased recruitment of motor regions and fronto-parietal mirror neuron and attentional control areas.

Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study

BACKGROUND In 2016, the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network proposed modifications to the MRI criteria to define dissemination in space (DIS) and time (DIT) for the diagnosis of multiple sclerosis in patients with clinically isolated syndrome (CIS). Changes to the DIS definition included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested. We compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for multiple sclerosis diagnosis in a large multicentre cohort of patients with CIS to provide evidence to guide revisions of multiple sclerosis diagnostic criteria. METHODS Brain and spinal cord MRI and optic nerve assessments from patients with typical CIS suggestive of multiple sclerosis done less than 3 months from clinical onset in eight European multiple sclerosis centres were included in this retrospective study. Eligible patients were 16-60 years, and had a first CIS suggestive of CNS demyelination and typical of relapsing-remitting multiple sclerosis, a complete neurological examination, a baseline brain and spinal cord MRI scan obtained less than 3 months from clinical onset, and a follow-up brain scan obtained less than 12 months from CIS onset. We recorded occurrence of a second clinical attack (clinically definite multiple sclerosis) at months 36 and 60. We evaluated MRI criteria performance for DIS, DIT, and DIS plus DIT with a time-dependent receiver operating characteristic curve analysis. FINDINGS Between June 16, 1995, and Jan 27, 2017, 571 patients with CIS were screened, of whom 368 met all study inclusion criteria. At the last evaluation (median 50·0 months [IQR 27·0-78·4]), 189 (51%) of 368 patients developed clinically definite multiple sclerosis. At 36 months, the two DIS criteria showed high sensitivity (2010 McDonald 0·91 [95% CI 0·85-0·94] and 2016 MAGNIMS 0·93 [0·88-0·96]), similar specificity (0·33 [0·25-0·42] and 0·32 [0·24-0·41]), and similar area under the curve values (AUC; 0·62 [0·57-0·67] and 0·63 [0·58-0·67]). Performance was not affected by inclusion of symptomatic lesions (sensitivity 0·92 [0·87-0·96], specificity 0·31 [0·23-0·40], AUC 0·62 [0·57-0·66]) or cortical lesions (sensitivity 0·92 [0·87-0·95], specificity 0·32 [0·24-0·41], AUC 0·62 [0·57-0·67]). Requirement of three periventricular lesions resulted in slightly lower sensitivity (0·85 [0·78-0·90], slightly higher specificity (0·40 [0·32-0·50], and similar AUC (0·63 [0·57-0·68]). Inclusion of optic nerve evaluation resulted in similar sensitivity (0·92 [0·87-0·96]), and slightly lower specificity (0·26 [0·18-0·34]) and AUC (0·59 [0·55-0·64]). AUC values were also similar for DIT (2010 McDonald 0·61 [0·55-0·67] and 2016 MAGNIMS 0·61 [0·55-0·66]) and DIS plus DIT (0·62 [0·56-0·67] and 0·64 [0·58-0·69]). INTERPRETATION The 2016 MAGNIMS criteria showed similar accuracy to the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis. Inclusion of symptomatic lesions is expected to simplify the clinical use of MRI criteria without reducing accuracy, and our findings suggest that needing three lesions to define periventricular involvement might slightly increase specificity, suggesting that these two factors could be considered during further revisions of multiple sclerosis diagnostic criteria. FUNDING UK MS Society, National Institute for Health Research University College London Hospitals Biomedical Research Centre, Dutch MS Research Foundation.

Brain reserve against physical disability progression over 5 years in multiple sclerosis

Objective: The brain reserve hypothesis links larger maximal lifetime brain growth (MLBG, estimated with intracranial volume [ICV]) with lower risk for cognitive decline/dementia. We examined whether larger MLBG is also linked to less physical disability progression over 5 years in a prospective sample of treatment-naive patients with multiple sclerosis (MS). Methods: Physical disability was measured with the Expanded Disability Status Scale (EDSS) at baseline and 5-year follow-up in 52 treatment-naive Serbian patients with MS. MRI measured disease burden (cerebral atrophy, T2 lesion volume) and MLBG: a genetically determined, premorbid (established during adolescence, stable thereafter) patient characteristic estimated with ICV (adjusted for sex). Logistic regression tested whether MLBG (smaller vs larger) predicts disability progression (stable vs worsened) independently of disease burden. Results: Disability progression was observed in 29 (55.8%) patients. Larger MLBG predicted lower risk for progression (odds ratio 0.13, 95% confidence interval 0.02–0.78), independently of disease burden. We also calculated absolute change in EDSS scores, and observed that patients with smaller MLBG showed worse EDSS change (0.91 ± 0.71) than patients with larger MLBG (0.42 ± 0.87). Conclusions: Larger MLBG was linked to lower risk for disability progression in patients with MS over 5 years, which is the first extension of the brain reserve hypothesis to physical disability. MLBG (ICV) represents a clinically available metric that may help gauge risk for future disability in patients with MS, which may advance the science and practice of early intervention. Potential avenues for future research are discussed.

Reading, writing, and reserve: Literacy activities are linked to hippocampal volume and memory in multiple sclerosis

Background: Engagement in cognitive leisure activities during early adulthood has been linked to preserved memory and larger hippocampal volume in persons with multiple sclerosis (MS). Objective: To investigate which specific types of cognitive leisure activities contribute to hippocampal volume and memory. Methods: We investigated links between three types of cognitive activities (Reading-Writing, Art-Music, Games-Hobbies) and (a) hippocampal volume within independent samples of Italian (n=187) and American (n=55) MS patients and (b) memory in subsamples of Italian (n=97) and American (n=53) patients. Results: Reading-Writing was the only predictor of hippocampal volume (rp=.204, p=.002), and the best predictor of memory (rp=.288, p=.001). Conclusions: Findings inform the development of targeted evidence-based enrichment programs aiming to bolster reserve against memory decline.