Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

Cognitive Impairment Is Part of the Phenotype of Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS).

BACKGROUND: Little is known about the impact of the cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) on cognition. OBJECTIVE: Our objective was to determine the frequency and severity of cognitive impairment in RFC1-positive patients and describe the pattern of deficits. METHODS: Participants underwent a comprehensive neuropsychological assessment. Volume of the cerebellum and its lobules was measured in those who underwent a 3 Tesla-magnetic resonance scan. RESULTS: Twenty-one patients underwent a complete assessment, including 71% scoring lower than the cutoff at the Montreal Cognitive assessment and 71% having a definite cerebellar cognitive affective/Schmahmann syndrome. Three patients had dementia and seven met the criteria of mild cognitive impairment. Severity of cognitive impairment did not correlate with severity of clinical manifestations. Performance at memory and visuospatial functions tests negatively correlated with the severity of cerebellar manifestations. CONCLUSION: Cognitive manifestations are frequent in RFC1-related disorders. They should be included in the phenotype and screened systematically. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Fatigue after spontaneous intracerebral haemorrhage: prevalence and associated factors.

BACKGROUND: Fatigue is a major complaint in stroke survivors, but data focusing on intracerebral haemorrhage (ICH) survivors are scarce. In a cohort of spontaneous ICH survivors, we assessed the long-term prevalence of fatigue and its associated factors. METHODS: We included consecutive 1-year ICH survivors from the prospective, observational, single-centre Prognosis of Intracerebral Haemorrhage (PITCH) study. We evaluated fatigue (defined as a score ≥ 4 in Chalder Fatigue Scale); the severity of neurological, depressive, and anxiety symptoms; and functional disability 1, 3, and 6 years after ICH. We performed univariable and multivariable models to evaluate clinical factors and brain magnetic resonance imaging (MRI) small vessel disease (SVD) markers associated with fatigue. RESULTS: Of 255 1-year ICH survivors, 153 (60%) underwent fatigue screening and were included in this study. Seventy-eight patients (51%) reported fatigue at 1-year, 56/110 (51%) at 3-year, and 27/67 (40%) at 6-year follow-up. Patients with fatigue exhibited more severe concomitant depressive/anxiety symptoms, but the severity of depressive symptoms was the only clinical factor significantly associated with 1-year fatigue in multivariable analysis (adjusted odds ratio 1.4 for one-point increase; 95% confidence interval 1.2-1.6). Patients with severe cortical atrophy at baseline had increased risk of fatigue at 1-year follow-up compared to patients with mild/no cortical atrophy (adjusted odds ratio 2.5; 95% confidence interval 1.1-5.8). CONCLUSIONS: Fatigue after ICH is frequent and long-lasting, and it is associated with cortical atrophy (but not with other MRI markers of cerebral SVD). The link between fatigue and depressive symptoms may represent a potential therapeutic target.

Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort.

BACKGROUND: Cerebral microbleeds (CMBs) have been observed in healthy elderly people undergoing systematic brain magnetic resonance imaging. The potential role of acute triggers on the appearance of CMBs remains unknown. We aimed to describe the incidence of new CMBs after transcatheter aortic valve replacement (TAVR) and to identify clinical and procedural factors associated with new CMBs including hemostatic measures and anticoagulation management. METHODS: We evaluated a prospective cohort of patients with symptomatic aortic stenosis referred for TAVR for CMBs (METHYSTROKE [Identification of Epigenetic Risk Factors for Ischemic Complication During the TAVR Procedure in the Elderly]). Standardized neurologic assessment, brain magnetic resonance imaging, and analysis of hemostatic measures including von Willebrand factor were performed before and after TAVR. Numbers and location of microbleeds on preprocedural magnetic resonance imaging and of new microbleeds on postprocedural magnetic resonance imaging were reported by 2 independent neuroradiologists blinded to clinical data. Measures associated with new microbleeds and postprocedural outcome including neurologic functional outcome at 6 months were also examined. RESULTS: A total of 84 patients (47% men, 80.9±5.7 years of age) were included. On preprocedural magnetic resonance imaging, 22 patients (26% [95% CI, 17%-37%]) had at least 1 microbleed. After TAVR, new microbleeds were observed in 19 (23% [95% CI, 14%-33%]) patients. The occurrence of new microbleeds was independent of the presence of microbleeds at baseline and of diffusion-weighted imaging hypersignals. In univariable analysis, a previous history of bleeding (P=0.01), a higher total dose of heparin (P=0.02), a prolonged procedure (P=0.03), absence of protamine reversion (P=0.04), higher final activated partial thromboplastin time (P=0.05), lower final von Willebrand factor high-molecular-weight:multimer ratio (P=0.007), and lower final closure time with adenosine-diphosphate (P=0.02) were associated with the occurrence of new postprocedural microbleeds. In multivariable analysis, a prolonged procedure (odds ratio, 1.22 [95% CI, 1.03-1.73] for every 5 minutes of fluoroscopy time; P=0.02) and postprocedural acquired von Willebrand factor defect (odds ratio, 1.42 [95% CI, 1.08-1.89] for every lower 0.1 unit of high-molecular-weight:multimer ratio; P=0.004) were independently associated with the occurrence of new postprocedural microbleeds. New CMBs were not associated with changes in neurologic functional outcome or quality of life at 6 months. CONCLUSIONS: One out of 4 patients undergoing TAVR has CMBs before the procedure and 1 out of 4 patients develops new CMBs. Procedural or antithrombotic management and persistence of acquired von Willebrand factor defect were associated with the occurrence of new CMBs. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02972008.

Quantitative susceptibility mapping demonstrates different patterns of iron overload in subtypes of early-onset Alzheimer's disease.

OBJECTIVES: We aimed to define brain iron distribution patterns in subtypes of early-onset Alzheimer's disease (EOAD) by the use of quantitative susceptibility mapping (QSM). METHODS: EOAD patients prospectively underwent MRI on a 3-T scanner and concomitant clinical and neuropsychological evaluation, between 2016 and 2019. An age-matched control group was constituted of cognitively healthy participants at risk of developing AD. Volumetry of the hippocampus and cerebral cortex was performed on 3DT1 images. EOAD subtypes were defined according to the hippocampal to cortical volume ratio (HV:CTV). Limbic-predominant atrophy (LPMRI) is referred to HV:CTV ratios below the 25th percentile, hippocampal-sparing (HpSpMRI) above the 75th percentile, and typical-AD between the 25th and 75th percentile. Brain iron was estimated using QSM. QSM analyses were made voxel-wise and in 7 regions of interest within deep gray nuclei and limbic structures. Iron distribution in EOAD subtypes and controls was compared using an ANOVA. RESULTS: Sixty-eight EOAD patients and 43 controls were evaluated. QSM values were significantly higher in deep gray nuclei (p < 0.001) and limbic structures (p = 0.04) of EOAD patients compared to controls. Among EOAD subtypes, HpSpMRI had the highest QSM values in deep gray nuclei (p < 0.001) whereas the highest QSM values in limbic structures were observed in LPMRI (p = 0.005). QSM in deep gray nuclei had an AUC = 0.92 in discriminating HpSpMRI and controls. CONCLUSIONS: In early-onset Alzheimer's disease patients, we observed significant variations of iron distribution reflecting the pattern of brain atrophy. Iron overload in deep gray nuclei could help to identify patients with atypical presentation of Alzheimer's disease. KEY POINTS: • In early-onset AD patients, QSM indicated a significant brain iron overload in comparison with age-matched controls. • Iron load in limbic structures was higher in participants with limbic-predominant subtype. • Iron load in deep nuclei was more important in participants with hippocampal-sparing subtype.

Long-term neuropsychiatric symptoms in spontaneous intracerebral haemorrhage survivors.

OBJECTIVE: Neuropsychiatric (NP) symptoms are prominent features of cognitive decline, but they have been understudied in patients with spontaneous intracerebral haemorrhage (ICH). In ICH survivors, we aimed at assessing NP symptoms prevalence and profiles, and their influence on long-term outcomes. METHODS: We analysed data from consecutive 6-month ICH survivors enrolled in the Prognosis of Intracerebral Haemorrhage study. We performed NP evaluation using the Neuropsychiatric Inventory Questionnaire. Patients underwent long-term clinical follow-up after ICH (median follow-up time 7.2 years, IQR 4.8-8.2). RESULTS: Out of 560 patients with ICH, 265 survived at 6 months. NP evaluation 6 months after ICH was feasible in 202 patients. NP symptoms were present in 112 patients (55%), and in 36 out of 48 patients (75%) with post-ICH dementia. Affective symptoms were present in 77 patients (38%), followed by vegetative symptoms (52 patients, 26%) and hyperactivity (47 patients, 23%). Apathy and hyperactivity were associated with post-ICH dementia and cerebral amyloid angiopathy MRI profile (all p<0.05). Apathy and hyperactivity prevailing over affective symptoms at 6-month follow-up were associated with higher risks of developing new-onset dementia (HR 5.40; 95% CI 2.27 to 12.84), while presence or severity of NP symptoms were not. CONCLUSION: NP symptoms were present in more than half of 6-month ICH survivors, with higher prevalence and severity in patients with post-ICH dementia. Distinctive NP profile might be associated to cognitive status and inform on long-term dementia risk.

Conservative Iron Chelation for Neuroferritinopathy.

BACKGROUND: Neuroferritinopathy is a rare inherited neurodegenerative disease with brain iron accumulation characterized by brain iron overload resulting in progressive movement disorders. No treatment is currently available. OBJECTIVE: We assessed conservative iron chelation with deferiprone at 30 mg/kg/day on the disease progression with controlled periods of discontinuation. METHODS: Four patients with confirmed molecular diagnosis of neuroferritinopathy were given deferiprone at different stages of disease progression and with clinical and biological monitoring to control benefit and risk. RESULTS: The four patients showed slight to high improvement. In one case, we managed to stabilize disease progression for more than 11 years. In another case, we were able to reverse symptoms after a few months of treatment. The earliest the treatment was started, the most efficient it was on disease progression. CONCLUSIONS: Conservative iron chelation should be further assessed in neuroferritinopathy. © 2022 International Parkinson and Movement Disorder Society.

Resting-State Functional Connectivity in Frontostriatal and Posterior Cortical Subtypes in Parkinson's Disease-Mild Cognitive Impairment.

BACKGROUND: The "dual syndrome hypothesis" distinguished two subtypes in mild cognitive impairment (MCI) in Parkinson's disease: frontostriatal, characterized by attentional and executive deficits; and posterior cortical, characterized by visuospatial, memory, and language deficits. OBJECTIVE: The aim was to identify resting-state functional modifications associated with these subtypes. METHODS: Ninety-five nondemented patients categorized as having normal cognition (n = 31), frontostriatal (n = 14), posterior cortical (n = 20), or mixed (n = 30) cognitive subtype had a 3 T resting-state functional magnetic resonance imaging scan. Twenty-four age-matched healthy controls (HCs) were also included. A group-level independent component analysis was performed to identify resting-state networks, and the selected components were subdivided into 564 cortical regions in addition to 26 basal ganglia regions. Global intra- and inter-network connectivity along with global and local efficiencies was compared between groups. The network-based statistics approach was used to identify connections significantly different between groups. RESULTS: Patients with posterior cortical deficits had increased intra-network functional connectivity (FC) within the basal ganglia network compared with patients with frontostriatal deficits. Patients with frontostriatal deficits had reduced inter-network FC between several networks, including the visual, default-mode, sensorimotor, salience, dorsal attentional, basal ganglia, and frontoparietal networks, compared with HCs, patients with normal cognition, and patients with a posterior cortical subtype. Similar results were also found between patients with a mixed subtype and HCs. CONCLUSION: MCI subtypes are associated with specific changes in resting-state FC. Longitudinal studies are needed to determine the predictive potential of these markers regarding the risk of developing dementia. © 2021 International Parkinson and Movement Disorder Society.

Myeloneuropathy induced by recreational nitrous oxide use with variable exposure levels.

BACKGROUND AND PURPOSE: Although several case series have described nitrous-oxide-associated neurological disorders, a comprehensive assessment of exposure characteristics (e.g., time to onset, level of exposure) in substance abusers has not been performed. The aim of this study was to describe the onset patterns of recreational use of nitrous-oxide-induced neurological disorders. METHODS: All cases of neurological disorders related to nitrous oxide recreational use reported to the Hauts-de-France addictovigilance center between January 2019 and August 2020 were selected. Only cases requiring hospitalization with informative data to perform the nitrous oxide causality assessment were included. RESULTS: A total of 20 cases from five hospitals were included. The male-to-female ratio was 6:1 and the median age was 19 years (range 16-34). The neurological presentation (myeloneuropathy 64%, 7/11; sensorimotor neuropathy 36%, 4/11) included for all patients gait disorders due to proprioceptive ataxia and limb hypoesthesia. The median dose used per occasion was 100 cartridges (range 5-960; n = 19). The median time from the start of nitrous oxide use to the onset of neurological symptoms was 6 months (range 0.7-54; n = 16). The cumulative dose was significantly higher in patients with damage to all four limbs than in patients with lower limb symptoms only (p = 0.042). CONCLUSIONS: A low intermittent exposure may be sufficient to cause neurological damage in some subjects, suggesting that, at the population level, there is no safe exposure to nitrous oxide in recreational settings. The severity of neurological impairment could increase once used at high doses and for prolonged durations of nitrous oxide.

Challenging the diagnosis of a posterior circulation dissecting aneurysm.

INTRODUCTION: I ntracranial vertebral dissections have polymorphs clinical presentations and can lead to haemorrhagic complications if they are intracranial. We here describe a case of a thrombosed dissecting aneurysm of postero-inferior cerebellar artery (PICA) revealed by a Wallenberg syndrome preceded by headaches. CASE: A 23-year-old patient, without neurological or vascular past medical history, was admitted for dizziness preceded by headache. The clinical examination on admission revealed an incomplete Wallenberg syndrome, associating hemiface sensitive deficit, Horner's syndrome, dysmetria and nystagmus. The brain MRI showed a latero-medullary infarct with a homolateral PICA thrombosed dissecting aneurysm. CONCLUSION: The diagnosis of intracranial dissecting aneurysms needs particular caution because aneurysm sac thrombosis can give false reassurance on angiographic MR sequences. Moreover, the anatomic features of intracranial artery walls make them prone to sub-adventitial dissection and subsequent subarachnoid haemorrhages. Therefore, antithrombotic therapy should be used with caution, due to the risk of bleeding in these intracranial dissections.

Long-term functional decline of spontaneous intracerebral haemorrhage survivors.

OBJECTIVE: To identify in patients who survived 6 months after a spontaneous intracerebral haemorrhage (ICH) baseline characteristics and new clinical events associated with functional decline. METHODS: In a single-centre study, we prospectively included 6-month survivors with a modified Rankin Scale (mRS) score 0-3. We defined functional decline by a transition to mRS 4-5. We evaluated associations of baseline characteristics and new clinical events with functional decline, using univariate and multivariable models. RESULTS: Of 560 patients, 174 (31%) had an mRS score 0-3 at 6 months. During a median follow-up of 9 years (IQR 8.1-9.5), 40 (23%) converted to mRS 4-5. Age, diabetes mellitus, ICH volume and higher mRS scores at 6 months were independently associated with functional decline. Among baseline MRI markers, presence of strictly lobar cerebral microbleeds (CMBs), and mixed lobar and deep CMBs were independently associated with functional decline. When new clinical events occurring during follow-up were added in multivariable models, age (cause-specific HR (CSHR): 1.07; 95% CI: 1.03 to 1.11), ICH volume (CSHR: 1.03; 95% CI: 1.01 to 1.06), mRS score at 6 months (CSHR per 1 point increase 1.61, 95% CI 1.07 to 2.43), occurrence of dementia (CSHR: 3.81, 95% CI: 1.78 to 8.16) and occurrence of any stroke (CSHR: 4.29, 95% CI: 1.80 to 10.22) remained independently associated with transition to mRS 4-5. INTERPRETATION: Almost one-fourth of patients with spontaneous ICH developed a functional decline over time. Age, ICH volume, higher mRS score at 6 months and new clinical events after ICH are the major determinants.

A multimodal, longitudinal study of cognitive heterogeneity in early-onset Alzheimer's disease.

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a heterogeneous pathology. Young patients with AD are particularly likely to have an atypical presentation. The objectives of the present cluster analysis were to determine whether patients with early-onset AD (EOAD) had several distinct cognitive profiles and to compare the resulting clusters with regard to clinical, neuroimaging, and laboratory characteristics. METHODS: We collected cognitive, behavioural, functional, neuroimaging, and laboratory data on 72 patients meeting the criteria for probable mild EOAD. The patients were first classified into clinical phenotype groups by a multidisciplinary board of clinicians. The patients' cognitive and functional decline was monitored for 24 months. A k-means clustering analysis was then used to determine clusters on the basis of the patients' neuropsychological test results. RESULTS: Two distinct clusters were identified: the patients in the first cluster (C1, n = 38) had a predominant memory impairment, whereas patients in the second (C2, n = 34) did not. Dyslipidaemia and the presence of ɛ4 apolipoprotein E allele were more frequent in C1, whereas the cognitive and functional decline was faster in the patients in C2. Moreover, posterior brain abnormalities were more severe in patients in C2 than in patients in C1. CONCLUSIONS: By applying a k-means clustering analysis, we identified two clusters of patients in an EOAD cohort. The clusters differed with regard to certain clinical, imaging, and laboratory characteristics. This clustering procedure might be of value for managing patients with EOAD in general and for identifying those at risk of more rapid decline in particular.

Seizures after decompressive hemicraniectomy for large middle cerebral artery territory infarcts: Incidence, associated factors, and impact on long-term outcomes.

BACKGROUND AND PURPOSE: Decompressive hemicraniectomy (DH) reduces mortality of large middle cerebral artery (MCA) territory infarcts. Survivors are at high risk of poststroke seizures (PSSs). This study aims to describe the incidence of PSSs, to identify associated factors, and to assess their impact on long-term outcomes. METHODS: We included consecutive patients who underwent DH for large MCA infarcts from May 2005 to December 2019 at Lille University Hospital. Patients were followed up at 3 months, 1 year, and 3 years. We analysed (i) the incidence and associated factors of early onset PSSs (EPSSs) with logistic regression models; (ii) the incidence and associated factors of late onset PSSs (LPSSs) in survivors at 7 days with a univariate Cox proportional hazard regression model for interval-censored data; and (iii) the impact of PSSs (EPSSs and LPSSs) on mortality with univariate and multivariate Cox proportional hazard regression models and modified Rankin Scale at 1 and 3 years, with univariate and adjusted multivariate ordinal logistic regression analyses. RESULTS: Of 248 patients (150 men, 60.5%; mean age = 50.4 ± 9.6 years), 106 (42.7%) presented PSSs (six inaugural seizures, 22 EPSSs, 78 LPSSs) during follow-up. The PSS cumulative incidence was 12.3% at 7 days, 24.9% at 3 months, 49.8% at 1 years, and 54.8% at 3 years. No predictor was significantly associated with either EPSSs or LPSSs. PSSs did not significantly impact mortality and long-term functional outcome. CONCLUSIONS: The incidence of PSSs after DH is high, reaching more than 50% 3 years after stroke, but PSSs did not influence long-term mortality or functional outcome.

Infarct Volume Before Hemicraniectomy in Large Middle Cerebral Artery Infarcts Poorly Predicts Catastrophic Outcome.

BACKGROUND AND PURPOSE: Infarct volumes predict malignant infarcts in patients undergoing decompressive hemicraniectomy (DH) for large middle cerebral artery territory infarcts. The aim of the study was to determine the optimal magnetic resonance imaging infarct volume threshold that predicts a catastrophic outcome at 1 year (modified Rankin Scale score of 5 or death). METHODS: We included consecutive patients who underwent DH for large middle cerebral artery infarcts. We analyzed infarct volumes before DH with semi-automated methods on b1000 diffusion-weighted imaging sequences and apparent diffusion coefficient maps. We studied infarct volume thresholds for prediction of catastrophic outcomes, and analyzed sensitivity, specificity, and the area under the curve, a value ≥0.70 indicating an acceptable prediction. RESULTS: Of 173 patients (109 men, 63%; median age 53 years), 42 (24.3%) had catastrophic outcomes. Magnetic resonance imaging b1000 diffusion-weighted imaging and apparent diffusion coefficient infarct volumes were associated to the occurrence of 1-year catastrophic outcome (adjusted odds ratio, 9.17 [95% CI, 2.00-42.04] and odds ratio, 4.18 [95% CI, 1.33-13.19], respectively, per 1 log increase). The optimal volume cutoff of were 211 mL on b1000 diffusion-weighted imaging and 181 mL on apparent diffusion coefficient maps. The 2 methods showed similar sensitivities and specificities and overlapping area under the curve of 0.64 (95% CI, 0.54-0.74). CONCLUSIONS: In patients with large middle cerebral artery infarcts, optimal magnetic resonance imaging infarct volume thresholds showed poor accuracy and low specificity to predict 1-year catastrophic outcome, with different b1000 diffusion-weighted imaging and apparent diffusion coefficient thresholds. In the setting of DH, optimal infarct volumes alone should not be used to deny DH, irrespectively of the method used.

Intraventricular dopamine infusion alleviates motor symptoms in a primate model of Parkinson's disease.

BACKGROUND: Continuous compensation of dopamine represents an ideal symptomatic treatment for Parkinson's disease (PD). The feasibility in intracerebroventricular administration (i.c.v.) of dopamine previously failed because of unresolved dopamine oxidation. OBJECTIVES: We aim to test the feasibility, safety margins and efficacy of continuous i.c.v. of anaerobic-dopamine (A-dopamine) with a pilot translational study in a non-human primate model of PD. METHODS: Continuous and circadian i.c.v. of A-dopamine was administered through a micro-pump connected to a subcutaneous catheter implanted into the right frontal horn of 8 non-human primates treated with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). A-dopamine was assessed at acute doses previously reported for dopamine as well as evaluating the long term therapeutic index of A-dopamine in comparison to anaerobically prepared L-dopa or methyl ester L-dopa. RESULTS: Over 60 days of a continuous circadian i.c.v. of A-dopamine improved motor symptoms (therapeutic index from 30 to 70 mg/day) without tachyphylaxia. No dyskinesia was observed even with very high doses. Death after 1 to 10 days (without neuronal alteration) was only observed with doses in excess of 160 mg whereas L-dopa i.c.v. was not effective at any dose. The technical feasibility of the administration regimen was confirmed for an anaerobic preparation of dopamine and for administration of a minimal infusion volume by micro-pump at a constant flow that prevented obstruction. CONCLUSION: Continuous circadian i.c.v. of A-dopamine appears to be feasible and shows efficacy without dyskinesia with a safe therapeutic index.

Use of MRI to predict symptomatic haemorrhagic transformation after thrombolysis for cerebral ischaemia.

BACKGROUND AND OBJECTIVE: Predictors of symptomatic haemorrhagic transformation (s-HT) of cerebral ischaemia after intravenous recombinant tissue-plasminogen activator (rt-PA) were identified in studies using CT scans. We evaluated whether MRI can identify other predictors. METHOD: We analysed predictors of s-HT in a cohort of consecutive patients who received intravenous rt-PA for cerebral ischaemia after MRI at baseline. We used receiver operating characteristic curves considering an area under the curve (AUC) of 0.70 or higher as indicating acceptable discrimination. RESULTS: Of 944 patients, 49 patients (5.2%) developed s-HT. Clinical factors independently associated with s-HT were age (adjusted OR (adjOR) 1.03 for 1 year increase; 95% CI 1.01 to 1.05), excessive alcohol consumption (adjOR 3.13; 95% CI 1.32 to 7.42), recent transient ischaemic attack (adjOR 2.88; 95% CI 1.04 to 7.95) and baseline national institutes of health stroke scale score (adjOR 1.06 for 1 point increase; 95% CI 1.02 to 1.10). MRI predictors were vascular hyperintensities (adjOR 3.89; 95% CI 1.50 to 10.08), old infarcts (adjOR 2.01; 95% CI 1.11 to 3.66) and volume of diffusion-weighted imaging (DWI) abnormality (adjOR 1.02 for 1 cm3 increase; 95% CI 1.01 to 1.03). The only variable with an acceptable discrimination was volume of DWI abnormality (AUC 0.72; 95% CI 0.64 to 0.79), a value of 4 cm3 predicting s-HT with a 78% sensitivity and 58% specificity. Variables that can be assessed only with MRI did not predict s-HT. CONCLUSION: Although the volume of DWI abnormality predicts s-HT, other imaging characteristics that can only be assessed with MRI were not significantly associated with s-HT. Trial registration number NCT01614080.

Predictors of outcome in 1-month survivors of large middle cerebral artery infarcts treated by decompressive hemicraniectomy.

BACKGROUND: Decompressive hemicraniectomy (DH) increases survival without severe dependency in patients with large middle cerebral artery (LMCA) infarcts. The objective was to identify predictors of 1-year outcome after DH for LMCA infarct. METHODS: We conducted this study in consecutive patients who underwent DH for LMCA infarcts, in a tertiary stroke centre. Using multivariable logistic regression analyses, we evaluated predictors of (1) 30-day mortality and (2) poor outcome after 1 year (defined as a modified Rankin Scale score of 4-6) in 30-day survivors. RESULTS: Of 212 patients (133 men, 63%; median age 51 years), 35 (16.5%) died within 30 days. Independent predictors of mortality were infarct volume before DH (OR 1.10 per 10 mL increase, 95% CI 1.04 to 1.16), delay between symptom onset and DH (OR 0.41, 95% CI 0.23 to 0.73 per 12 hours increase) and midline shift after DH (OR 2.59, 95% CI 1.09 to 6.14). The optimal infarct volume cut-off to predict death was 210 mL or more. Among the 177 survivors, 77 (43.5%) had a poor outcome at 1 year. Independent predictors of poor outcome were age (OR 1.08 per 1 year increase, 95% CI 1.03 to 1.12) and weekly alcohol consumption of 300 g or more (OR 5.30, 95% CI 2.20 to 12.76), but not infarct volume. CONCLUSION: In patients with LMCA infarcts treated by DH, stroke characteristics (infarct volume before DH, midline shift after DH and early DH) predict 30-day mortality, while patients' characteristics (age and excessive alcohol intake) predict 1-year outcome survivors.

Three-year changes of cortical 18F-FDG in amnestic vs. non-amnestic sporadic early-onset Alzheimer's disease.

PURPOSE: To examine and compare longitudinal changes of cortical glucose metabolism in amnestic and non-amnestic sporadic forms of early-onset Alzheimer's disease and assess potential associations with neuropsychological performance over a 3-year period time. METHODS: Eighty-two participants meeting criteria for early-onset (< 65 years) sporadic form of probable Alzheimer's disease and presenting with a variety of clinical phenotypes (47 amnestic and 35 non-amnestic forms) were included at baseline and followed up for 1.44 ± 1.23 years. All of the participants underwent a work-up at baseline and every year during the follow-up period, which includes clinical examination, neuropsychological testing, genotyping, cerebrospinal fluid biomarker assays, and structural MRI and 18F-FDG PET. Vertex-wise partial volume-corrected glucose metabolic maps across the entire cortical surface were generated and longitudinally assessed together with the neuropsychological scores using linear mixed-effects modeling as a function of amnestic and non-amnestic sporadic forms of early-onset Alzheimer's disease. RESULTS: Similar evolution patterns of glucose metabolic decline between amnestic and non-amnestic forms were observed in widespread neocortical cortices. However, only non-amnestic forms appeared to have a greater reduction of glucose metabolism in lateral orbitofrontal and bilateral medial temporal cortices associated with more severe declines of neuropsychological performance compared with amnestic forms. Furthermore, results suggest that glucose metabolic decline in amnestic forms would progress along an anterior-to-posterior axis, whereas glucose metabolic decline in non-amnestic forms would progress along a posterior-to-anterior axis. CONCLUSIONS: We found differences in spatial distribution and temporal trajectory of glucose metabolic decline between amnestic and non-amnestic early-onset Alzheimer's disease groups, suggesting that one might want to consider treating the two forms of the disease as two separate entities.

A Fully Automatic Method for Optic Radiation Tractography Applicable to Multiple Sclerosis Patients.

The optic radiations (OR) are white matter tracts forming the posterior part of the visual ways. As an important inter-individual variability exists, atlases may be inefficient to locate the OR in a given subject. We designed a fully automatic method to delimitate the OR on a magnetic resonance imaging using tractography. On 15 healthy subjects, we evaluated the validity of our method by comparing the outputs to the Jülich post-mortem histological atlas, and its reproducibility. We also evaluated its feasibility on 98 multiple sclerosis (MS) patients. We correlated different visual outcomes with the inflammatory lesions volume within the OR reconstructed with different methods (our method, atlas, TractSeg). Our method reconstructed the OR bundle in all healthy subjects (< 2 h for most of them), and was reproducible. It demonstrated good classification indexes: sensitivity up to 0.996, specificity up to 0.993, Dice coefficient up to 0.842, and an area under the receiver operating characteristic (ROC) curve of 0.981. Our method reconstructed the OR in 91 of the 98 MS patients (92.9%, < 6 h for most of patients). Compared to an atlas-based approach and the TractSeg method, the inflammatory lesions volume in the OR measured with our method better correlated with the visual cortex volume, visual acuity and mean peripapillar retinal nerve fiber layer thickness. Our method seems to be efficient to reconstruct the OR in healthy subjects, and seems applicable to MS patients. It may be more relevant than an atlas based approach.

Texture parameters of R2* maps are correlated with iron concentration and red blood cells count in clot analogs: A 7-T micro-MRI study.

BACKGROUND AND PURPOSE: Previous studies have suggested that mechanical revascularization in acute ischemic stroke (AIS) patients could be affected by clot histology. In this 7-T micro-MRI study, we used R2* relaxometry of clot analogs to evaluate the relationship between texture parameters of R2* maps and clot constituents. MATERIALS AND METHODS: Twelve AIS clot analogs were experimentally generated to obtain a wide range of red blood cell concentrations. All clots underwent a MR acquisition using a 7-T micro-MR system. A 3D multi-echo gradient-echo sequence was performed and R2* maps were generated. First order and second order statistics of R2* histograms within the clots were calculated. Iron concentration in clots was measured using absorption spectrometry and red blood cell count (RBC) was obtained by histopathological analysis. RESULTS: RBC count was strongly correlated with iron concentration within clots (r=0.87, P<.001). Higher RBC count and iron concentration were significantly correlated with first order parameters including: (a) global positive shift of the R2* histogram with higher '10th percentile', 'median', 'mean' and '90th percentile'; (b) increase of the global magnitude of voxel values with higher 'total energy' and 'root mean squared'; (c) greater uniformity of the voxel values with higher 'uniformity' and lower 'entropy'. Second order statistical parameters confirmed that higher RBC count and iron concentration correlated with (a) greater concentration of high gray-level values in the image; (b) more "coarse" texture of R2* maps. CONCLUSIONS: Texture analysis of MRI-R2* maps can accurately estimate the red blood cell count and iron content of AIS clot analogs.