Robert A. Dineen

Disconnection as a mechanism for cognitive dysfunction in multiple sclerosis

Disconnection of cognitively important processing regions by injury to the interconnecting white matter provides a potential mechanism for cognitive dysfunction in multiple sclerosis. The contribution of tract-specific white matter injury to dysfunction in different cognitive domains in patients with multiple sclerosis has not previously been studied. We apply tract-based spatial statistics (TBSS) to diffusion tensor imaging (DTI) in a cohort of multiple sclerosis patients to identify loci where reduced white matter tract fractional anisotropy (FA) predicts impaired performance in cognitive testing. Thirty-seven multiple sclerosis patients in remission (median age 43.5 years; Expanded Disability Status Scale range 1.5-6.5; 35 relapsing remitting, two secondary-progressive) underwent 3 T MRI including high-resolution DTI. Multiple sclerosis patients underwent formal testing of performance in multiple cognitive domains. Normalized cognitive scores were used for voxel-wise statistical analysis using TBSS, while treating age as a covariate of no interest. Permutation-based inference on cluster size (t > 2, P <0.05 corrected) was used to correct for multiple comparisons. Statistical mapping revealed differential patterns of FA reduction for tests of sustained attention, working memory and processing speed, visual working memory and verbal learning and recall. FA was not associated with frontal lobe function or visuospatial perception. Cognitively relevant tract localizations only partially overlapped with areas of high FLAIR lesion probability, confirming the contribution of normal-appearing white matter abnormality to cognitive dysfunction. Of note, tract localizations showing significant associations with cognitive impairment were found to interconnect cortical regions thought to be involved in processing in these cognitive domains, or involve possible compensatory processing pathways. This suggests that TBSS reveals functionally relevant tract injury underlying cognitive dysfunction in patients with multiple sclerosis.

The Fornix in Health and Disease: An Imaging Review

The fornix is a discrete white matter tract bundle that is critical for normal cognitive functioning. Although clearly visualized at magnetic resonance imaging, its involvement in pathologic processes is often overlooked. Certain disease processes show a predilection for involvement of the fornix; in other pathologic conditions, its involvement is a rare but recognized finding. As part of the Papez circuit, it is critical in formation of memory, with damage or disease resulting in anterograde amnesia. Many different pathologic conditions can affect the fornix. Midline tumors such as gliomas or lymphoma can infiltrate it. As part of the limbic system, it may be affected by herpes simplex encephalitis. Involvement by inflammatory conditions such as multiple sclerosis may illustrate its importance in global cognitive function. An appreciation of forniceal atrophy may aid in assessment of mesial temporal sclerosis. Metabolic conditions such as Wernicke encephalopathy have been reported to involve it. The original discoveries of its role in memory arose from surgical trauma, but as a midline structure, it is susceptible to the shearing forces of diffuse axonal injury. Infarction of the fornix is rare but can result in acute amnesic syndromes. Its role in degenerative conditions such as Alzheimer disease and psychiatric conditions such as schizophrenia is a topic of research interest. Recognition of involvement of the fornix by various pathologic processes may aid in explaining the troubling clinical symptoms of amnesia.

Metrics and Textural Features of MRI Diffusion to Improve Classification of Pediatric Posterior Fossa Tumors

BACKGROUND AND PURPOSE: Qualitative radiologic MR imaging review affords limited differentiation among types of pediatric posterior fossa brain tumors and cannot detect histologic or molecular subtypes, which could help to stratify treatment. This study aimed to improve current posterior fossa discrimination of histologic tumor type by using support vector machine classifiers on quantitative MR imaging features. MATERIALS AND METHODS: This retrospective study included preoperative MRI in 40 children with posterior fossa tumors (17 medulloblastomas, 16 pilocytic astrocytomas, and 7 ependymomas). Shape, histogram, and textural features were computed from contrast-enhanced T2WI and T1WI and diffusivity (ADC) maps. Combinations of features were used to train tumor-type-specific classifiers for medulloblastoma, pilocytic astrocytoma, and ependymoma types in separation and as a joint posterior fossa classifier. A tumor-subtype classifier was also produced for classic medulloblastoma. The performance of different classifiers was assessed and compared by using randomly selected subsets of training and test data. RESULTS: ADC histogram features (25th and 75th percentiles and skewness) yielded the best classification of tumor type (on average >95.8% of medulloblastomas, >96.9% of pilocytic astrocytomas, and >94.3% of ependymomas by using 8 training samples). The resulting joint posterior fossa classifier correctly assigned >91.4% of the posterior fossa tumors. For subtype classification, 89.4% of classic medulloblastomas were correctly classified on the basis of ADC texture features extracted from the Gray-Level Co-Occurence Matrix. CONCLUSIONS: Support vector machine–based classifiers using ADC histogram features yielded very good discrimination among pediatric posterior fossa tumor types, and ADC textural features show promise for further subtype discrimination. These findings suggest an added diagnostic value of quantitative feature analysis of diffusion MR imaging in pediatric neuro-oncology.

Reproducibility of Graph-Theoretic Brain Network Metrics: A Systematic Review

This systematic review aimed to assess the reproducibility of graph-theoretic brain network metrics. Primary research studies of test-retest reliability conducted on healthy human subjects were included that quantified test-retest reliability using either the intraclass correlation coefficient (ICC) or the coefficient of variance. The MEDLINE, Web of Knowledge, Google Scholar, and OpenGrey databases were searched up to February 2014. Risk of bias was assessed with 10 criteria weighted toward methodological quality. Twenty-three studies were included in the review (n=499 subjects) and evaluated for various characteristics, including sample size (5-45), retest interval (<1 h to >1 year), acquisition method, and test-retest reliability scores. For at least one metric, ICCs reached the fair range (ICC 0.40-0.59) in one study, the good range (ICC 0.60-0.74) in five studies, and the excellent range (ICC>0.74) in 16 studies. Heterogeneity of methods prevented further quantitative analysis. Reproducibility was good overall. For the metrics having three or more ICCs reported for both functional and structural networks, six of seven were higher in structural networks, indicating that structural networks may be more reliable over time. The authors were also able to highlight and discuss a number of methodological factors affecting reproducibility.

Tranexamic acid for spontaneous intracerebral hemorrhage:a randomized controlled pilot trial (ISRCTN50867461)

BACKGROUND Spontaneous intracerebral hemorrhage (ICH) can be devastating, particularly if hematoma expansion (HE) occurs. Tranexamic acid (TA), an antifibrinolytic drug, significantly reduced mortality in bleeding patients after trauma in the large CRASH-2 trial. The CRASH-2 ICH substudy found that TA nonsignificantly reduced mortality and dependency in traumatic ICH. The aim of this study was to assess the feasibility of performing a randomized controlled trial of tranexamic acid in spontaneous ICH, ahead of a definitive study. METHODS We performed a single-center, prospective, randomized (2:1), double-blind, placebo-controlled blinded endpoint trial of TA (intravenous 1 g bolus, 1 g infusion/8 h) in acute (<24 hours) spontaneous ICH. The primary objective was to test the feasibility of recruiting to the trial. Other objectives included tolerability (adverse events) and the effect of TA on HE and death and dependency. RESULTS The trial was feasible, with 24 patients enrolled (TA, n=16; placebo, n=8) between March 2011 and March 2012, and acceptable-only 3 patients declined to participate. All patients received the correct randomized treatment; 1 patient in the TA group did not complete the infusion because of neurologic deterioration. There were no significant differences in secondary outcomes including adverse events, HE, death, and dependency. One patient in the TA group had a deep vein thrombosis . CONCLUSIONS This, the first randomized controlled trial of TA in ICH, found that the protocol could be delivered on schedule (2 patients/mo) and was feasible. Larger studies are needed to assess safety and efficacy of TA in ICH.

Cancer presenting during pregnancy: radiological perspectives.

Malignancy presenting during pregnancy is rare. When it does, there are important considerations and challenges for the radiologist. The physiological changes of pregnancy may mask signs and symptoms of malignancy leading to delayed presentation. Endocrine and physiological changes during pregnancy can interact with tumour biology to alter the behaviour and patterns of growth of certain tumours. The timing and choice of imaging technique pose potential risks to the foetus, but this must be weighed against the risks to both mother and foetus of inadequate investigation or misdiagnosis. This review outlines the general principles and approach to imaging the pregnant patient with suspected malignancy, following which there is a more detailed discussion of the effects of pregnancy on tumour biology and presentation of specific tumours. Imaging strategies are discussed for the different entities, and where possible, evidence-based imaging recommendations are made.

Intravenous tranexamic acid for hyperacute primary intracerebral hemorrhage: Protocol for a randomized, placebo-controlled trial:

Rationale Outcome after intracerebral hemorrhage remains poor. Tranexamic acid is easy to administer, readily available, inexpensive, and effective in other hemorrhagic conditions. Aim This randomized trial aims to test the hypothesis that intravenous tranexamic acid given within 8 h of spontaneous intracerebral hemorrhage reduces death or dependency. Design Phase III prospective double-blind randomized placebo-controlled trial. Participants within 8 h of spontaneous intracerebral hemorrhage are randomized to receive either intravenous tranexamic acid 1 g 10 min bolus followed by 1 g 8 h infusion, or placebo. Sample size estimates A trial of 2000 participants (300 from start-up phase and 1700 from main phase) will have 90% power to detect an ordinal shift of the modified Rankin Scale with odds ratio 0.79. Study outcomes The primary outcome is death or dependency measured by ordinal shift analysis of the 7 level mRS at day 90. Secondary outcomes are neurological impairment at day 7 and disability, quality of life, cognition, and mood at day 90. Safety outcomes are death, serious adverse events, thromboembolic events, and seizures. Cost outcomes are length of stay in hospital, readmission, and institutionalization. Discussion This pragmatic trial is assessing efficacy of tranexamic acid after spontaneous intracerebral hemorrhage. Recruitment started in 2013; as of 15th January 2016 1355 participants have been enrolled, from 95 centers in seven countries. Recruitment is due to end in 2017. TICH-2 Trial is registered as ISRCTN93732214.

Tool-use and the left hemisphere: What is lost in ideomotor apraxia?

Impaired tool related action in ideomotor apraxia is normally ascribed to loss of sensorimotor memories for habitual actions (engrams), but this account has not been tested against a hypothesis of a general deficit in representation of hand-object spatial relationships. Rapid reaching for familiar tools was compared with reaching for abstract objects in apraxic patients (N=9) and in a control group with right hemisphere posterior stroke. The apraxic patients alone showed an impairment in rotating the wrist to correctly grasp an inverted tool but not when inverting the hand to avoid a barrier and grasp an abstract object, and the severity of the impairment in tool reaching correlated with pantomime of tool-use. A second experiment with two apraxic patients tested whether barrier avoidance was simply less spatially demanding than reaching for a tool. However, the patient with damage limited to the inferior parietal lobe still showed a selective problem for tools. These results demonstrate that some apraxic patients are selectively impaired in their interaction with familiar tools, and this cannot be explained by the demands of the task on postural or spatial representation. However, traditional engram theory cannot account for associated problems with imitation of novel actions nor the absence of any correlated deficit in recognition of the methods of grasp of common tools. A revised theory is presented which follows the dorsal and ventral streams model (Milner & Goodale, 2008) and proposes preservation of motor control by the dorsal stream but impaired modulating input to it from the conceptual systems of the left temporal lobe.

Tool use and action planning in apraxia

Apraxia after left inferior parietal lesions has been widely interpreted as evidence of damage or impaired access to representations of tool-use, but most research has investigated pantomime of tool actions, not handling of actual tools. An alternative account is that inferior parietal damage does not affect tool-use representations but impairs cognitive processing about postural and hand-tool spatial relationships which is necessary for planning and controlling any complex action. Four apraxic patients and 10 age-matched controls were asked to reach rapidly for tools or abstract objects of similar dimensions. Under conditions of time pressure and divided attention, the patients frequently failed to invert the hand to grasp inverted tools by the handle, whereas ability to invert the hand to avoid a barrier and grasp abstract objects was largely unimpaired. Frequency of errors in tool grasping correlated with severity of apraxia. When inverted tools were correctly grasped, rotation of the wrist occurred later during the reaching movement than when inverting the hand to grasp an abstract object. These data are consistent with the theory of degraded access to tool-use representations in apraxia, but this theory cannot account for co-occurring deficits in imitating or matching meaningless hand or body postures.

Safety and efficacy of intensive vs. guideline antiplatelet therapy in high-risk patients with recent ischemic stroke or transient ischemic attack: rationale and design of the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial (ISRCTN47823388)

Rationale The risk of recurrence following a stroke or transient ischemic attack is high, especially immediately after the event. Hypothesis Because two antiplatelet agents are superior to one in patients with non-cardioembolic events, more intensive treatment might be even more effective. Sample size estimates The sample size of 4100 patients will allow a shift to less recurrence, and less severe recurrence, to be detected (odds ratio 0·68) with 90% power at 5% significance. Methods and design Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (ISRCTN47823388) is comparing the safety and efficacy of intensive (combined aspirin, clopidogrel, and dipyridamole) vs. guideline antiplatelet therapy, both given for one-month. This international collaborative parallel-group prospective randomized open-label blinded-end-point phase III trial plans to recruit 4100 patients with acute ischemic stroke or transient ischemic attack. Randomization and data collection are performed over a secure Internet site with real-time data validation and concealment of allocation. Outcomes, serious adverse events, and neuroimaging are adjudicated centrally with blinding to treatment allocation. Study outcome The primary outcome is stroke recurrence and its severity (‘ordinal recurrence’ based on modified Rankin Scale) at 90 days, with masked assessment centrally by telephone. Secondary outcomes include vascular events, functional measures (disability, mood, cognition, quality of life), and safety (bleeding, death, serious adverse events). Discussion The trial has recruited more than 50% of its target sample size (latest number: 2399) and is running in 104 sites in 4 countries. One-third of patients presented with a transient ischemic attack.