Lavier Gomes

Diagnosis-related regional gray matter loss over two years in first episode schizophrenia and bipolar disorder.

BACKGROUND We examined gray- and white-matter brain volumes in first episode psychosis (FEP) at initial presentation and at two-year follow-up. We predicted that FEP subjects would show longitudinal reductions in fronto-temporal gray- and white-matter volumes compared with controls. Furthermore, we expected groups to be differentiated by diagnosis-related reductions. METHODS Twenty-five schizophrenia and 8 bipolar disorder FEP patients underwent a structural MRI scan at first presentation and 2 years later. Matched healthy subjects (n = 22) underwent a single identical scan. RESULTS At initial presentation FEP subjects had significantly less gray- and white-matter than healthy subjects. Diagnostic dissociations were revealed both at first presentation and at follow-up. In schizophrenia patients, gray-matter deficits were observed in lateral and medial frontal regions and in bilateral posterior temporal lobe regions, with additional extensive losses over time in lateral fronto-temporal regions and left anterior cingulate gyrus. By contrast, gray matter deficit in bipolar patients was localized to bilateral inferior temporal gyri with additional loss over time observed only in the anterior cingulate cortex. CONCLUSIONS The results are consistent with a dual process model of psychosis, in which the diagnosis-related gray matter loss is determined by neurodevelopmental gray-matter volumetric differences which predate symptom onset, and diagnosis-related neurodegenerative gray-matter loss over time.

Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study

Background and objectives: Regional cerebral atrophy occurs in carriers of the Huntington’s disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change. Methods: Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject’s early to late T1 images. Results: Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra. Conclusions: While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD.

An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axon dysinnervation

Microtubules are essential components of axon guidance machinery. Among β-tubulin mutations, only those in TUBB3 have been shown to cause primary errors in axon guidance. All identified mutations in TUBB2B result in polymicrogyria, but it remains unclear whether TUBB2B mutations can cause axon dysinnervation as a primary phenotype. We have identified a novel inherited heterozygous missense mutation in TUBB2B that results in an E421K amino acid substitution in a family who segregates congenital fibrosis of the extraocular muscles (CFEOM) with polymicrogyria. Diffusion tensor imaging of brains of affected family members reveals aberrations in the trajectories of commissural projection neurons, implying a paucity of homotopic connections. These observations led us to ask whether axon dysinnervation is a primary phenotype, and why the E421K, but not other, TUBB2B substitutions cause CFEOM. Expression of exogenous Tubb2b-E421K in developing callosal projection neurons is sufficient to perturb homotopic connectivity, without affecting neuronal production or migration. Using in vitro biochemical assays and yeast genetics, we find that TUBB2B-E421K αβ-heterodimers are incorporated into the microtubule network where they alter microtubule dynamics and can reduce kinesin localization. These data provide evidence that TUBB2B mutations can cause primary axon dysinnervation. Interestingly, by incorporating into microtubules and altering their dynamic properties, the E421K substitution behaves differently than previously identified TUBB2B substitutions, providing mechanistic insight into the divergence between resulting phenotypes. Together with previous studies, these findings highlight that β-tubulin isotypes function in both conserved and divergent ways to support proper human nervous system development.

Cortical dysfunction underlies disability in multiple sclerosis.

Background: Gray matter atrophy has been implicated in the development of secondary progressive multiple sclerosis (SPMS). Cortical function may be assessed by transcranial magnetic stimulation (TMS). Determining whether cortical dysfunction was a feature of SPMS could be of pathophysiological significance. Objectives: Consequently, novel paired-pulse threshold tracking TMS techniques were used to assess whether cortical dysfunction was a feature of SPMS. Methods: Cortical excitability studies were undertaken in 15 SPMS, 25 relapsing–remitting MS patients (RRMS) and 66 controls. Results: Short interval intracortical inhibition (SPMS 3.0 ± 2.1%; RRMS 12.8 ± 1.7%, p < 0.01; controls 10.5 ± 0.7%, p < 0.01) and motor evoked potential (MEP) amplitude (SPMS 11.5 ± 2.2%; RRMS 26.3 ± 3.6%, p <0.05; controls 24.7 ± 1.8%, p < 0.01) were reduced in SPMS, while intracortical facilitation (SPMS -5.2 ± 1.9%; RRMS -2.0 ± 1.4, p < 0.05; controls -0.9 ± 0.7, p < 0.01) and resting motor threshold were increased (SPMS 67.5 ± 4.5%; RRMS 56.0 ± 1.5%, p < 0.01; controls 59.0 ± 1.1%, p < 0.001). Further, central motor conduction time was prolonged in SPMS (9.1 ± 1.2 ms, p < 0.001) and RRMS (7.0 ± 0.9 ms, p < 0.05) patients compared with controls (5.5 ± 0.2 ms). The observed changes in cortical function correlated with the Expanded Disability Status Scale. Conclusion: Together, these findings suggest that cortical dysfunction is associated with disability in MS, and documentation of such cortical dysfunction may serve to quantify disease severity in MS.

Skull‐base osteomyelitis: fungal vs. bacterial infection

Skull-base osteomyelitis (SBO) occurs secondary to invasive bacterial and fungal infection. Distinguishing between fungal and bacterial aetiologies of SBO has significant therapeutic implications. An 18-year (1990-2007) retrospective review of patients with SBO presenting to Westmead Hospital was performed. Epidemiological, clinical, laboratory and radiology data were collated. Twenty-one patients (median age 58 years) with SBO were identified: ten (48%) had bacterial and 11 (52%) had fungal SBO. Diabetes mellitus (57%) and chronic otitis externa (33%) were the most frequent co-morbidities; immunosuppression was present in five cases (24%). Cranial nerve deficits occurred in ten (48%) patients. The commonest pathogens were Pseudomonas aeruginosa (50% bacterial SBO) and a zygomycete (55% fungal SBO). Compared to bacterial SBO, fungal SBO was more frequently associated with underlying chronic sinusitis, sinonasal pain, facial/periorbital swelling and nasal stuffiness or discharge and the absence of purulent ear discharge (all p <0.05). Bacterial SBO was more frequently associated with deafness, ear pain or ear discharge (all p <0.05). Median time to presentation was longer in patients with bacterial SBO (26.3 weeks vs. 8.1 weeks, p 0.08). Overall 6-month survival was 88% (14/18 patients). All four deaths occurred in patients with fungal SBO. Immunosuppression was a risk factor for death (p <0.05). Early diagnostic sampling is recommended in patients at increased risk of fungal SBO to enable optimal antimicrobial and surgical management.

Automated generation of curved planar reformations from MR images of the spine

A novel method for automated curved planar reformation (CPR) of magnetic resonance (MR) images of the spine is presented. The CPR images, generated by a transformation from image-based to spine-based coordinate system, follow the structural shape of the spine and allow the whole course of the curved anatomy to be viewed in individual cross-sections. The three-dimensional (3D) spine curve and the axial vertebral rotation, which determine the transformation, are described by polynomial functions. The 3D spine curve passes through the centres of vertebral bodies, while the axial vertebral rotation determines the rotation of vertebrae around the axis of the spinal column. The optimal polynomial parameters are obtained by a robust refinement of the initial estimates of the centres of vertebral bodies and axial vertebral rotation. The optimization framework is based on the automatic image analysis of MR spine images that exploits some basic anatomical properties of the spine. The method was evaluated on 21 MR images from 12 patients and the results provided a good description of spine anatomy, with mean errors of 2.5 mm and 1.7 degrees for the position of the 3D spine curve and axial rotation of vertebrae, respectively. The generated CPR images are independent of the position of the patient in the scanner while comprising both anatomical and geometrical properties of the spine.

The utility of multimodal evoked potentials in multiple sclerosis prognostication

The ability to predict disability development in multiple sclerosis (MS) is limited. While abnormalities of evoked potentials (EP) have been associated with disability, the prognosticating utility of EP in MS remains to be fully elucidated. The present study assessed the utility of multimodal EP as a prognostic biomarker of disability in a cohort of clinically heterogeneous MS patients. Median and tibial nerve somatosensory, visual, and brainstem auditory EP were performed at initial assessment on 63 MS patients (53 relapsing-remitting and 10 secondary progressive) who were followed for an average of 2 years. A combined EP score (CEPS) was calculated consisting of the total number of abnormal EP tests, and was correlated with the Expanded Disability Status Scale (EDSS) at baseline and follow-up. There was a significant correlation between multimodal EP and baseline and follow-up EDSS. Specifically, tibial nerve P37 latencies correlated with EDSS (R(BASELINE)=0.49, p<0.01; R(FOLLOW-UP)=0.47, p<0.01), as did the median nerve N13 (R(BASELINE)=0.40, p<0.01; R(FOLLOW-UP)=0.35, p<0.05) and N20 latencies (R(BASELINE)=0.43, p<0.01; R(FOLLOW-UP)=0.47, p<0.01), and P100 full-field (R(BASELINE)=0.50, p<0.001; R(FOLLOW-UP)=0.45, p<0.001) and central field latencies (R(BASELINE)=0.60, p<0.001; R(FOLLOW-UP)=0.50, p<0.001). In addition, there was a significant correlation between the CEPS with baseline (R=0.65, p<0.001) and follow-up (R=0.57, p<0.01) EDSS. In contrast, white matter disease burden, as measured by T2 lesion load, exhibited a weaker correlation with EDSS (R(BASELINE)=0.28, p<0.05). In conclusion, these findings suggest that abnormalities of EP, as quantified by the novel CEPS, may be a useful biomarker for prognosticating clinical disability in MS, and may aid in the quantification of MS disease severity and in guiding therapeutic decisions.

Cerebral nocardiosis characterized by magnetic resonance spectroscopy in vivo.

We describe a patient with multiple cerebral lesions that initially were believed to be tumor metastases but were later found to be caused by Nocardia asteroides, after magnetic resonance spectroscopy (MRS) findings suggested that the lesions were infective in origin. This case report demonstrates the ability of MRS, a noninvasive imaging modality, to aid in the diagnosis of brain infection.

Cognitive control network anatomy correlates with neurocognitive behavior: A longitudinal study.

Cognitive control is the process of employing executive functions, such as attention, planning or working memory, to guide appropriate behaviors in order to achieve a specific goal. Functional magnetic resonance imaging studies suggest a superordinate cognitive control network, comprising the dorsal regions of the lateral prefrontal cortex (DLPFC), anterior cingulate cortex (dACC) and parietal cortex (DPC). How gray matter structure changes across this network throughout neurodevelopment and how these changes impact cognitive control are not yet fully understood. Here we investigate changes in gray matter volume of the key nodes of the cognitive control network using structural MRI scans from 176 participants aged 8–38 years. One hundred and eleven of these also completed a longitudinal follow‐up at two years. We compare these with performance on a cognitive battery also measured at these two time points. We found that volume decreases in the cognitive control network were associated with improved performance in executive function (in left DLPFC and bilateral DPC), information processing (in bilateral dACC and right DPC) and emotion identification tasks (left DLPFC). These results were significant after controlling for age. Furthermore, gray matter changes were coordinated across the network. These findings imply age‐independent synaptic pruning in the cognitive control network may have a role in improving performance in cognitive domains. This study provides insight into the direct impact of structural changes on behavior within this network during neurodevelopment and provides a normative evidence base to better understand development of cognitive dysfunction in brain disorders. Hum Brain Mapp 38:631–643, 2017.

Potential structural and functional biomarkers of upper motor neuron dysfunction in ALS

Abstract Assessment of upper motor neuron (UMN) function in amyotrophic lateral sclerosis (ALS) remains clinically based. Given the potential difficulties in identifying UMN signs, objective biomarkers of UMN dysfunction are important. Consequently, the present study assessed utility of cortical thickness analysis combined with threshold tracking transcranial magnetic stimulation (TMS) as biomakers of UMN dysfunction in ALS. Cortical thickness analysis and threshold tracking TMS studies were undertaken on 25 ALS patients and results were compared to healthy control subjects, with different control groups used for each technique. Structural and functional abnormalities were evident in both motor cortices in the ALS cohort and were heralded by marked reduction of short-interval intracortical inhibition (SICI RAPB 1.4 ± 2.4%; SICI LAPB 3.6 ± 1.9%; SICI CONTROLS10.5 ± 1.1%, p <0.01), resting motor threshold (p <0.05) and cortical silent period duration (p <0.001) combined with increase in MEP amplitude (p <0.05) and intracortical facilitation (p <0.05). Significant cortical thinning was evident in the bitemporal regions (p <0.05), while precentral gyrus cortical thinning was evident in 56% of cases and when combined with TMS abnormalities disclosed UMN dysfunction in 88% of cases. In conclusion, findings from the present study establish that a combination of structural and functional assessment of corticomotoneurons may increase the yield of objectively identifying UMN dysfunction in ALS.