Morphometric in vivo evidence of thalamic atrophy correlated with cognitive and motor dysfunction in Huntington's disease: The IMAGE-HD study.

In Huntington's disease (HD), neurodegeneration causes progressive atrophy to the striatum, cortical areas, and white matter tracts - components of corticostriatal circuitry. Such processes may affect the thalamus, a key circuit node. We investigated whether differences in dorsal thalamic morphology were detectable in HD, and whether thalamic atrophy was associated with neurocognitive, neuropsychiatric and motor dysfunction. Magnetic resonance imaging scans and clinical outcome measures were obtained from 34 presymptomatic HD (pre-HD), 29 early symptomatic HD (symp-HD), and 26 healthy control individuals who participated in the IMAGE-HD study. Manual region of interest (ROI) segmentation was conducted to measure dorsal thalamic volume, and thalamic ROI underwent shape analysis using the spherical harmonic point distribution method. The symp-HD group had significant thalamic volumetric reduction and global shape deflation, indicative of atrophy, compared to pre-HD and control groups. Thalamic atrophy significantly predicted neurocognitive and motor dysfunction within the symp-HD group only. Thalamic morphology differentiates symp-HD from pre-HD and healthy individuals. Thalamic changes may be one of the structural bases (endomorphotypes), of the endophenotypic neurocognitive and motor manifestations of disease. Future research should continue to investigate the thalamus as a potential in vivo biomarker of disease progression in HD.

Increased functional connectivity of thalamic subdivisions in patients with Parkinson's disease.

Parkinson's disease (PD) affects 2-3% of the population over the age of 65 with loss of dopaminergic neurons in the substantia nigra impacting the functioning of basal ganglia-thalamocortical circuits. The precise role played by the thalamus is unknown, despite its critical role in the functioning of the cerebral cortex, and the abnormal neuronal activity of the structure in PD. Our objective was to more clearly elucidate how functional connectivity and morphology of the thalamus are impacted in PD (n = 32) compared to Controls (n = 20). To investigate functional connectivity of the thalamus we subdivided the structure into two important regions-of-interest, the first with putative connections to the motor cortices and the second with putative connections to prefrontal cortices. We then investigated potential differences in the size and shape of the thalamus in PD, and how morphology and functional connectivity relate to clinical variables. Our data demonstrate that PD is associated with increases in functional connectivity between motor subdivisions of the thalamus and the supplementary motor area, and between prefrontal thalamic subdivisions and nuclei of the basal ganglia, anterior and dorsolateral prefrontal cortices, as well as the anterior and paracingulate gyri. These results suggest that PD is associated with increased functional connectivity of subdivisions of the thalamus which may be indicative alterations to basal ganglia-thalamocortical circuitry.

Regional structural hypo- and hyperconnectivity of frontal-striatal and frontal-thalamic pathways in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) has been predominantly considered as a frontotemporal cortical disease, with limited direct investigation of frontal-subcortical connections. We aim to characterize the grey and white matter components of frontal-thalamic and frontal-striatal circuits in bvFTD. Twenty-four patients with bvFTD and 24 healthy controls underwent morphological and diffusion imaging. Subcortical structures were manually segmented according to published protocols. Probabilistic pathways were reconstructed separately from the dorsolateral, orbitofrontal and medial prefrontal cortex to the striatum and thalamus. Patients with bvFTD had smaller cortical and subcortical volumes, lower fractional anisotropy, and higher mean diffusivity metrics, which is consistent with disruptions in frontal-striatal-thalamic pathways. Unexpectedly, regional volumes of the striatum and thalamus connected to the medial prefrontal cortex were significantly larger in bvFTD (by 135% in the striatum, p = .032, and 217% in the thalamus, p = .004), despite smaller dorsolateral prefrontal cortex connected regional volumes (by 67% in the striatum, p = .002, and 65% in the thalamus, p = .020), and inconsistent changes in orbitofrontal cortex connected regions. These unanticipated findings may represent compensatory or maladaptive remodeling in bvFTD networks. Comparisons are made to other neuropsychiatric disorders suggesting a common mechanism of changes in frontal-subcortical networks; however, longitudinal studies are necessary to test this hypothesis.

Morphometric analysis of thalamic volume in progressive supranuclear palsy: In vivo evidence of regionally specific bilateral thalamic atrophy.

We investigated whether differences were detectable in the volume and shape of the dorsal thalamus on magnetic resonance imaging in patients with progressive supranuclear palsy (PSP). Manual segmentation of the left and right thalami on magnetic resonance imaging scans occurred in 22 patients with clinically diagnosed PSP and 23 healthy controls; thalamic volumes (left, right, total) were calculated. Between group differences were explored by multivariate analysis of co-variance, using age and intracranial volume as covariates. Analysis of the shape of the thalamus was performed using the spherical harmonic point distribution method software package. Patients with PSP were found to have significant bilateral thalamic atrophy on magnetic resonance imaging; there was significant shape deflation over the anterior-lateral and anterior-ventral surfaces bilaterally, and over the right caudal thalamus. Recognizing decreased thalamic morphology in PSP patients in vivo may be an important component of an ensemble of diagnostic biomarkers in the future, particularly given the difficulty of distinguishing PSP from other Parkinsonian conditions early in the disease course.

Longitudinal assessment of reflexive and volitional saccades in Niemann-Pick Type C disease during treatment with miglustat.

BACKGROUND: Niemann-Pick Type C disease (NPC), is an autosomal recessive neurovisceral disorder of lipid metabolism. One characteristic feature of NPC is a vertical supranuclear gaze palsy particularly affecting saccades. However, horizontal saccades are also impaired and as a consequence a parameter related to horizontal peak saccadic velocity was used as an outcome measure in the clinical trial of miglustat, the first drug approved in several jurisdictions for the treatment of NPC. As NPC-related neuropathology is widespread in the brain we examined a wider range of horizontal saccade parameters and to determine whether these showed treatment-related improvement and, if so, if this was maintained over time. METHODS: Nine adult NPC patients participated in the study; 8 were treated with miglustat for periods between 33 and 61 months. Data were available for 2 patients before their treatment commenced and 1 patient was untreated. Tasks included reflexive saccades, antisaccades and self-paced saccades, with eye movements recorded by an infrared reflectance eye tracker. Parameters analysed were reflexive saccade gain and latency, asymptotic peak saccadic velocity, HSEM-α (the slope of the peak duration-amplitude regression line), antisaccade error percentage, self-paced saccade count and time between refixations on the self-paced task. Data were analysed by plotting the change from baseline as a proportion of the baseline value at each test time and, where multiple data values were available at each session, by linear mixed effects (LME) analysis. RESULTS: Examination of change plots suggested some modest sustained improvement in gain, no consistent changes in asymptotic peak velocity or HSEM-α, deterioration in the already poor antisaccade error rate and sustained improvement in self-paced saccade rate. LME analysis showed statistically significant improvement in gain and the interval between self-paced saccades, with differences over time between treated and untreated patients. CONCLUSIONS: Both qualitative examination of change scores and statistical evaluation with LME analysis support the idea that some saccadic parameters are robust indicators of efficacy, and that the variability observed across measures may indicate locally different effects of neurodegeneration and of drug actions.

Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat.

Niemann-Pick disease type C (NPC) is a rare neurovisceral disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment available to date is miglustat, an iminosugar inhibiting the accumulation of lipid by-products in neurons. This study explored how changes in cerebellar grey and white matter volumes, and in subcortical volumes, related to patient treatment status and disability and ataxia ratings. Nine adult-onset NPC patients and 17 matched controls underwent T1-weighted MRI. One patient was not receiving miglustat, and pre-treatment data were available for a further patient. Semi-automated cerebellar and subcortical segmentation was undertaken, and the rates of change in putamen, hippocampal, thalamic and caudal volumes, and grey and white matter cerebellar volumes, were compared to rates of change in Iturriaga disability score, Brief Ataxia Rating Scale (BARS), and horizontal saccadic gain. Untreated NPC patients appeared to lose cerebellar grey and white matter, bilateral thalamic volume, and right caudate volume faster than treated patients. Cerebellar grey matter volume loss and volume loss in the left thalamus were significantly correlated with Iturriaga disability scale changes. Change in both cerebellar grey and white matter was correlated with decrease in horizontal saccadic gain, but not with change in BARS. This is the first study to examine longitudinal treatment effects of miglustat on cerebellar and subcortical volumes in patients with adult-onset NPC, and is evidence that miglustat may have a protective effect on cerebellar and subcortical structure and function.

Validation of a protocol for manual segmentation of the thalamus on magnetic resonance imaging scans.

We present a validated protocol for manual segmentation of the thalamus on T1-weighted magnetic resonance imaging (MRI) scans using brain image analysis software. The MRI scans of five normal control subjects were randomly selected from a larger cohort recruited from Lund University Hospital and Landskrona Hospital, Sweden. MRIs were performed using a 3.0T Philips MR scanner, with an eight-channel head coil, and high resolution images were acquired using a T1-weighted turbo field echo (T1 TFE) pulse sequence, with resulting voxel size 1×1×1 mm3. Manual segmentation of the left and right thalami and volume measurement was performed on 28-30 contiguous coronal slices, using ANALYZE 11.0 software. Reliability of image analysis was performed by measuring intra-class correlations between initial segmentation and random repeated segmentation of the left and right thalami (in total 10 thalami for segmentation); inter-rater reliability was measured using volumes obtained by two other experienced tracers. Intra-class correlations for two independent raters were 0.95 and 0.98; inter-class correlations between the expert rater and two independent raters were 0.92 and 0.98. We anticipate that mapping thalamic morphology in various neuropsychiatric disorders may yield clinically useful disease-specific biomarkers.

The Australian, US, Scandinavian Imaging Exchange (AUSSIE): an innovative, virtually-integrated health research network embedded in health care.

OBJECTIVE: To describe the development, design and function of an innovative international clinical research network for neuroimaging research, based in Australia, within a joint state health service/medical school. This Australian, US, Scandinavian Imaging Exchange (AUSSIE) network focuses upon identifying neuroimaging biomarkers for neuropsychiatric and neurodegenerative disease. METHODS: We describe a case study of the iterative development of the network, identifying characteristic features and methods which may serve as potential models for virtual clinical research networks. This network was established to analyse clinically-derived neuroimaging data relevant to neuropsychiatric and neurodegenerative disease, specifically in relation to subcortical brain structures. RESULTS: The AUSSIE network has harnessed synergies from the individual expertise of the component groups, primarily clinical neuroscience researchers, to analyse a variety of clinical data. CONCLUSION: AUSSIE is an active virtual clinical research network, analogous to a connectome, which is embedded in health care and has produced significant research, advancing our understanding of neuropsychiatric and neurodegenerative disease through the lens of neuroimaging.

Midline brain abnormalities in established bipolar affective disorder.

BACKGROUND: Morphologic changes of cortico-limbic regions have been reported in bipolar disorder, but it remains unclear whether midline brain abnormalities relevant to cortico-limbic connectivity are also present. METHODS: We used magnetic resonance imaging to investigate the size of the adhesio interthalamica (AI) and cavum septi pellucidi (CSP), as well as third ventricular volume, in 26 patients with bipolar I disorder and 24 matched controls. RESULTS: CSP length and prevalence of a large CSP did not differ between the groups, but bipolar patients had significantly shorter AI and larger third ventricles compared to controls. LIMITATIONS: A comprehensive investigation of medication effects was not possible due to incomplete medication data. CONCLUSIONS: These findings implicate a role for the AI and connected brain regions in the neurobiology of bipolar disorder.

Midline brain structures in teenagers with first-presentation borderline personality disorder.

Brain morphologic changes have been reported in borderline personality disorder (BPD), but it remains largely unknown whether BPD is associated with midline brain abnormalities. We used magnetic resonance imaging to investigate the length of the adhesio interthalamica (AI) and cavum septum pellucidum (CSP) as well as third ventricular volume in 20 teenagers with first-presentation BPD and 20 healthy controls. While the CSP length did not differ between the groups, the AI was significantly shorter in BPD patients than in controls. Furthermore, the BPD patients had a significantly larger third ventricle than controls. These preliminary findings suggest that ongoing neuroimaging studies should further evaluate a potential involvement of midline brain structures in the pathogenesis of BPD.

The positive effect of integrated care on depressive symptoms in stroke survivors.

BACKGROUND: Depressive symptoms occur in approximately one-third of stroke patients. We sought to evaluate whether an integrated model of stroke care and secondary prevention reduced depressive symptomatology in stroke survivors. METHODS: The integrated care (IC) model is a multifaceted program that provides ongoing collaboration between a specialist stroke service and primary care physicians, using telephone tracking, a bi-directional information feedback loop, management of vascular risk factors, and regular screening for depressive symptoms. RESULTS: Patients exposed to the IC model exhibited significantly fewer depressive symptoms than controls at 12 months post stroke (as measured by the PHQ-9 screening tool; p = 0.006). At 12 months, 30/91 (33%) of the treatment group had depressive symptoms, compared to 52/95 (55%) of the control group (p = 0.003). With other variables adjusted for, the major associates of being depressed at 12 months were group allocation and physical disability. CONCLUSION: The integrated care approach provides a framework for detecting and monitoring depressive symptoms, and appears to be protective against post-stroke depression.