Executive dysfunction correlates with caudate nucleus atrophy in patients with white matter changes on MRI: a subset of LADIS.

White matter changes (WMC) are common magnetic resonance imaging (MRI) findings, particularly in the elderly. Recent studies such as the Leukoaraiosis and Disability Study (LADIS) have found that WMC relate to adverse outcomes including cognitive impairment, depression, disability, unsteadiness and falls in cross-sectional and follow-up studies. Frontostriatal (or frontosubcortical) brain circuits may serve many of these functions, with the caudate nuclei playing a role in convergence of cognitive functions. This study aimed to determine whether reduced caudate volume relates to cognitive functions (executive functions, memory functions and speed of processing) and WMC. We determined caudate nuclei volumes, through manual tracing, on a subgroup of the LADIS study (n=66) from four centres with baseline and 3-year follow-up MRI scans. Regression analysis was used to assess relationships between caudate volume, cognitive function and WMC. Severity of WMC did not relate to caudate volume. Smaller caudate volumes were significantly associated with poorer executive functioning at baseline and at 3 years, but were not associated with scores of memory or speed of processing. Thus, in patients with WMC, a surrogate of small vessel disease, caudate atrophy relates to the dysexecutive syndrome, supporting the role of caudate as an important part of the frontostriatal circuit.

Saccadic eye movement characteristics in adult Niemann-Pick Type C disease: relationships with disease severity and brain structural measures.

Niemann-Pick Type C disease (NPC) is a rare genetic disorder of lipid metabolism. A parameter related to horizontal saccadic peak velocity was one of the primary outcome measures in the clinical trial assessing miglustat as a treatment for NPC. Neuropathology is widespread in NPC, however, and could be expected to affect other saccadic parameters. We compared horizontal saccadic velocity, latency, gain, antisaccade error percentage and self-paced saccade generation in 9 adult NPC patients to data from 10 age-matched controls. These saccadic measures were correlated with appropriate MRI-derived brain structural measures (e.g., dorsolateral prefrontal cortex, frontal eye fields, supplemental eye fields, parietal eye fields, pons, midbrain and cerebellar vermis) and with measures of disease severity and duration. The best discriminators between groups were reflexive saccade gain and the two volitional saccade measures. Gain was also the strongest correlate with disease severity and duration. Most of the saccadic measures showed strongly significant correlations with neurophysiologically appropriate brain regions. While our patient sample is small, the apparent specificity of these relationships suggests that as new diagnostic methods and treatments become available for NPC, a broader range of saccadic measures may be useful tools for the assessment of disease progression and treatment efficacy.

Shape alterations in the striatum in chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is an uncommon autosomal recessive disorder due to mutations of the VPS13A gene, which encodes for the membrane protein chorein. ChAc presents with progressive limb and orobuccal chorea, but there is often a marked dysexecutive syndrome. ChAc may first present with neuropsychiatric disturbance such as obsessive-compulsive disorder (OCD), suggesting a particular role for disruption to striatal structures involved in non-motor frontostriatal loops, such as the head of the caudate nucleus. Two previous studies have suggested a marked reduction in volume in the caudate nucleus and putamen, but did not examine morphometric change. We investigated morphometric change in 13 patients with genetically or biochemically confirmed ChAc and 26 age- and gender-matched controls. Subjects underwent magnetic resonance imaging and manual segmentation of the caudate nucleus and putamen, and shape analysis using a non-parametric spherical harmonic technique. Both structures showed significant and marked reductions in volume compared with controls, with reduction greatest in the caudate nucleus. Both structures showed significant shape differences, particularly in the head of the caudate nucleus. No significant correlation was shown between duration of illness and striatal volume or shape, suggesting that much structural change may have already taken place at the time of symptom onset. Our results suggest that striatal neuron loss may occur early in the disease process, and follows a dorsal-ventral gradient that may correlate with early neuropsychiatric and cognitive presentations of the disease.

The neuropsychiatry of neuroacanthocytosis syndromes.

The neuroacanthocytoses are a group of disorders characterised by peripheral blood acanthocytes, central nervous system as well as neuromuscular symptoms. These disorders uniformly result in pathology in the basal ganglia, which account for the characteristic motor symptoms such as chorea or dystonia, but may also account for the apparent elevated rates of major mental disorders in these syndromes. Elevated rates of dysexecutive syndromes, obsessive-compulsive disorder, depression and schizophrenia-like psychosis appear to occur in chorea-acanthocytosis, McLeod's syndrome, pantothenate kinase-associated neurodegeneration, and Huntington's disease-like 2. Disruptions to key frontostriatal loops secondary to pathology in the striatum and pallidum appear to predispose individuals to major neuropsychiatric syndromes; however, treatment can be instituted for a number of these manifestations, which lessens the overall burden of disease in neuroacanthocytosis patients and their families.

Shape analysis of the neostriatum in subtypes of frontotemporal lobar degeneration: neuroanatomically significant regional morphologic change.

Frontostriatal circuit mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD) and may differ across subtypes of FTLD. We manually segmented the neostriatum (caudate nucleus and putamen) in FTLD subtypes: behavioral variant frontotemporal dementia, FTD, n=12; semantic dementia, SD, n=13; and progressive non-fluent aphasia, PNFA, n=9); in comparison with controls (n=27). Diagnoses were based on international consensus criteria. Manual bilateral segmentation of the caudate nucleus and putamen was conducted blind to diagnosis by a single analyst, on MRI scans using a standardized protocol. Intracranial volume was calculated via a stereological point counting technique and was used for normalizing the shape analysis. Segmented binaries were analyzed using the Spherical Harmonic (SPHARM) Shape Analysis tools (University of North Carolina) to perform comparisons between FTLD subtypes and controls for global shape difference, local significance maps and mean magnitude maps of shape displacement. Shape analysis revealed that there was significant shape difference between FTLD subtypes and controls, consistent with the predicted frontostriatal dysfunction and of significant magnitude, as measured by displacement maps. These differences were not significant for SD compared to controls; lesser for PNFA compared to controls; whilst FTD showed a more specific pattern in regions relaying fronto- and corticostriatal circuits. Shape analysis shows regional specificity of atrophy, manifest as shape deflation, with a differential between FTLD subtypes, compared to controls.

Shape analysis of the neostriatum in frontotemporal lobar degeneration, Alzheimer's disease, and controls.

BACKGROUND AND PURPOSE: Frontostriatal circuit mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD), but not Alzheimer's disease, or healthy aging. We measured the neostriatum (caudate nucleus and putamen) volume in FTLD (n=34), in comparison with controls (n=27) and Alzheimer's disease (AD, n=19) subjects. METHODS: Diagnoses were based on international consensus criteria. Manual bilateral segmentation of the caudate nucleus and putamen was conducted blind to diagnosis by a single analyst, on MRI scans using a standardized protocol. Intra-cranial volume was calculated via a stereological point counting technique and was used for scaling the shape analysis. The manual segmentation binaries were analyzed using UNC Shape Analysis tools (University of North Carolina) to perform comparisons among FTLD, AD, and controls for global shape, local p-value significance maps, and mean magnitude of shape displacement. RESULTS: Shape analysis revealed that there was significant shape difference between FTLD, AD, and controls, consistent with the predicted frontostriatal dysfunction and of significant magnitude, as measured by displacement maps. There was a lateralized difference in shape for the left caudate for FTLD compared to AD; non-specific global atrophy in AD compared to controls; while FTLD showed a more specific pattern in regions relaying fronto- and corticostriatal circuits. CONCLUSIONS: Shape analysis shows regional specificity of atrophy, manifest as shape deflation, with implications for frontostriatal and corticostriatal motoric circuits, in FTLD, AD, and controls.

Gray matter density in limbic and paralimbic cortices is associated with trauma load and EMDR outcome in PTSD patients.

There is converging evidence of gray matter (GM) structural alterations in different limbic structures in Post-Traumatic Stress Disorder (PTSD) patients. The aim of this study was to evaluate GM density in PTSD in relation to trauma load, and to assess the GM differences between responders (R) and non-responders (NR) to EMDR therapy. Magnetic Resonance Imaging (MRI) scans of 21 subjects exposed to occupational trauma, who developed PTSD (S), and of 22 who did not (NS), were compared by means of an optimized Voxel-Based Morphometry (VBM) analysis as implemented in SPM. Within S, further comparisons were made between 10 R and 5 NR. A regression analysis between GM density and the Traumatic Antecedents Questionnaire (TAQ) was also performed on all 43 subjects. Results showed a significantly lower GM density in S as compared to NS in the left posterior cingulate and the left posterior parahippocampal gyrus. Moreover, NR showed a significantly lower GM density as compared to R in bilateral posterior cingulate, as well as anterior insula, anterior parahippocampal gyrus and amygdala in the right hemisphere. Regression analysis showed that GM density negatively correlated with trauma load in bilateral posterior cingulate, left anterior insula, and right anterior parahippocampal gyrus. In conclusion, a GM lower density in limbic and paralimbic cortices were found to be associated with PTSD diagnosis, trauma load, and EMDR treatment outcome, suggesting a view of PTSD characterized by memory and dissociative disturbances.

Caudate nucleus volumes in stroke and vascular dementia.

We aimed to assess the volume of the nucleus caudatus as a neuroanatomical substrate of fronto-subcortical circuits, in stroke patients with/without dementia, and the relationship to potential determinants of neural circuit integrity such as white matter hyperintensities (WMH) and stroke volume. Stroke only (Stroke) (n=19) and stroke with Vascular Dementia (VaD) (n=16) and healthy control (n=20) subjects, matched on demographic variables, underwent extensive neuropsychiatric assessments and manual MRI-based volumetric measurements for intracranial area (ICA), stroke volume, and bilateral caudate volume. WMH on MRI were quantified using an automated algorithm. Multivariate analysis of covariance (controlling for age and ICA), revealed that across the three groups, caudate volumes were significantly different. There was a significant difference in bilateral caudate nucleus volume between subjects by diagnosis (Stroke, VaD, control). The control group was largest in overall mean volume of the diagnostic groups, followed by the Stroke group (86% of controls), and finally, the VaD group (72%). There was a partial correlation between total caudate volume and the total volume of deep WMH including periventricular regions and brainstem, controlling for ICA; and for total stroke volume. Stroke patients with VaD have smaller caudate nuclei compared to those without dementia and healthy controls, with the stroke-only patients being intermediate in their caudate volume status. There was preliminary evidence of negative correlation of caudate volume with volume of deep WMH and total stroke volume, suggesting cerebrovascular disease contributes to caudate atrophy,which, in turn may disrupt fronto-subcortical circuits.

Caudate volumes in public transportation workers exposed to trauma in the Stockholm train system.

The caudate nucleus is a structure implicated in the neural circuitry of psychological responses to trauma. This study aimed to quantify the volume of the caudate in persons exposed to trauma. Thirty-six subjects under 65 were recruited from transport workers in Stockholm who reported having been unintentionally responsible for a person-under-the-train accident or among employees having experienced an assault in their work (1999-2001) between 3 months and 6 years before MRI scanning. In those exposed to the trauma, a DSM-IV diagnosis of post-traumatic stress disorder (PTSD) was made by an independent psychiatrist, with subjects being classified as PTSD or no PTSD. MRI data were analyzed blindly to all clinical information by an experienced rater using a standardized manual tracing protocol to quantify the volume of the caudate. Within-group comparisons of PTSD (n=19) and no PTSD (n=17) found the right caudate nucleus to be significantly (9%) larger than the left: a right hemisphere baseline asymmetry. A multivariate analysis of covariance (MANCOVA) was conducted to assess the volume of the caudate nucleus (right and left) in relation to the diagnosis of no PTSD (n=17) or PTSD (n=19). After adjustment for the covariates (age, sex, intracranial volume, years since trauma, and number of trauma episodes), there was a significant difference in raw right caudate nucleus volume between subjects with PTSD compared with those without PTSD. Volume of the left caudate nucleus was not significantly different between the PTSD and no PTSD groups. The right caudate volume in the PTSD group was 9% greater compared with the no PTSD group. There is a larger right hemisphere volume of the caudate within those exposed to trauma with active PTSD compared with those without PTSD, superimposed upon a baseline caudate asymmetry.

Volumetrics of the caudate nucleus: reliability and validity of a new manual tracing protocol.

Our aim was to develop a reliable and valid manual segmentation protocol for tracing the caudate nucleus in MRI for volumetric and, potentially, shape analysis of the caudate. Using the protocol, two inter- and intra-rater reliability studies were conducted using five different raters on two different image analysis platforms (ANALYZE, Mayo Biomedical Imaging Resource, Rochester MN, USA, and HERMES, Nuclear Diagnostics AB, Stockholm, Sweden). Reference images for the detailed protocol are described. Two studies were performed. In study 1, the intra-rater class correlation ICC(1,1) for an experienced rater (JCLL) using this protocol for caudate nucleus volumes was evaluated by repeating right and left caudate measurements on 10 scans (20 comparisons) and was 0.972. The inter-rater class correlation ICC(1,k) with OL was 0.922 on 5 scans (10 comparisons) and with BL was 0.960 on 5 scans (10 comparisons). In study 2, VT obtained an intra-rater class correlation of 0.9 on 5 scans (involving 10 comparisons, e.g. right and left caudate). The inter-rater class correlation ICC(1,k) was 0.988 on 5 scans (again involving 10 comparisons) with EM. We therefore developed a novel, reliable and reference image-based, method of outlining the caudate nucleus on axial MRI scans, usable in two different image analysis laboratories, across two different sets number of tracers reliably, and across software platforms. This method is therefore potentially usable for any image analysis package capable of displaying and measuring outlined voxels from MRI brain scans.

Delayed onset of posttraumatic stress disorder among male combat veterans: a case series.

OBJECTIVE: Authors investigated the nature of delayed-onset posttraumatic stress disorder (PTSD) among combat veterans. METHODS: PTSD, along with cognitive and emotional functioning, was assessed in a case series of elderly Australian war veterans. RESULTS: Fifteen elderly male subjects consecutively referred to an outpatient psychiatric clinic were identified as having PTSD with significantly delayed onset. In most cases, the onset of PTSD symptoms was associated with unrelated medical complaints, psychosocial stress, and/or mild cognitive impairment. CONCLUSION: Environmental stressors, coupled with age-related neurodegeneration, may potentially contribute to the late-life recrudescence or emergence of PTSD symptoms in veterans exposed to combat-related trauma.