Frontotemporal Gray Matter Research Articles

Arithmetic skills are associated with left fronto-temporal gray matter volume in 536 children and adolescents

There are large individual differences in arithmetic skills. Although a number of brain-wide association studies have attempted to identify the neural correlates of these individual differences, studies have focused on relatively small sample sizes and have yielded inconsistent results. In the current voxel-based morphometry study, we merged six structural imaging datasets of children and adolescents (from 7.5 to 15 years) whose levels of arithmetic skills were assessed, leading to a combined sample of n = 536. Controlling for individual differences in age, gender, as well as language, and intelligence, we found a unique positive relation between arithmetic skill and gray matter volume in the left inferior frontal gyrus (IFG) and middle temporal gyrus (MTG). Our results suggest that individual differences in arithmetic skills are associated with structural differences in left fronto-temporal areas, rather than in regions of the parietal cortex and hippocampus that are often associated with arithmetic processing.

Association between empathy and drinking among a community sample of heavy drinkers: Sex differences and neural correlates

Alcohol use disorder (AUD) is a major health problem, yet most individuals with AUD do not perceive a need for formal treatment and do not receive treatment. The lack of treatment seeking among individuals with AUD may suggest a lack of self-awareness and insight into the seriousness of AUD related problems, as well as lack of empathy for the impact of one’s drinking on others. Recent work has suggested that empathy may be impaired among individuals seeking treatment for AUD. Further these impairments may differ by sex such that males with lower empathy reported more drinking consequences and greater drinking intensity, but there was no association between empathy and drinking among females. The current study used regression analyses (alpha = 0.05) to examine the association between empathy (as measured by the four scales of the Interpersonal Reactivity Index), independent components of gray matter volume in regions associated with empathy, and drinking variables among non-treatment seeking drinkers with AUD (N = 136) and also examined these effects by sex. Results showed greater perspective taking was associated with less temporoparietal and frontotemporal gray matter volume (B(SE) = −0.912 (0.043), p = 0.034). An interaction between perspective taking and sex was associated with craving, such that higher perspective taking was associated with less craving for males only (B(SE) = −0.48 (0.243), p = 0.049; R2 = 0.087). Empathic concern was related to lower percent heavy drinking days for both males and females (B(SE) = −1.57 (0.743), p = 0.035; R2 = 0.11). The current study found empathy may be an important predictor of craving for males and frequency of heavy drinking for males and females. Future work should investigate whether empathy predicts treatment seeking.

Four-modality imaging of unmedicated subjects with schizophrenia: 18F-fluorodeoxyglucose and 18F-fallypride PET, diffusion tensor imaging, and MRI

Diminished prefrontal function, dopaminergic abnormalities in the striatum and thalamus, reductions in white matter integrity and frontotemporal gray matter deficits are the most replicated findings in schizophrenia. We used four imaging modalities (18F-fluorodeoxyglucose and 18F-fallypride PET, diffusion tensor imaging, structural MRI) in 19 healthy and 25 schizophrenia subjects to assess the relationship between functional (dopamine D2/D3 receptor binding potential, glucose metabolic rate) and structural (fractional anisotropy, MRI) correlates of schizophrenia and their additive diagnostic prediction potential. Multivariate ANOVA was used to compare structural and functional image sets for identification of schizophrenia. Integration of data from all four modalities yielded better predictive power than less inclusive combinations, specifically in the thalamus, left dorsolateral prefrontal and temporal regions. Among the modalities, fractional anisotropy showed highest discrimination in white matter whereas 18F-fallypride binding showed highest discrimination in gray matter. Structural and functional modalities displayed comparable discriminative power but different topography, with higher sensitivity of structural modalities in the left prefrontal region. Combination of functional and structural imaging modalities with inclusion of both gray and white matter appears most effective in diagnostic discrimination. The highest sensitivity of 18F-fallypride PET to gray matter changes in schizophrenia supports the primacy of dopaminergic abnormalities in its pathophysiology.

Sleep Duration and Subsequent Cortical Thinning in Cognitively Normal Older Adults.

To determine the association between self-reported sleep duration and cortical thinning among older adults. We studied 122 cognitively normal participants in the Baltimore Longitudinal Study of Aging with a mean age = 66.6 y (range, 51-84) at baseline sleep assessment and 69.5 y (range, 56-86) at initial magnetic resonance imaging (MRI) scan. Participants reported average sleep duration and completed a mean of 7.6 1.5-T MRI scans (range, 3-11), with mean follow-up from initial scan of 8.0 y (range, 2.0-11.8). In analyses adjusted for age, sex, education, race, and interval between sleep assessment and initial MRI scan, participants reporting > 7 h sleep at baseline had thinner cortex in the inferior occipital gyrus and sulcus of the left hemisphere at initial MRI scan than those reporting 7 h (cluster P < 0.05). In adjusted longitudinal analyses, compared to those reporting 7 h of sleep, participants reporting < 7 h exhibited higher rates of subsequent thinning in the superior temporal sulcus and gyrus, inferior and middle frontal gyrus, and superior frontal sulcus of the left hemisphere, and in the superior frontal gyrus of the right hemisphere; those reporting > 7 h of sleep had higher rates of thinning in the superior frontal and middle frontal gyrus of the left hemisphere (cluster P < 0.05 for all). In sensitivity analyses, adjustment for apolipoprotein E (APOE) e4 genotype reduced or eliminated some effects but revealed others. When reports of < 7 h of sleep were compared to reports of 7 or 8 h combined, there were no significant associations with cortical thinning. Among cognitively normal older adults, sleep durations of < 7 h and > 7 h may increase the rate of subsequent frontotemporal gray matter atrophy. Additional studies, including those that use objective sleep measures and investigate mechanisms linking sleep duration to gray matter loss, are needed.

Concurrent white and gray matter degeneration of disease-specific networks in early-stage Alzheimer's disease and behavioral variant frontotemporal dementia

This study investigates regional coherence between white matter (WM) microstructure and gray matter (GM) volume and perfusion measures in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) using a correlational approach. WM-GM coherence, compared with controls, was stronger between cingulum WM and frontotemporal GM in AD, and temporoparietal GM in bvFTD. In addition, in AD compared with controls, coherence was stronger between inferior fronto-occipital fasciculus WM microstructure and occipital GM perfusion. In this first study assessing regional WM-GM coherence in AD and bvFTD, we show that WM microstructure and GM volume and perfusion measures are coherent, particularly in regions implicated in AD and bvFTD pathology. This indicates concurrent degeneration in disease-specific networks. Our methodology allows for the detection of incipient abnormalities that go undetected in conventional between-group analyses.

Commentary: Clinical Approach to the Differential Diagnosis between Behavioral Variant Frontotemporal Dementia and Primary Psychiatric Disorders.

We welcome the recently published review by Ducharme and colleagues (1) and wish to highlight matters pertinent to aggressive behavior in their report. Aggression in psychiatric hospitals has gained widespread public attention (2). Mentally ill treatment-refractory patients who display aggressive behavior are either transferred to maximum-security forensic state hospitals (3) or sent to correctional facilities, which often struggle to keep up with the epidemic of mental illness and shortage of psychiatrists (4). Fourteen percent of patients with behavioral variant frontotemporal dementia (bvFTD) present initially to psychiatric care due to criminal behaviors (5). This highlights the importance of considering bvFTD as one of the key differential diagnosis in treatment-refractory forensic patients with progressively worsening cognitive functioning and high rates of violence as well as in patients with new-onset criminal behavior. Emerging biomarker-based reports indicate substantial overlap in cognitive dysfunction and underlying anatomical and functional brain abnormalities, such as frontotemporal gray matter loss, spanning psychotic disorders (6), and dementias (1). These findings call for novel dimensional approaches to psychiatric diagnoses and treatment such as those emphasized by the Research Domain Criteria (RDoC) initiative (7). We have reported on our successful management of such a case from a maximum-security hospital, who presented with long history of psychosis refractory to multiple treatment interventions including clozapine and electroconvulsive therapy (8). Our treatment decisions were driven by revision of diagnosis from schizoaffective disorder to FTD, based on cognition (Repeatable Battery for the Assessment of Neuropsychological Status and Montreal Cognitive Assessment) and neuroimaging (structural magnetic resonance imaging) workup, as well as by utilizing measurement-based care (MBC) (9). The principles of MBC include routine measurements of symptoms, side effect, and tolerability along with modification of treatment regime based on these measurements, while best defined for treatment of major depression can be extended to management of other chronic mental illnesses (9). We used data collected as part of state-law mandated monitoring of restraint(s) and/or seclusion(s) (10) to serve as measurements, which guided our decision to change medications or their dose. For example, during the course of treatment and as reported previously (8), we re-evaluated the utility of medroxyprogesterone by reducing its dose and frequency, which was associated with sharp increase in aggression. Utilizing principles of MBC, we re-instated the dose of medroxyprogesterone and added sertraline, which in turn resulted in even greater reduction in aggression. As impulsivity and disinhibition are hypothesized to underlie the aggression in bvFTD patients, 37.4% of whom exhibit criminal behaviors (5), we implemented structured behavioral and environmental modification programs. These interventions led to considerable improvement in the patient’s psychosis, social behaviors, impulsivity, aggression, and insight, despite persistent cognitive symptoms. This systematic review by Ducharme and colleagues is a valuable addition to literature offering a clear, step-wise differential diagnosis algorithm directly applicable to various clinical settings. However, lack of access to neuroimaging and expert consultation services in state hospitals and correctional facilities may hinder accurate diagnosis of bvFTD leading to under- or over-diagnosis, especially as its prevalence is 10–100 times lower than primary psychiatric disorders. This calls for system-level efforts, such as greater collaboration between academic centers and forensic mental health settings (4), as well as mechanistic research targeting pathophysiology and treatment developments of this devastating neurodegenerative syndrome.

Clinical Significance of Fronto-Temporal Gray Matter Atrophy in Executive Dysfunction in Patients with Chronic Kidney Disease: The VCOHP Study.

Background & ObjectivesIt is well known that cognitive impairment in patients with chronic kidney disease (CKD) is characterized by executive dysfunction, rather than memory dysfunction, although the precise mechanism of this remains to be elucidated. The purpose of the present study is to examine the correlation between gray matter volume (GMV) and executive function in CKD patients.Design, Setting, Participants, MeasurementsThis cross-sectional study recruited 95 patients with non-dialysis-dependent CKD (NDD-CKD) with no history of cerebrovascular disease, who underwent brain magnetic resonance imaging (MRI) and Trail Making Test (TMT) in the VCOHP Study. The subjects underwent brain MRI and TMT part A (TMT-A) and part B (TMT-B). The segmentation algorithm from Statistical Parametric Mapping 8 software was applied to every T1-weighted MRI scan to extract tissue maps corresponding to gray matter, white matter, and cerebrospinal fluid. GMV was normalized by dividing by the total intracranial volume, calculated by adding GMV, white matter volume, and cerebrospinal fluid space volume. Then, normalized whole-brain GMV was divided into four categories of brain lobes; frontal, parietal, temporal, and occipital. We assessed the correlation between normalized GMV and TMT using multivariable regression analysis.ResultsNormalized whole-brain GMV was significantly inversely correlated to the scores of TMT-A, TMT-B, and ΔTMT (TMT-B minus TMT-A). These correlations remained significant even after adjusting for relevant confounding factors. Normalized frontal and temporal GMV, but not parietal and occipital GMV, were significantly inversely correlated with TMT-A, TMT-B, and ΔTMT using multivariable regression analysis.ConclusionsThe present study demonstrates the correlation between normalized GMV, especially in the frontal and temporal lobes, and executive function, suggesting that fronto-temporal gray matter atrophy might contribute to executive dysfunction in NDD-CKD.

Baseline brain perfusion and brain structure in patients with major depression: a multimodal magnetic resonance imaging study.

Abnormal regional cerebral blood flow (rCBF) and grey matter volume have been frequently reported in patients with major depressive disorder (MDD). However, it is unclear to what extent structural and functional change co-occurs in patients with MDD and whether markers of neural activity, such as rCBF, can be predicted by structural change. Using MRI, we investigated resting-state rCBF and brain structure in patients with MDD and healthy controls between July 2008 and January 2013. We acquired perfusion images obtained with continuous arterial spin labelling, used voxel-based morphometry to assess grey matter volume and integrated biological parametric mapping analyses to investigate the impact of brain atrophy on rCBF. We included 43 patients and 29 controls in our study. Frontotemporal grey matter volume was reduced in patients compared with controls. In patients, rCBF was reduced in the anterior cingulate and bilateral parahippocampal areas and increased in frontoparietal and striatal regions. These abnormalities were confirmed by analyses with brain volume as a covariate. In patients with MDD there were significant negative correlations between the extent of depressive symptoms and bilateral parahippocampal rCBF. We found a positive correlation between depressive symptoms and rCBF for right middle frontal cortical blood flow. Medication use in patients has to be considered as a limitation of our study. Our data suggest that while changes of cerebral blood flow and brain volume co-occur in patients with MDD, structural change is not sufficient to explain altered neural activity in patients at rest. Abnormal brain structure and function in patients with MDD appear to reflect distinct levels of neuropathology.

Early stage of behavioral variant frontotemporal dementia: clinical and neuroimaging correlates

The early stages of behavioral variant frontotemporal dementia (bvFTD) are still not completely characterized. In a consecutive series of patients with probable bvFTD diagnosis confirmed by follow-up, we retrospectively evaluated the features at onset. Patients were reclassified according to presenting features and current diagnostic criteria into probable and possible bvFTD. The term “pre-bvFTD” was adopted for patients with cognitive and/or behavioral impairment not fulfilling bvFTD criteria and no deficits in activities of daily living. One hundred ninety-four subjects were included; at first visit, 70% (n = 136) patients were already classified as probable bvFTD. Of the remaining 30% (n = 58), 60% fulfilled criteria for possible bvFTD, while 40% did not, and were classified as pre-FTD. The neuropsychological pattern in possible bvFTD and pre-bvFTD was similar, although possible bvFTD showed more behavioral abnormalities. Pre-bvFTD subjects had frontotemporal gray matter atrophy, although less extensive than possible bvFTD. Conclusively, most bvFTD patients fulfill current diagnostic criteria at first admission, whereas a relatively small group is characterized by mild behavioral and/or cognitive abnormalities in spite of frontotemporal gray matter atrophy. Our preliminary findings will require a validation in prospective studies involving larger samples of patients.

Cognitive severity-specific neuronal degenerative network in charcoal burning suicide-related carbon monoxide intoxication: a multimodality neuroimaging study in Taiwan.

While carbon monoxide (CO) intoxication often triggers multiple intraneuronal immune- or inflammatory-related cascades, it is not known whether the pathological processes within the affected regions evolve equally in the long term. To understand the neurodegenerative networks, we examined 49 patients with a clinical diagnosis of CO intoxication related to charcoal burning suicide at the chronic stage and compared them with 15 age- and sex-matched controls. Reconstructions of degenerative networks were performed using T1 magnetic resonance imaging, diffusion-tensor imaging, and fluorodeoxyglucose positron emission tomography (PET). Tract-specific fractional anisotropy (FA) quantification of 11 association fibers was performed while the clinical significance of the reconstructed structural or functional networks was determined by correlating them with the cognitive parameters. Compared with the controls, the patients had frontotemporal gray matter (GM) atrophy, diffuse white matter (WM) FA decrement, and axial diffusivity (AD) increment. The patients were further stratified into 3 groups based on the cognitive severities. The spatial extents within the frontal-insular-caudate GM as well as the prefrontal WM AD increment regions determined the cognitive severities among 3 groups. Meanwhile, the prefrontal WM FA values and PET signals also correlated significantly with the patient's Mini-Mental State Examination score. Frontal hypometabolic patterns in PET analysis, even after adjusted for GM volume, were highly coherent to the GM atrophic regions, suggesting structural basis of functional alterations. Among the calculated major association bundles, only the anterior thalamic radiation FA values correlated significantly with all chosen cognitive scores. Our findings suggest that fronto-insular-caudate areas represent target degenerative network in CO intoxication. The topography that occurred at a cognitive severity-specific level at the chronic phase suggested the clinical roles of frontal areas. Although changes in FA are also diffusely distributed, different regional changes in AD suggested unequal long-term compensatory capacities among WM bundles. As such, the affected WM regions showing irreversible changes may exert adverse impacts to the interconnected GM structures.

Grey matter atrophy in mild cognitive impairment / early Alzheimer disease associated with delusions: a voxel-based morphometry study.

Grey matter atrophy in the right hemisphere has been shown to be more severe in dementia patients with delusions, suggesting a neuroanatomical localization that may be pertinent to impending neurodegeneration. Delusional symptoms may arise when atrophy in these areas reduces the regulatory functions of the right hemisphere, in tandem with asymmetric neuropathology in the left hemisphere. We hypothesized that delusional patients with either amnestic mild cognitive impairment (MCI) or early Alzheimer Disease (AD) would experience more pronounced grey matter atrophy in the right frontal lobe compared with matched patients without delusions. We used neuroimaging and clinical data obtained from the Alzheimer's Disease Neuroimaging Initiative. A comparison group of twenty-nine nondelusional MCI/early AD participants were compared with twenty-nine delusional participants using voxel-based morphometry, matched at baseline by age, sex, education, and Mini-Mental State Exam score. All included participants were diagnosed with amnestic MCI at study baseline. Fifteen voxel clusters of decreased grey matter in participants with delusions were detected. Prominent grey matter decrease was observed in the right precentral gyrus, right inferior frontal gyrus, right insula, and left middle occipital gyrus, areas that may be involved in control of thought and emotions. Greater right fronto-temporal grey matter atrophy was observed in MCI or early AD participants with delusions compared to matched patients without delusions. Consistent with our predictions, asymmetric grey matter atrophy in the right hemisphere may contribute to development of delusions through loss of executive inhibition.

EPA-1018 - Source-based morphometry of gray matter volume in patients with schizophrenia who have persistent auditory verbal hallucinations

Abnormal brain structure of frontal and temporal brain regions has been suggested to occur in patients with schizophrenia who have frequent auditory verbal hallucinations (AVH). However, it is unknown whether this is specific to this patient subgroup. In this study tested the hypothesis that frontotemporal gray matter volume changes would characterize patients with persistent AVH (pAVH) in contrast to healthy controls and patients without AVH. Using structural magnetic resonance imaging at 3T, we studied 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH, whereas the remaining 10 patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Using a multivariate statistical technique for structural data, i.e. 'source-based morphometry' (SBM), we investigated naturally grouping patterns of gray matter volume variation among individuals, the magnitude of their expression between-groups and the relationship between gray matter volume and AVH-specific measures. SBM identified a lower expression of medial and inferior frontal as well as bilateral temporal gray matter volume between pAVH and nAVH. This pattern did not differ between nAVH patients and controls and was associated with 'physical' AVH characteristics (such as symptom duration, location, frequency and intensity) in the pAVH patient group. These results suggest that a pattern of lower gray matter volume in medial frontal and bilateral temporal cortical regions differentiates between patients with persistent AVH and non-hallucinating patients. Moreover, the data support a specific role of this neural pattern in AVH symptom expression.

Source-based morphometry of gray matter volume in patients with schizophrenia who have persistent auditory verbal hallucinations

Abnormal structure of frontal and temporal brain regions has been suggested to occur in patients with schizophrenia who have frequent auditory verbal hallucinations (AVH). However, it is unknown whether this is specific to this patient subgroup. This study tested the hypothesis that frontotemporal gray matter volume changes would characterize patients with persistent AVH (pAVH) in contrast to healthy controls and patients without AVH. Using structural magnetic resonance imaging at 3T, we studied 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH, whereas the remaining 10 patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Using a multivariate statistical technique for structural data, i.e. "source-based morphometry" (SBM), we investigated naturally grouping patterns of gray matter volume variation among individuals, the magnitude of their expression between-groups and the relationship between gray matter volume and AVH-specific measures. SBM identified a reduction of medial and inferior frontal, insular and bilateral temporal gray matter volume between pAVH and nAVH. This pattern did not differ between nAVH patients and controls and was associated with "physical" AVH characteristics (such as symptom duration, location, frequency and intensity) in the pAVH patient group. These results suggest that a pattern of lower gray matter volume in medial frontal, insular and bilateral temporal cortical regions differentiates between patients with persistent AVH and non-hallucinating patients. Moreover, the data support a specific role of this neural pattern in AVH symptom expression.

Sex chromosomes and the brain: a study of neuroanatomy in XYY syndrome

To assess global and regional brain matter variations associated with XYY syndrome by comparison with Klinefelter syndrome and typical development. We used two conceptually distinct voxel-based magnetic resonance imaging methods to examine brain structure in young males with XYY syndrome: (1) volumetric comparison to assess global grey and white matter volumes and (2) support vector machine-based multivariate pattern classification analysis to assess regional neuroanatomy. We assessed verbal, non-verbal, and spatial abilities with the Differential Ability Scales (DAS), and we measured autism diagnostic criteria in eight males with XYY syndrome using the Social Responsiveness Scale and the Autism Diagnostic Interview-Revised (ADI-R). A comparison of 36 typically developing males (mean age 11 y, SD 1 y 9 mo), 31 males with Klinefelter syndrome (mean age 9 y 8 mo, SD 1 y 8 mo), and eight males with XYY syndrome (mean age 11 y 6 mo, SD 1 y 11 mo) showed that total white and grey matter volumes were significantly, or nearly significantly, higher in males with XYY syndrome than in males belonging to the other two groups (grey matter: XYY males vs typically developing males, p<0.006; XYY vs males with Klinefelter syndrome, p<0.001; white matter: XYY males vs typically developing males, p=0.061; XYY males vs males with Klinefelter syndrome, p=0.004). Voxel-based multivariate pattern classification analysis indicates that, after controlling for global volumes, regional brain variations in XYY syndrome are more like those found in Klinefelter syndrome than those occurring in typical development. Further, visualization of classification parameters suggests that insular and frontotemporal grey matter and white matter, including known language areas, are reduced in males with XYY syndrome, similar to what is seen in Klinefelter syndrome. In males with XYY syndrome, DAS verbal and non-verbal scores were significantly lower than in typically developing participants (both p<0.001). DAS scores were not significantly different between XYY and Klinefelter syndrome groups. In five of eight males with XYY syndrome, the Social Responsiveness Scale score exceeded the cut-off for a likely diagnosis of autism spectrum disorder (ASD). In three of eight males with XYY syndrome, the ADI-R score met the cut-off for ASD diagnosis; in another two, ADI-R scores within the social and communication domains met the cut-off values for a diagnosis of ASD. The results suggest that genetic variations associated with XYY syndrome result in increased brain matter volumes, a finding putatively related to the increased frequency of ASDs in individuals with this condition. In addition, frontotemporal grey and white matter reductions in XYY syndrome provide a likely neuroanatomical correlate for observed language impairments.

Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD

Granulin (GRN) mutations have been identified as a major cause of frontotemporal lobar degeneration (FTLD) by haploinsufficiency mechanism, although their effects on brain tissue dysfunction and damage still remain to be clarified. In this study, we investigated the pattern of neuroimaging abnormalities in FTLD patients, carriers and noncarriers of GRN Thr272fs mutation, and in presymptomatic carriers. We assessed regional gray matter (GM) atrophy, and resting (RS)-functional magnetic resonance imaging (fMRI). The functional connectivity maps of the salience (SN) and the default mode (DMN) networks were considered. Frontotemporal gray matter atrophy was found in all FTLD patients (more remarkably in those GRN Thr272fs carriers), but not in presymptomatic carriers. Functional connectivity within the SN was reduced in all FTLD patients (again more remarkably in those mutation carriers), while it was enhanced in the DMN. Conversely, presymptomatic carriers showed increased connectivity in the SN, with no changes in the DMN. Our findings suggest that compensatory mechanisms of brain plasticity are present in GRN-related FTLD, but with different patterns at a preclinical and symptomatic disease stage.

Atypical language lateralisation associated with right fronto-temporal grey matter increases — a combined fMRI and VBM study in left-sided mesial temporal lobe epilepsy patients

By combining language functional magnetic resonance imaging and voxel-based morphometry in patients with left-sided mesial temporal lobe epilepsy and hippocampal sclerosis, we studied whether atypical language dominance is associated with temporal and/or extratemporal cortical changes. Using verbal fluency functional magnetic resonance imaging for language lateralisation, we identified 20 patients with left-sided mesial temporal lobe epilepsy with hippocampal sclerosis and atypical language lateralisation. These patients were compared with a group of 20 matched left-sided mesial temporal lobe epilepsy patients who had typical language lateralisation. Using T1-weighted 3D images of all patients and voxel-based morphometry, we compared grey matter volumes between the groups of patients. We also correlated grey matter volumes with the degree of atypical language activation. Patients with atypical language lateralisation had increases of grey matter volumes, mainly within right-sided temporo-lateral cortex (x=59, y=-16, z=-1, T=6.36, p<.001 corrected), and less significantly within frontal brain regions compared to patients with typical language lateralisation. The degree of atypical fronto-temporal language activation (measured by lateralisation indices and relative functional magnetic resonance imaging activity) was correlated with right-sided temporal and frontal grey matter volumes. Patients with atypical language lateralisation did not differ in terms of language performance from patients with typical language dominance. Atypical language lateralisation in patients with left-sided mesial temporal lobe epilepsy was associated with increased grey matter volume within the non-epileptic right temporal and frontal lobe. Grey matter increases associated with atypical language might represent morphological changes underlying functional reorganisation of the language network. This hard-wired reorganised atypical language network seems to be suitable to support language functions.

Mapping the brain in younger and older asymptomatic HIV-1 men: Frontal volume changes in the absence of other cortical or diffusion tensor abnormalities

IntroductionOver the past decade the developments made in treating people with human immune deficiency virus (HIV) have greatly improved quality of life and life expectancy. However, the nature of asymptomatic HIV-associated minor neurocognitive disorder (HAND) remains unclear. In this study we explored the occurrence of neuropsychological and neuroimaging changes in medically and psychiatrically stable HIV-1 infected patients on highly active antiretroviral treatment (HAART) from two separate age groups. MethodsParticipants included 20 HIV-1 infected younger (aged 20–40) and 20 HIV-1 older patients (aged 50–75). Comparisons were made with 20 age- and education-matched younger and 22 matched older healthy seronegative males. Participants were stable on treatment and asymptomatic at study onset with undetectable HIV-1 viral loads, and free of medical or psychiatric co-morbidity, alcohol or substance misuse. A detailed neuropsychological assessment was used and volumetric-magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) performed to assess grey and white-matter integrity. ResultsWe found significant effects of ageing on memory, grey and white matter measures. Comparison of the HIV-positive and HIV-negative groups did not show significant differences on the neuropsychological tests after Bonferroni correction, and there were no significant age by HIV status interactions. However, we did find reduced grey matter volume on MRI in our HIV-positive participants within the medial and superior frontal gyri. We also found significant ageing effects in fronto-temporal grey and white matter, independent of the effect of HIV. ConclusionsThe results from this study suggest that HIV-1 disease by itself does not significantly impair cognitive function when patients are otherwise asymptomatic. Nevertheless, the imaging techniques were sensitive enough to detect subtle grey matter changes not normally evident until much later in the disease. If confirmed in a longitudinal study this frontal grey matter change could represent an important biomarker for trials in HIV disease.

S29-6 MMN in schizophrenia: relationship to functional status, generator sources and grey matter loss

Reduced MMN in schizophrenia is arguably the most robust physiological marker in the biological psychiatry literature of the disorder. The first paper reporting this finding was published by an Australian group in 1991 (Shelley et al., Biol Psychiatry, 1991, 30, 1059:62). There are now over 120 publications reporting MMN in schizophrenia patients and although the story is somewhat more complex than originally envisaged, there are few failures to replicate the initial findings. Here I report data from two studies that address some of these complexities, one investigating the relationship of MMN to different types of deviants with grey matter loss and functional status and a second examining generator sources of MMN in recent onset and more chronic schizophrenia. In study 1, MMN was recorded to duration, frequency and intensity deviants in 18 schizophrenia patients with an established illness and 18 matched controls. Functional status was assessed using the SOFAS. High-resolution structural magnetic resonance scans were acquired to generate average cerebral cortex models using cortical pattern matching and provided grey matter estimates. MMN amplitude to all deviants was reduced in schizophrenia patients and both frequency and duration MMN correlated with SOFAS. However, only frequency MMN in patients was correlated with frontotemporal grey matter reduction. In study 2, cortically constrained LORETA source analysis of MMN to duration deviants in 16 recent onset patients, 19 chronic patients and 35 age-matched controls was conducted. LORETA analysis revealed strong MMN sources in temporal cortex and weak sources in frontal regions. Both sources were reduced in schizophrenia with a trend towards a more marked reduction in recent onset patients. Our findings suggest a close association between frequency MMN, cerebral pathology and functioning in established schizophrenia while reduced MMN to duration deviants appears to be associated with early stages of the disorder.

Correlations between gray matter reductions and cognitive deficits in dementia with Lewy Bodies and Parkinson's disease with dementia

There is controversy regarding whether Dementia with Lewy Bodies (DLB) and Parkinson's disease with dementia (PDD) may or not be different manifestations of the same disorder. The purpose of the present study was to investigate possible correlations between brain structure and neuropsychological functions in clinically diagnosed patients with DLB and PDD. The study sample consisted of 12 consecutively referred DLB patients, 16 PDD patients, and 16 healthy control subjects recruited from an outpatient setting, who underwent MRI and neuropsychological assessment. Voxel-based morphometry results showed that DLB patients had greater gray matter atrophy in the right superior frontal gyrus, the right premotor area and the right inferior frontal lobe compared to PDD. Furthermore, the anterior cingulate and prefrontal volume correlated with performance on the Continuous Performance Test while the right hippocampus and amygdala volume correlated with Visual Memory Test in the DLB group. In conclusion, DLB patients had more fronto-temporal gray matter atrophy than PDD patients and these reductions correlated with neuropsychological impairment.

MRI Correlates of Protein Deposition and Disease Severity in Postmortem Frontotemporal Lobar Degeneration

Background: Frontotemporal lobar degeneration (FTLD) can be classified based on the presence of the microtubule-associated protein tau and the TAR DNA binding protein-43 (TDP-43). Future treatments will likely target these proteins, therefore it is important to identify biomarkers to help predict protein biochemistry. Objective: To determine whether there is an MRI signature pattern of tau or TDP-43 using a large cohort of FTLD subjects and to investigate how patterns of atrophy change according to disease severity using a large autopsy-confirmed cohort of FTLD subjects. Methods: Patterns of gray matter loss were assessed using voxel-based morphometry in 37 tau-positive and 44 TDP-43-positive subjects compared to 35 age and gender-matched controls, and compared to each other. Comparisons were also repeated in behavioral variant frontotemporal dementia (bvFTD) subjects (n = 15 tau-positive and n = 30 TDP-43-positive). Patterns of atrophy were also assessed according to performance on the Clinical Dementia Rating (CDR) scale and Mini-Mental State Examination (MMSE). Results: The tau-positive and TDP-43-positive groups showed patterns of frontotemporal gray matter loss compared to controls with no differences observed between the groups, for all subjects and for bvFTD subjects. Patterns of gray matter loss increased in a graded manner by CDR and MMSE with loss in the frontal lobes, insula and hippocampus in mild subjects, spreading to the temporal and parietal cortices and striatum in more advanced disease. Conclusion: There is no signature pattern of atrophy for tau or TDP-43; however, patterns of atrophy in FTLD progress with measures of clinical disease severity.