Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset.

PURPOSE: To identify the neurobiological traits of amyotrophic lateral sclerosis (ALS) and to elucidate functional differences between ALS of spinal and bulbar onset. We hypothesized that glucose metabolism distribution might vary between groups. METHODS: The study groups comprised 32 patients with ALS of either bulbar (n = 13) or spinal (n = 19) onset and 22 subjects as controls. They were investigated by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (FDG PET), comparing the patient groups with each other and with the controls by statistical parametric mapping. RESULTS: Highly significant relative increases in glucose metabolism distribution were found in the group comprising all 32 ALS patients as compared with the controls in the bilateral amygdalae, midbrain, pons and cerebellum. Relative hypermetabolism was also found in patients with spinal onset as compared with the controls in the right midbrain. In patients with bulbar onset compared with the controls and with patients with spinal onset, large relatively hypometabolic areas were found in the bilateral frontal cortex, right insula, anterior cingulate, precuneus and inferior parietal lobe. Patients with spinal onset had significantly higher scores in a neuropsychological test assessing verbal fluency compared with patients with bulbar onset. CONCLUSION: This large FDG PET investigation provided unprecedented evidence of relatively increased metabolism in the amygdalae, midbrain and pons in ALS patients as compared with control subjects, possibly due to local activation of astrocytes and microglia. Highly significant relative decreases in metabolism were found in large frontal and parietal regions in the bulbar onset patients as compared with the spinal onset patients and the controls, suggesting a differential metabolic and neuropsychological state between the two conditions.

Differences at brain SPECT between depressed females with and without adult ADHD and healthy controls: etiological considerations.

BACKGROUND: Comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and mood disorders is common. Alterations of the cerebellum and frontal regions have been reported in neuro-imaging studies of ADHD and major depression. METHODS: Thirty chronically depressed adult females of whom 16 had scores below, and 14 scores above, cut-offs on the 25-items Wender Utah Retrospective Scale (WURS-25) and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) were divided into subgroups designated "Depression" and "Depression + ADHD", respectively. Twenty-one of the patients had some audiological symptom, tinnitus and/or hearing impairment. The patients were investigated with other rating scales and 99mTc-HMPAO SPECT. Controls for 99mTc-HMPAO SPECT were 16 healthy females. SPECT was analyzed by both statistical parametric mapping (SPM2) and the computerized brain atlas (CBA). Discriminant analysis was performed on the volumes of interest generated by the CBA, and on the scores from rating scales with the highest group differences. RESULTS: The mean score of a depression rating scale (MADRS-S) was significantly lower in the "Depression" subgroup compared to in the "Depression + ADHD" subgroup. There was significantly decreased tracer uptake within the bilateral cerebellum at both SPM and CBA in the "Depression + ADHD" subgroup compared to in the controls. No decrease of cerebellar tracer uptake was observed in "Depression". Significantly increased tracer uptake was found at SPM within some bilateral frontal regions (Brodmann areas 8, 9, 10, 32) in the "Depression + ADHD" subgroup compared to in "Depression". An accuracy of 100% was obtained for the discrimination between the patient groups when thalamic uptake was used in the analysis along with scores from Socialization and Impulsivity scales. CONCLUSION: The findings confirm the previous observation of a cerebellar involvement in ADHD. Higher bilateral frontal 99mTc-HMPAO uptake in "Depression + ADHD" compared to in "Depression" indicate a difference between these subgroups. 99mTc-HMPAO uptake mechanisms are discussed.

Principal component analysis in mild and moderate Alzheimer's disease--a novel approach to clinical diagnosis.

Principal component analysis (PCA) provides a method to explore functional brain connectivity. The aim of this study was to identify regional cerebral blood flow (rCBF) distribution differences between Alzheimer's disease (AD) patients and controls (CTR) by means of volume of interest (VOI) analysis and PCA. Thirty-seven CTR, 30 mild AD (mildAD) and 27 moderate AD (modAD) subjects were investigated using single photon emission computed tomography with (99m)Tc-hexamethylpropylene amine oxime. Analysis of covariance (ANCOVA), PCA, and discriminant analysis (DA) were performed on 54 VOIs. VOI analysis identified in both mildAD and modAD subjects a decreased rCBF in six regions. PCA in mildAD subjects identified four principal components (PCs) in which the correlated VOIs showed a decreased level of rCBF, including regions that are typically affected early in the disease. In five PCs, including parietal-temporal-limbic cortex, and hippocampus, a significantly lower rCBF in correlated VOIs was found in modAD subjects. DA significantly discriminated the groups. The percentage of subjects correctly classified was 95, 70, and 81 for CTR, mildAD and modAD groups, respectively. PCA highlighted, in mildAD and modAD, relationships not evident when brain regions are considered as independent of each other, and it was effective in discriminating groups. These findings may allow neurophysiological inferences to be drawn regarding brain functional connectivity in AD that might not be possible with univariate analysis.

Principal component analysis of FDG PET in amnestic MCI.

PURPOSE: The purpose of the study is to evaluate the combined accuracy of episodic memory performance and (18)F-FDG PET in identifying patients with amnestic mild cognitive impairment (aMCI) converting to Alzheimer's disease (AD), aMCI non-converters, and controls. METHODS: Thirty-three patients with aMCI and 15 controls (CTR) were followed up for a mean of 21 months. Eleven patients developed AD (MCI/AD) and 22 remained with aMCI (MCI/MCI). (18)F-FDG PET volumetric regions of interest underwent principal component analysis (PCA) that identified 12 principal components (PC), expressed by coarse component scores (CCS). Discriminant analysis was performed using the significant PCs and episodic memory scores. RESULTS: PCA highlighted relative hypometabolism in PC5, including bilateral posterior cingulate and left temporal pole, and in PC7, including the bilateral orbitofrontal cortex, both in MCI/MCI and MCI/AD vs CTR. PC5 itself plus PC12, including the left lateral frontal cortex (LFC: BAs 44, 45, 46, 47), were significantly different between MCI/AD and MCI/MCI. By a three-group discriminant analysis, CTR were more accurately identified by PET-CCS + delayed recall score (100%), MCI/MCI by PET-CCS + either immediate or delayed recall scores (91%), while MCI/AD was identified by PET-CCS alone (82%). PET increased by 25% the correct allocations achieved by memory scores, while memory scores increased by 15% the correct allocations achieved by PET. CONCLUSION: Combining memory performance and (18)F-FDG PET yielded a higher accuracy than each single tool in identifying CTR and MCI/MCI. The PC containing bilateral posterior cingulate and left temporal pole was the hallmark of MCI/MCI patients, while the PC including the left LFC was the hallmark of conversion to AD.

Mitochondrial function is related to alterations at brain SPECT in depressed patients.

INTRODUCTION: 99mTc-d,l-hexamethylpropylene amine oxime (99mTc-HMPAO) retention in brain is proportional to cerebral blood flow and related to both the local hemodynamic state and to the cellular content of reduced glutathione. Alterations of the regional distribution of 99mTc-HMPAO retention, with discrepant results, have been reported at functional brain imaging of unipolar depression. Since mitochondrial involvement has been reported in depressed patients, the aim of the study was to explore whether the 99mTc-HMPAO retention at single-photon emission computed tomography in depressed patients may relate to different levels of mitochondrial function. METHODS: All patients had audiological and muscular symptoms, somatic symptoms that are common in depression. Citrate synthase (CS) activity assessed in muscle mitochondria correlated strongly with the activities of three mitochondrial respiratory chain enzymes and was used as a marker of mitochondrial function. K-means clustering performed on CS grouped eight patients with low and 11 patients with normal CS. Voxel-based analysis was performed on the two groups by statistical parametric mapping. RESULTS: Voxel-based analysis showed significantly higher 99mTc-HMPAO retention in the patients with low CS compared with the patients with normal CS in the posterior and inferior frontal cortex, the superior and posterior temporal cortex, the somato-sensory cortex, and the associative parietal cortex. CONCLUSION: Low muscle CS in depressed patients is related to higher regional 99mTc-HMPAO retention that may reflect cerebrovascular adaptation to impaired intracellular metabolism and/or intracellular enzymatic changes, as previously reported in mitochondrial disorder. Mitochondrial dysfunction in varying proportions of the subjects may explain some of the discrepant results for 99mTc-HMPAO retention in depression.

Effects of EMDR psychotherapy on 99mTc-HMPAO distribution in occupation-related post-traumatic stress disorder.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a derangement of mood control with involuntary, emotionally fraught recollections that may follow deep psychological trauma in susceptible individuals. This condition is treated with pharmacological and/or cognitive therapies as well as psychotherapy with eye movement desensitization and reprocessing (EMDR). However, only a very limited number of studies have been published dealing with work-related PTSD, and investigations on the effect of treatment on cerebral blood flow represent an even smaller number. AIM: To investigate the short-term outcome of occupation-related PTSD after EMDR therapy by 99mTc-HMPAO SPECT. METHOD: Fifteen patients, either train drivers suffering from PTSD after having been unintentionally responsible for a person-under-train accident or employees assaulted in the course of duty, were recruited for the study. 99mTc-HMPAO SPECT was performed on these patients both before and after EMDR therapy while they listened to a script portraying the traumatic event. Tracer distribution analysis was then carried out at volume of interest (VOI) level using a three-dimensional standardized brain atlas, and at voxel level by SPM. The CBF data of the 15 patients were compared before and after treatment as well as with those of a group of 27 controls who had been exposed to the same psychological traumas without developing PTSD. RESULTS: At VOI analysis significant CBF distribution differences were found between controls and patients before and after treatment (P=0.023 and P=0.0039, respectively). Eleven of the 15 patients responded to treatment, i.e., following EMDR they no longer fulfilled the DSM-IV criteria for PTSD. When comparing only the eleven responders with the controls, the significant group difference found before EMDR (P=0.019) disappeared after treatment. Responders and non-responders showed after therapy significant regional differences in frontal, parieto-occipital and visual cortex and in hippocampus. SPM analysis showed significant uptake differences between patients and controls in the orbitofrontal cortex (Brodmann 11) and the temporal pole (Brodmann 38) both before and after treatment. A significant tracer distribution difference present before treatment in the uncus (Brodmann 36) disappeared after treatment, while a significant difference appeared in the lateral temporal lobe (Brodmann 21). CONCLUSION: Significant 99mTc-HMPAO uptake regional differences were found, mainly in the peri-limbic cortex, between PTSD patients and controls exposed to trauma but not developing PTSD. Tracer uptake differences between responders and patients not responding to EMDR were found after treatment suggesting a trend towards normalization of tracer distribution after successful therapy. These findings in occupational related PTSD are consistent with previously described effects of psychotherapy on anxiety disorders.

Optimisation of statistical methodologies for a better diagnosis of neurological and psychiatric disorders by means of SPECT.

In the last years there has been a wide consensus on the importance of brain imaging in assessing neurodegenerative and psychiatric disorders. Different techniques for functional and anatomical examination are currently clinically implemented in neurology and psychiatry to improve sensitivity, specificity and accuracy of the diagnosis of various diseases. In addition, the increasing life expectancy in the Western world raises the social importance and the economical impact of age-related neurodegenerative disorders since the incidence of Alzheimer disease and Parkinson disease is higher in the elderly. An early diagnosis of neuro-psychiatric diseases and the assessment of "natural" changes of regional cerebral blood flow (rCBF) distribution during normal aging are hence of utmost importance. In the recent past brain disorders have extensively been investigated by means of optimised nuclear medicine techniques, instruments and algorithms. Diagnosis can be better achieved by identifying those structures in which CBF or metabolism deviate from normality resulting in significant changes as compared to a reference database. In the present paper we present some studies investigating, by means of recently implemented diagnostic tools, patients bearer of various neuro-psychiatric disorders. The improved nuclear medicine techniques and instrumentation, the state-of-the-art software for brain imaging standardisation and the use of sophisticated multivariate data analysis are extensively reviewed.

Brief Report: alterations in cerebral blood flow as assessed by PET/CT in adults with autism spectrum disorder with normal IQ.

Specific biological markers for autism spectrum disorder (ASD) have not yet been established. Functional studies have shown abnormalities in the anatomo-functional connectivity of the limbic-striatal "social" brain. This study aimed to investigate regional cerebral blood flow (rCBF) at rest. Thirteen patients with ASD of normal intelligence and ten IQ-, sex- and age-matched healthy controls (HC) underwent PET/CT using [1-(11)C]butanol, a perfusion tracer. As compared to HC, ASD showed significant CBF increases in the right parahippocampal, posterior cingulate, primary visual and temporal cortex, putamen, caudatus, substantia nigra and cerebellum. No statistically significant correlation between CBF and IQ was found. The limbic, posterior associative and cerebellar cortices showed increased blood flow in ASD, confirming previous findings about the neurobiology of ASD.

Imaging the neurobiological substrate of atypical depression by SPECT.

PURPOSE: Neurobiological abnormalities underlying atypical depression have previously been suggested. The purpose of this study was to explore differences at functional brain imaging between depressed patients with and without atypical features and healthy controls. METHODS: Twenty-three out-patients with chronic depressive disorder recruited from a service for patients with audiological symptoms were investigated. Eleven fulfilled the DSM-IV criteria for atypical depression (mood reactivity and at least two of the following: weight gain, hypersomnia, leaden paralysis and interpersonal rejection sensitivity). Twenty-three healthy subjects served as controls. Voxel-based analysis was applied to explore differences in (99m)Tc-HMPAO uptake between groups. RESULTS: Patients in the atypical group had a higher prevalence of bilateral hearing impairment and higher depression and somatic distress ratings at the time of SPECT. Significantly higher tracer uptake was found bilaterally in the atypical group as compared with the non-atypicals in the sensorimotor (Brodmann areas, BA1-3) and premotor cortex in the superior frontal gyri (BA6), in the middle frontal cortex (BA8), in the parietal associative cortex (BA5, BA7) and in the inferior parietal lobule (BA40). Significantly lower tracer distribution was found in the right hemisphere in the non-atypicals compared with the controls in BA6, BA8, BA44, BA45 and BA46 in the frontal cortex, in the orbito-frontal cortex (BA11, BA47), in the postcentral parietal cortex (BA2) and in the multimodal association parietal cortex (BA40). CONCLUSION: The differences found between atypical and non-atypical depressed patients suggest different neurobiological substrates in these patient groups. The putative links with the clinical features of atypical depression are discussed. These findings encourage the use of functional neuroimaging in psychiatric disorders.

Effects of an intensive rehabilitation programme on patients with Huntington's disease: a pilot study.

OBJECTIVE: To investigate the effects of an intensive, inpatient rehabilitation programme on individuals affected by Huntington's disease. DESIGN: A pilot study. Within-subjects design. SETTING: Inpatient rehabilitation home of the Italian welfare system. SUBJECTS: Forty patients, early and middle stage of the disease, were recruited to an intensive, inpatient rehabilitation protocol. INTERVENTIONS: The treatment programme included respiratory exercises and speech therapy, physical and occupational therapy and cognitive rehabilitation exercises. The programme involved three-week admission periods of intensive treatment that could be repeated three times a year. MAIN MEASURES: A standard clinical assessment was performed at the beginning of each admission using the Zung Depression Scale, Mini-Mental State Examination (MMSE), Barthel Index, Tinetti Scale and Physical Performance Test (PPT). Tinetti and PPT were also used at the end of each admission to assess the outcomes in terms of motor and functional performance. RESULTS: Each three-week period of treatment resulted in highly significant (P < 0.001) improvements of motor performance and daily life activities. The average increase was 4.7 for Tinetti and 5.21 for PPT scores. No carry-over effect from one admission to the next was apparent but at the same time, no motor decline was detected over two years, indicating that patients maintained a constant level of functional, cognitive as well as motor performance. CONCLUSIONS: Intensive rehabilitation treatments may positively influence the maintenance of functional and motor performance in patients with Huntington's disease.

Identification by [99mTc]ECD SPECT of anterior cingulate hypoperfusion in progressive supranuclear palsy, in comparison with Parkinson's disease.

PURPOSE: Progressive supranuclear palsy (PSP) is an akinetic-rigid syndrome that can be difficult to differentiate from Parkinson's disease (PD), particularly at an early stage. [99mTc]ethyl cysteinate dimer (ECD) SPECT could represent a widely available tool to assist in the differential diagnosis. In this study we used voxel-based analysis and Computerised Brain Atlas (CBA)-based principal component analysis (PCA) of [99mTc]ECD SPECT data to test whether: (1) specific patterns of rCBF abnormalities can differentiate PSP from controls and PD; (2) networks of dysfunctional brain regions can be found in PSP vs controls and PD. METHODS: Nine PD patients, 16 PSP patients and ten controls were studied with [99mTc]ECD SPECT using a brain-dedicated device (Ceraspect). Voxel-based analysis was performed with statistical parametric mapping. PCA was applied to volume of interest data after spatial normalisation to CBA. RESULTS: The voxel-based analysis showed hypoperfusion of the anterior cingulate and medial frontal cortex in PSP compared with controls and PD. In PSP patients the rCBF impairment extended to the pre-supplementary motor area and prefrontal cortex, areas involved in executive function and motor networks. Compared with PSP patients, PD patients showed a mild rCBF decrease in associative visual areas which could be related to the known impairment of visuospatial function. The PCA identified three principal components differentiating PSP patients from controls and/or PD patients that included groups of cortical and subcortical brain regions with relatively decreased (cingulate cortex, prefrontal cortex and caudate) or increased (parietal cortex) rCBF, representing distinct functional networks in PSP. CONCLUSION: Anterior cingulate hypoperfusion seems to be an early, distinct brain abnormality in PSP as compared with PD.

Regional cerebral blood flow during auditory recall in 47 subjects exposed to assaultive and non-assaultive trauma and developing or not posttraumatic stress disorder.

OBJECTIVE: Psychological trauma leads to posttraumatic stress disorder (PTSD) in susceptible subjects. The aim of this study was to investigate the differences in regional cerebral blood flow (rCBF) between two groups of subjects exposed to different types of traumatic stressor either developing or not developing PTSD. METHODS: Twenty subjects developing (S) and 27 not developing (NS) PTSD after being exposed to either earlier person-under-the-train accident (NA) or being assaulted in the underground environment (A) were included in the study. 99mTc-HMPAO SPECT was performed and the uptake in 29 regions of the brain (VOIs), bilaterally, was assessed. rCBF distribution was compared, using analysis of variance (ANOVA), between groups (S/NS) and type (A/NA) during a situation involving an auditory evoked re-experiencing of the traumatic event. Discriminant analysis was applied to test the concordance between clinical diagnosis and SPECT findings. RESULTS: In the general analyses significant differences were found between groups and types and there was a significant hemisphere x type interaction. S showed higher CBF than NS and so did A as compared to NA, particularly in the right hemisphere. Discriminant analysis correctly classified 66% of cases (p < 0001) in testing S/NS and 72% (p < 0001) in testing NA/A. CONCLUSIONS: Under recall of their traumatic experience we found higher relative CBF distribution values in S as compared to NS. CBF was higher in the right hemisphere and particularly in assaulted subjects. These findings underscore the role upon trauma recall of both the right hemisphere and the nature of the stressing event.

Regional cerebral blood flow as assessed by principal component analysis and (99m)Tc-HMPAO SPET in healthy subjects at rest: normal distribution and effect of age and gender.

The increasing implementation of standardisation techniques in brain research and clinical diagnosis has highlighted the importance of reliable baseline data from normal control subjects for inter-subject analysis. In this context, knowledge of the regional cerebral blood flow (rCBF) distribution in normal ageing is a factor of the utmost importance. In the present study, rCBF was investigated in 50 healthy volunteers (25 men, 25 women), aged 31-78 years, who were examined at rest by means of single-photon emission tomography (SPET) using technetium-99m d, l-hexamethylpropylene amine oxime (HMPAO). After normalising the CBF data, 27 left and 27 right volumes of interest (VOIs) were selected and automatically outlined by standardisation software (computerised brain atlas). The heavy load of flow data thus obtained was reduced in number and grouped in factors by means of principal component analysis (PCA). PCA extracted 12 components explaining 81% of the variance and including the vast majority of cortical and subcortical regions. Analysis of variance and regression analyses were performed for rCBF, age and gender before PCA was applied and subsequently for each single extracted factor. There was a significantly higher CBF on the right side than on the left side ( P<0.001). In the overall analysis, a significant decrease was found in CBF ( P=0.05) with increasing age, and this decrease was particularly evident in the left hemisphere ( P=0.006). When gender was specifically analysed, CBF was found to decrease significantly with increasing age in females ( P=0.037) but not in males. Furthermore, a significant decrease in rCBF with increasing age was found in the brain vertex ( P=0.05), left frontotemporal cortex ( P=0.012) and temporocingulate cortex ( P=0.003). By contrast, relative rCBF in central structures increased with age ( P=0.001). The ability of standardisation software and PCA to identify functionally connected brain regions might contribute to a better understanding of the relationships between rCBF at rest, anatomically defined brain structures, ageing and gender.

Principal component and volume of interest analyses in depressed patients imaged by 99mTc-HMPAO SPET: a methodological comparison.

Previous regional cerebral blood flow (rCBF) studies on patients with unipolar major depressive disorder (MDD) have analysed clusters of voxels or single regions and yielded conflicting results, showing either higher or lower rCBF in MDD as compared to normal controls (CTR). The aim of this study was to assess rCBF distribution changes in 68 MDD patients, investigating the data set with both volume of interest (VOI) analysis and principal component analysis (PCA). The rCBF distribution in 68 MDD and 66 CTR, at rest, was compared. Technetium-99m d, l-hexamethylpropylene amine oxime single-photon emission tomography was performed and the uptake in 27 VOIs, bilaterally, was assessed using a standardising brain atlas. Data were then grouped into factors by means of PCA performed on rCBF of all 134 subjects and based on all 54 VOIs. VOI analysis showed a significant group x VOI x hemisphere interaction ( P<0.001). rCBF in eight VOIs (in the prefrontal, temporal, occipital and central structures) differed significantly between groups at the P<0.05 level. PCA identified 11 anatomo-functional regions that interacted with groups ( P<0.001). As compared to CTR, MDD rCBF was relatively higher in right associative temporo-parietal-occipital cortex ( P<0.01) and bilaterally in prefrontal ( P<0.005) and frontal cortex ( P<0.025), anterior temporal cortex and central structures ( P<0.05 and P<0.001 respectively). Higher rCBF in a selected group of MDD as compared to CTR at rest was found using PCA in five clusters of regions sharing close anatomical and functional relationships. At the single VOI level, all eight regions showing group differences were included in such clusters. PCA is a data-driven method for recasting VOIs to be used for group evaluation and comparison. The appearance of significant differences absent at the VOI level emphasises the value of analysing the relationships among brain regions for the investigation of psychiatric disease.