Abstract Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary movements. The most ...common inherited form of PTD is associated with the DYT1 mutation on chromosome 9q34. A less frequent form is linked to the DYT6 locus on chromosome 8q21-22. Both forms are autosomal dominant with incomplete (∼30%) clinical penetrance. Extensive functional and microstructural imaging with positron emission tomography (PET) and diffusion tensor MRI (DTI) has been performed on manifesting and non-manifesting carriers of these mutations. The results are consistent with the view of PTD as a neurodevelopmental circuit disorder involving cortico-striatal-pallido-thalamocortical (CSPTC) and related cerebellar–thalamo-cortical pathways. Studies of resting regional metabolism have revealed consistent abnormalities in PTD involving multiple interconnected elements of these circuits. In gene carriers, changes in specific subsets of these regions have been found to relate to genotype, phenotype, or both. For instance, genotypic abnormalities in striatal metabolic activity parallel previously reported reductions in local D2 receptor availability. Likewise, we have identified a unique penetrance-related metabolic network characterized by increases in the pre–supplementary motor area (SMA) and parietal association areas, associated with relative reductions in the cerebellum, brainstem, and ventral thalamus. Interestingly, metabolic activity in the hypermetabolic areas has recently been found to be modified by the penetrance regulating D216H polymorphism. The DTI data raise the possibility that metabolic abnormalities in mutation carriers reflect adaptive responses to developmental abnormalities in the intrinsic connectivity of the motor pathways. Moreover, findings of increased motor activation responses in these subjects are compatible with the reductions in cortical inhibition that have been observed in this disorder. Future research will focus on clarifying the relationship of these changes to clinical penetrance in dystonia mutation carriers, and the reversibility of disease-related functional abnormalities by treatment.
The differential diagnosis of parkinsonian disorders can be challenging, especially early in the disease course. PET imaging with
18F-fluorodeoxyglucose (FDG) has been used to identify ...characteristic patterns of regional glucose metabolism in patient cohorts with idiopathic Parkinson's disease (PD), as well as variant forms of parkinsonism such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBGD). In this study, we assessed the utility of FDG PET in the differential diagnosis of individual patients with clinical parkinsonism.
135 parkinsonian patients were referred for FDG PET to determine whether their diagnosis could be made accurately based upon their scans. Imaging-based diagnosis was obtained by visual assessment of the individual scans and also by computer-assisted interpretation. The results were compared with 2-year follow-up clinical assessments made by independent movement disorders specialists who were blinded to the original PET findings.
We found that blinded computer assessment agreed with clinical diagnosis in 92.4% of all subjects (97.7% early PD, 91.6% late PD, 96% MSA, 85% PSP, 90.1% CBGD, 86.5% healthy control subjects). Concordance of visual inspection with clinical diagnosis was achieved in 85.4% of the patients scanned (88.4% early PD, 97.2% late PD, 76% MSA, 60% PSP, 90.9% CBGD, 90.9% healthy control subjects).
This study demonstrates that FDG PET performed at the time of initial referral for parkinsonism accurately predicted the clinical diagnosis of individual patients made at subsequent follow-up. Computer-assisted methodologies may be particularly helpful in situations where experienced readers of FDG PET images are not readily available.
To use (18)F-fluorodeoxyglucose (FDG) and PET to investigate changes in regional metabolism associated with mild cognitive impairment (MCI) in Parkinson disease (PD). Cognitive abnormalities are ...common in PD. However, little is known about the functional abnormalities that underlie the manifestations of MCI in this disorder.
We used FDG PET to measure regional glucose metabolism in patients with PD with multiple-domain MCI (MD-MCI; n = 18), with single-domain MCI (SD-MCI; n = 15), and without MCI (N-MCI; n = 18). These patients were matched for age, education, disease duration, and motor disability. Maps of regional metabolism in the three groups were compared using statistical parametric mapping (SPM). We also computed the expression of a previously validated cognition-related spatial covariance pattern (PDCP) in the patient groups and in an age-matched healthy control cohort (n = 15). PDCP expression was compared across groups using analysis of variance.
SPM revealed decreased prefrontal and parietal metabolism (p < 0.001) in MD-MCI relative to N-MCI, as well as an increase in brainstem/cerebellar metabolism (p < 0.001) in this group. In these regions, SD-MCI occupied an intermediate position between the two other groups. PDCP expression was abnormally elevated in the N-, SD-, and MD-MCI groups (p < 0.05), increasing stepwise with worsening cognitive impairment (p < 0.01).
Early cognitive decline in Parkinson disease as defined by mild cognitive impairment is associated with discrete regional changes and abnormal metabolic network activity. The quantification of these alterations with (18)F-fluorodeoxyglucose PET may allow for the objective assessment of the progression and treatment of this disease manifestation.
The neural basis for the transition from preclinical to symptomatic Huntington's disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers ...(p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with 11C-raclopride and 18F-fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD-related metabolic network. We found that striatal D2 binding declined over time (P < 0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P < 0.003) but declined at 44 months (P < 0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P < 0.01). Striatal metabolism was abnormally low at all time points (P < 0.005). By contrast, thalamic metabolism was elevated at baseline (P < 0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.
Cognitive dysfunction is common in Parkinson disease (PD), even early in its clinical course. This disease manifestation has been associated with impaired verbal learning performance as well as ...abnormal expression of a specific PD-related cognitive spatial covariance pattern (PDCP). It is not known, however, how this metabolic network relates to the cognitive response to dopaminergic therapy on the individual patient level.
We assessed treatment-mediated changes in verbal learning and PDCP expression in 17 patients with PD without dementia who underwent cognitive testing and metabolic imaging in the unmedicated and levodopa-treated conditions. We also determined whether analogous changes were present in 12 other patients with PD without dementia who were evaluated before and during the treatment of cognitive symptoms with placebo.
Levodopa-mediated changes in verbal learning correlated with concurrent changes in PDCP expression (r = -0.60, p < 0.01). The subset of patients with meaningful cognitive improvement on levodopa (n = 8) exhibited concurrent reductions in PDCP expression (p < 0.01) with treatment; network modulation was not evident in the remaining subjects. Notably, the levodopa cognitive response correlated with baseline PDCP levels (r = 0.70, p = 0.002). By contrast, placebo did not affect PDCP expression, even in the subjects (n = 7) with improved verbal learning during treatment.
These findings suggest that cognitive dysfunction in PD may respond to treatment depending upon the degree of baseline PDCP expression. Quantification of treatment-mediated network changes can provide objective information concerning the efficacy of new agents directed at the cognitive manifestations of this disease.
Network analysis of functional brain imaging data is an innovative approach to study circuit abnormalities in neurodegenerative diseases. In Parkinson's disease, spatial covariance analysis of ...resting-state metabolic images has identified specific regional patterns associated with motor and cognitive symptoms. With functional imaging, these metabolic networks have recently been used to measure system-related progression and to evaluate novel treatment strategies. Network analysis is also being used to characterize specific functional biomarkers for Huntington's disease and Alzheimer's disease. These networks have been particularly helpful in uncovering compensatory mechanisms in genetically at-risk individuals. Ongoing developments in network applications are likely to enhance the role of functional imaging in the investigation of neurodegenerative disorders.
Background: Impaired cortical inhibiton and maladaptive cortical plasticity are functional hallmarks of sporadic focal dystonias. Whether or not these mechanisms translate to generalized dystonias ...and whether these features reflect state or trait characteristics are topics of research in hereditary dystonias.
Methods: We present a series of studies using a multitracer approach with positron emission tomography (PET) and diffusion tensor MRI (DTI) in the DYT1 and the DYT6 genotype.
Results: In these hereditary dystonias functional and microstructural abnormalities were found in cortico‐striatal‐pallido‐thalamocortical (CSPTC) and cerebellar‐thalamo‐cortical circuits. Genotype‐specific abnormalities were localized to the basal ganglia, SMA and cerebellum. Functional changes, as potential correlates of maladaptive sensorimotor plasticity were found throughout the sensorimotor system and were more pronounced in affected mutation carriers than in their non‐manifesting counterparts. In both genotypes, striatal metabolic abnormalities were paralleled by genotype‐specific reductions in D2 receptor availability. However, these reductions failed to show a clear association with clinical or functional markers of the disease. By contrast, microstructural changes of cerebellar pathways clearly related to penetrance and may thus represent the main intrinsic abnormality underlying cortical downstream effects, such as increased sensorimotor responsivity.
Conclusions: These studies are consistent with the view of primary torsion dystonia as a neurodevelopmental circuit disorder involving CSPTC and related cerebellar pathways.
To identify metabolic brain networks that are associated with Tourette syndrome (TS) and comorbid obsessive-compulsive disorder (OCD).
We utilized (18)F-fluorodeoxyglucose and PET imaging to examine ...brain metabolism in 12 unmedicated patients with TS and 12 age-matched controls. We utilized a spatial covariance analysis to identify 2 disease-related metabolic brain networks, one associated with TS in general (distinguishing TS subjects from controls), and another correlating with OCD severity (within the TS group alone).
Analysis of the combined group of patients with TS and healthy subjects revealed an abnormal spatial covariance pattern that completely separated patients from controls (p < 0.0001). This TS-related pattern (TSRP) was characterized by reduced resting metabolic activity of the striatum and orbitofrontal cortex associated with relative increases in premotor cortex and cerebellum. Analysis of the TS cohort alone revealed the presence of a second metabolic pattern that correlated with OCD in these patients. This OCD-related pattern (OCDRP) was characterized by reduced activity of the anterior cingulate and dorsolateral prefrontal cortical regions associated with relative increases in primary motor cortex and precuneus. Subject expression of OCDRP correlated with the severity of this symptom (r = 0.79, p < 0.005).
These findings suggest that the different clinical manifestations of TS are associated with the expression of 2 distinct abnormal metabolic brain networks. These, and potentially other disease-related spatial covariance patterns, may prove useful as biomarkers for assessing responses to new therapies for TS and related comorbidities.
Multiple system atrophy (MSA), the most common of the atypical parkinsonian disorders, is characterized by the presence of an abnormal spatial covariance pattern in resting state metabolic brain ...images from patients with this disease. Nonetheless, the potential utility of this pattern as a MSA biomarker is contingent upon its specificity for this disorder and its relationship to clinical disability in individual patients.
We used (18)Ffluorodeoxyglucose PET to study 33 patients with MSA, 20 age- and severity-matched patients with idiopathic Parkinson disease (PD), and 15 healthy volunteers. For each subject, we computed the expression of the previously characterized metabolic covariance patterns for MSA and PD (termed MSARP and PDRP, respectively) on a prospective single-case basis. The resulting network values for the individual patients were correlated with clinical motor ratings and disease duration.
In the MSA group, disease-related pattern (MSARP) values were elevated relative to the control and PD groups (p < 0.001 for both comparisons). In this group, MSARP values correlated with clinical ratings of motor disability (r = 0.57, p = 0.0008) and with disease duration (r = -0.376, p = 0.03). By contrast, MSARP expression in the PD group did not differ from control values (p = 1.0). In this group, motor ratings correlated with PDRP (r = 0.60, p = 0.006) but not with MSARP values (p = 0.88).
MSA is associated with elevated expression of a specific disease-related metabolic pattern. Moreover, differences in the expression of this pattern in patients with MSA correlate with clinical disability. The findings suggest that the MSARP may be a useful biomarker in trials of new therapies for this disorder.
To determine whether changes in D(2) receptor availability are present in carriers of genetic mutations for primary dystonia.
Manifesting and nonmanifesting carriers of the DYT1 and DYT6 dystonia ...mutations were scanned with (11)C raclopride (RAC) and PET. Measures of D(2) receptor availability in the caudate nucleus and putamen were determined using an automated region-of-interest approach. Values from mutation carriers and healthy controls were compared using analysis of variance to assess the effects of genotype and phenotype. Additionally, voxel-based whole brain searches were conducted to detect group differences in extrastriatal regions.
Significant reductions in caudate and putamen D(2) receptor availability were evident in both groups of mutation carriers relative to healthy controls (p < 0.001). The changes were greater in DYT6 relative to DYT1 carriers (-38.0 +/- 3.0% vs -15.0 +/- 3.0%, p < 0.001). By contrast, there was no significant difference between manifesting and nonmanifesting carriers of either genotype. Voxel-based analysis confirmed these findings and additionally revealed reduced RAC binding in the ventrolateral thalamus of both groups of mutation carriers. As in the striatum, the thalamic binding reductions were more pronounced in DYT6 carriers and were not influenced by the presence of clinical manifestations.
Reduced D(2) receptor availability in carriers of dystonia genes is compatible with dysfunction or loss of D(2)-bearing neurons, increased synaptic dopamine levels, or both. These changes, which may be present to different degrees in the DYT1 and DYT6 genotypes, are likely to represent susceptibility factors for the development of clinical manifestations in mutation carriers.
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