Functional imaging in hereditary dystonia.

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 D(2) 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.

Abnormal striatal and thalamic dopamine neurotransmission: Genotype-related features of dystonia.

OBJECTIVE: To determine whether changes in D(2) receptor availability are present in carriers of genetic mutations for primary dystonia. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Abnormal structure-function relationships in hereditary dystonia.

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 (approximately 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 D(2) 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 role of radiotracer imaging in Parkinson disease.

Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

Decreased striatal D2 receptor binding in non-manifesting carriers of the DYT1 dystonia mutation.

To determine whether reduced striatal D2 receptor binding reported in patients with idiopathic torsion dystonia is associated with the genotype, the authors used PET and [11C]-raclopride to assess non-manifesting carriers of the DYT1 mutation. D2 receptor binding was reduced by approximately 15% in caudate and putamen (p < 0.005). These results suggest that striatal D2 binding reductions are a trait feature of the DYT1 genotype.

Regional metabolism in primary torsion dystonia: effects of penetrance and genotype.

BACKGROUND: The authors have previously used [18F]fluorodeoxyglucose (FDG) PET to identify a reproducible pattern of regional glucose metabolism that was expressed in both manifesting and nonmanifesting carriers of the DYT1 primary dystonia mutation. OBJECTIVE: To identify specific regions that discriminated subjects according to clinical penetrance and genotype. METHODS: FDG PET was used to scan 12 nonmanifesting and 11 manifesting DYT1 gene carriers, 6 nonmanifesting DYT6 gene carriers and 7 manifesting DYT6 gene carriers, as well as 11 control subjects. The data from all five groups were analyzed with statistical parametric mapping and analysis of variance with posthoc contrasts. RESULTS: A dissociation of metabolic changes was found related to phenotype and genotype. Manifesting gene carriers of both genotypes exhibited bilateral hypermetabolism in the presupplementary motor area (Brodmann area [BA] 6) and parietal association cortices (BA 40/7) compared with the respective nonmanifesting counterparts. By contrast, genotype-specific increases in metabolism were found in the putamen, anterior cingulate (BA 24/32), and cerebellar hemispheres of DYT1 carriers. Genotype-specific changes in DYT6 involved hypometabolism of the putamen and hypermetabolism in the temporal cortex (BA 21). CONCLUSIONS: Dystonia may be associated with abnormal movement preparation caused by defective sensorimotor integration. Whereas clinical manifestations are related to cortical dysfunction, metabolic abnormalities in subcortical structures may represent trait features that are specific for individual dystonia genotypes.

Effects of levodopa on motor sequence learning in Parkinson's disease.

BACKGROUND: Dopaminergic therapy with levodopa improves motor function in PD patients, but the effects of levodopa on cognition in PD remain uncertain. OBJECTIVE: To use H(2)(15)O and PET to assess the effect of levodopa infusion on motor sequence learning in PD. METHODS: Seven right-handed PD patients were scanned "on" and "off" levodopa while performing a sequence learning task. The changes in learning performance and regional brain activation that occurred during this intervention were assessed. RESULTS: During PET imaging, levodopa infusion reduced learning performance as measured by subject report (p < 0.05). This behavioral change was accompanied by enhanced activation during treatment in the right premotor cortex and a decline in the ipsilateral occipital association area (p < 0.01). Levodopa-induced changes in learning-related activation responses in the occipital association cortex correlated with changes in learning indexes (p < 0.01). CONCLUSIONS: Levodopa treatment appears to have subtle detrimental effects on cognitive function in nondemented PD patients. These effects may be mediated through an impairment in brain activation in occipital association cortex.

Hyperventilation-induced human cerebral magnetic fields non-invasively monitored by multichannel 'direct current' magnetoencephalography.

Self-paced hyperventilation (HV) induces slow cerebral magnetic field changes which were monitored and mapped continuously over 15 min using 49-channel DC-coupled ('direct current') magnetoencephalography (DC-MEG) based on a modulation technique. In nine/nine healthy subjects HV caused an increase (range: 1.1-6.2 pT) of the mean global DC-MEG field strength which slowly decayed after HV termination (mean time constant: 2 min). The complex HV-related field patterns were distinctly different from mainly dipolar somatosensory evoked field maps (N20m) in four/four subjects. Thus, current sources in the primary somatosensory cortex need not regularly dominate DC-field changes as had been previously considered. Rather, DC-MEG enabled the monitoring of a widely distributed HV-induced enhanced cortical excitability which may serve as model to study epileptic or post-anoxic cerebral hyperexcitability.

[Melanoma of the oral cavity. Review of the literature]. / Melanomi nel cavo orale. Revisione della letteratura.

The location of melanoma in the oral cavity is extremely rare: its frequency varies between 0.2 and 8%. Oral melanoma strikes mainly male subjects and is more frequently seen at the level of the hard palate and gingiva. Today the clinicopathological classification of oral melanoma is not yet clearly outlined, and that is why the skin form is often taken as a reference. The acral lentiginous subtype proves to be the most common in this seat. In many cases (up to 50%) the diagnosis of melanoma is made on lesions which have evolved from the pre-existing pigmented lesions: as a consequence, every pigmented lesion of undetermined origin must be biopsied as a routine. The prognosis often proves poor and the surgical approach, combined with the chemotherapeutic one, is the first choice treatment. Lymph node dissection is not routinely practiced.

Abnormal renal acidification in alcoholic liver disease.

After ingestion of 150 mEq. of calcium chloride (CaCl-2), urinary acidification was studied for 6 hours in 22 normokalemic patients with alcoholic liver disease (L) of varying severity, and in 7 control (C) subjects during 10 studies. The degree of the induced systemic acidosis was similar in all groups. Nine L patients were unable to normally lower urine pH below 5.25 (L-I) and these were compared with the 13 L patients achieving lower pH (L-II) and with control subjects. This defect was consistently reproduced. Titratable acid excretion was less in L-I than in the other groups. The percentage contribution of ammonium to maximal net acid excretion was significantly higher in L-I and L-II than in C. No L-I patient had spontaneous metabolic acidosis, nor was there evidence of encephalopathy or of proximal tubular dysfunction. Sodium excretion was significantly lower in L-I than in either L-II or C. Sodium sulfate and sodium phosphate infused after acid-loading rapidly reduced urine pH into the appropriately acidic range in L-I patients with alcoholic liver disease by means of a simple, safe, and short acid-loading test. Although the mechanism of this renal tubular acidfying defect remains unknown a low distal delivery of sodium by limiting the transtubular potential difference may have been partially responsible.