Neurogenic orthostatic hypotension as the initial feature of Parkinson disease.

Autonomic failure is a common finding in patients with Parkinson disease (PD). Here we describe a patient with PD in whom autonomic symptoms began 3 years before motor deficits.

Is cerebral autoregulation impaired in Parkinson's disease? A transcranial Doppler study.

Orthostatic hypotension (OH) is one of the many autonomic disturbances observed in Parkinson's disease (PD). It has been debated whether an additional impairment of cerebral autoregulation (CA) in PD patients may exacerbate the consequences of OH upon brain perfusion. We assessed CA in PD patients and the potential influence of dopaminergic agents. CA was determined by means of transcranial Doppler (TCD) monitoring of the middle cerebral artery (MCA) at rest and during a thigh cuff release test inducing a systemic blood pressure (BP) drop. Fourteen patients were investigated when taking their usual dopaminergic medication and after drug discontinuation for 12 h. A control group was composed of 11 age-matched subjects (CS). In comparison with PD patients, CS presented a significantly higher increase of the mean cerebral blood flow velocities in the MCA after the BP drop. Mean velocities were increased above the initial values in all CS, whereas a flattened curve was observed in PD patients. No significant differences could be further observed between the PD patients regarding the BP, the cerebrovascular resistance, the heart rate and the pulsatility index. These results provide evidence of an impaired cerebral autoregulation in PD patients which appears independent of dopaminergic treatment.

Cardiac and extracardiac sympathetic denervation in Parkinson's disease with orthostatic hypotension and in pure autonomic failure.

UNLABELLED: The uptake of 6-(18)F-fluorodopamine by cardiac noradrenergic nerves enables visualization of the sympathetic innervation of the left ventricular myocardium by PET. Patients with Parkinson's disease (PD) and orthostatic hypotension (OH) (PD+OH) or with pure autonomic failure (PAF) have markedly decreased myocardial 6-(18)F-fluorodopamine-derived radioactivity, consistent with cardiac sympathetic denervation, a phenomenon that neurochemical, neuropharmacologic, and, most recently, postmortem neuropathologic studies have confirmed. In this study, we examined whether 6-(18)F-fluorodopamine can visualize sympathetic innervation in extracardiac organs and, if so, whether patients with PD+OH or PAF have neuroimaging evidence of extracardiac noradrenergic denervation. METHODS: To validate the method, healthy volunteers underwent 6-(18)F-fluorodopamine scanning of the head, thorax, and abdomen, with or without treatment with desipramine to block sympathoneural uptake of catecholamines. (13)N-Ammonia scanning was used to address possible group differences in 6-(18)F-fluorodopamine delivery by blood perfusion. RESULTS: Desipramine treatment was associated with decreased 6-(18)F-fluorodopamine-derived radioactivity in the heart, renal cortex, and thyroid gland but not in the liver, spleen, renal pelvis, or salivary glands. Both the PD+OH group and the PAF group had decreased 6-(18)F-fluorodopamine-derived radioactivity in the heart (P < 0.0001) and renal cortex (P = 0.02 and P = 0.005, respectively). The PD+OH group also had decreased radioactivity in the thyroid gland (P = 0.01). Neither group had decreased radioactivity in the other organs, after correction for (13)N-ammonia-derived radioactivity. CONCLUSION: 6-(18)F-Fluorodopamine scanning visualizes sympathetic innervation in the heart, renal cortex, and thyroid gland. Both PD+OH and PAF involve decreased noradrenergic innervation that is most prominent in the heart but is also detectable in extracardiac organs.

Cerebral blood flow and metabolism in multiple system atrophy of the Shy-Drager syndrome type: a PET study.

To investigate the role of the autonomic nervous system in cerebral blood flow (CBF) and metabolism, CBF and oxygen metabolism in patients with multiple system atrophy of the Shy-Drager syndrome type were examined. Seven patients with Shy-Drager syndrome were imaged using positron emission tomography and 15O-labeled gases. There was excellent local coupling between CBF and the cerebral metabolic rate of oxygen in the resting state. Elevation of blood pressure induced by leg raising increased CBF. The inhalation of CO2 also increased CBF in the Shy-Drager patients. These results showed that autoregulation is impaired in Shy-Drager syndrome, but local metabolic-flow coupling in the resting state and the CBF response to CO2 inhalation are spared. We conclude that the autonomic nervous system plays an important role in autoregulation, but not in local metabolic-flow coupling in the resting state. We suggest that metabolic mechanisms may mediate resting metabolic-flow coupling.

Sympathetic cardioneuropathy in dysautonomias.

BACKGROUND: The classification of dysautonomias has been confusing, and the pathophysiology obscure. We examined sympathetic innervation of the heart in patients with acquired, idiopathic dysautonomias using thoracic positron-emission tomography and assessments of the entry rate of the sympathetic neurotransmitter norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover). We related the laboratory findings to signs of sympathetic neurocirculatory failure (orthostatic hypotension and abnormal blood-pressure responses associated with the Valsalva maneuver), central neural degeneration, and responsiveness to treatment with levodopa-carbidopa (Sinemet). METHODS: Cardiac scans were obtained after intravenous administration of 6-[18F]fluorodopamine in 26 patients with dysautonomia. Fourteen had sympathetic neurocirculatory failure--three with no signs of central neurodegeneration (pure autonomic failure), two with parkinsonism responsive to treatment with levodopa-carbidopa, and nine with central neurodegeneration unresponsive to treatment with levodopa-carbidopa (the Shy-Drager syndrome). The rates of cardiac norepinephrine spillover were estimated on the basis of concentrations of intravenously infused [3H]norepinephrine during catheterization of the right side of the heart. RESULTS: Patients with pure autonomic failure or parkinsonism and sympathetic neurocirculatory failure had no myocardial 6-[18F]fluorodopamine-derived radioactivity or cardiac norepinephrine spillover, indicating loss of myocardial sympathetic-nerve terminals, whereas patients with the Shy-Drager syndrome had increased levels of 6-[18F]fluorodopamine-derived radioactivity, indicating intact sympathetic terminals and absent nerve traffic. Patients with dysautonomia who did not have sympathetic neurocirculatory failure had normal levels of 6-[18F]fluorodopamine-derived radioactivity in myocardium and normal rates of cardiac norepinephrine spillover. CONCLUSIONS: The results of 6-[18F]fluorodopamine positron-emission tomography and neurochemical analyses support a new clinical pathophysiologic classification of dysautonomias, based on the occurrence of sympathetic neurocirculatory failure, signs of central neurodegeneration, and responsiveness to levodopa-carbidopa.

Glucose metabolism in the cortical and subcortical brain structures in multiple system atrophy and Parkinson's disease: a positron emission tomographic study.

The brain glucose metabolism was studied by PET with 18F-FDG in 11 patients with multiple system atrophy (MSA) and 12 patients with idiopathic Parkinson's disease (PD). Seven of the 11 MSA patients were diagnosed as having olivopontocerebellar atrophy, two had striatonigral degeneration, while two demonstrated Shy-Drager syndrome. The glucose metabolic rates for each region in the PD patients showed no difference from the normal controls. The frontal, temporal and parietal cortical glucose metabolic rates and the caudate, the putaminal, the cerebellar and the brainstem glucose metabolic rates in the MSA patients decreased significantly from the controls. The atrophy of the cerebellum and the brainstem in the MSA patients were scored by MRI. The cerebellar and brainstem glucose metabolism in the MSA patients decreased as the atrophy score in such regions advanced in each group; however, some patients with no atrophy showed a decreased glucose metabolism. Although the cerebellar and the brainstem glucose metabolism decreased in all MSA patients, such a decrease was not observed in the SND patients. The decrease in the glucose metabolism for the non-cortical regions in the MSA patients seems to be due to a diffuse depletion of the neurons not restricted to the nigrostriatal neurons. Deafferentation to the cerebral cortices seems to result in a decreased cortical metabolism. The differences in the glucose metabolism between MSA and PD as assessed by PET may be caused by the pathophysiological differences between MSA and PD, and such differences therefore appear to be useful when making a differential diagnosis between MSA and PD. The relative sparing of the brainstem and cerebellar glucose metabolism is considered to be a feature of patients with SND.

[Quantitative changes in cerebral blood flow of Shy-Drager syndrome induced by upright position: assessment by 99mTc-HMPAO].

We assessed orthostatic changes of cerebral blood flow (CBF) in 4 patients with Shy-Drager syndrome. Brain perfusion index (BPI) was measured by 99mTc-hexamethylpropylene amine oxime (99mTc-HMPAO). Cerebral angiography using aortic time-activity curve as an input function BPI values in supine and upright positions in Shy-Drager syndrome were compared with those in 2 cerebrovascular disease patients without orthostatic hypotension. BPI values in the upright position were significantly decreased in patients with Shy-Drager syndrome as compared with these in the supine position. No significant decrease in BPI was noted in the patients without orthostatic hypotension. These results suggest that the BPI measurement by 99mTc-HMPAO cerebral angiography is useful for the noninvasive evaluation of the orthostatic changes of the CBF.

Benzodiazepine receptor binding in cerebellar degenerations studied with positron emission tomography.

We used positron emission tomography with [11C]flumazenil to study gamma-aminobutyric acid type A/benzodiazepine receptor binding quantitatively in the cerebral hemispheres, basal ganglia, thalamus, cerebellum, and brainstem of 72 subjects, including 14 with multiple system atrophy of the ataxic (olivopontocerebellar atrophy) type, 5 with multiple system atrophy of the extrapyramidal/autonomic (Shy-Drager syndrome) type, 18 with sporadic olivopontocerebellar atrophy, 15 with dominantly inherited olivopontocerebellar atrophy, and 20 normal control subjects with similar age and sex distributions. In comparison with data obtained from the normal control subjects, we found significantly decreased ligand influx in the cerebellum and brainstem of multiple system atrophy patients of the olivopontocerebellar atrophy type and in patients with sporadic olivopontocerebellar atrophy, but not in patients with multiple system atrophy of the Shy-Drager syndrome type. Despite these differences in ligand influx, benzodiazepine binding was largely preserved in the cerebral hemispheres, basal ganglia, thalamus, cerebellum, and brainstem in patients with multiple system atrophy of both types as well as those with sporadic or dominantly inherited olivopontocerebellar atrophy as compared with normal control subjects. The finding of relative preservation of benzodiazepine receptors indicates that these sites are available for pharmacological therapy in these disorders.

Detection of reverse flow by duplex ultrasonography in orthostatic hypotension.

BACKGROUND AND PURPOSE: The aim of this study is to elucidate the effect of orthostatic hypotension on changes in cerebral blood flow. METHODS: Blood flow velocities of both the common carotid artery and vertebral artery were measured using duplex ultrasonography in 12 patients: 6 with familial amyloidotic polyneuropathy, 3 with Shy-Drager syndrome, 2 with pandysautonomia, and 1 with senile orthostatic hypotension. Simultaneously, peripheral blood flow was also evaluated by laser-Doppler flowmetry. RESULTS: The patients showing dizziness or syncope when tilted to a 70 degrees upright position exhibited characteristic reverse flow at the end-diastolic phase on the Doppler flow image of both the common carotid and vertebral arteries, which was effectively treated by infusion of 2.5 micrograms/min norepinephrine for 10 minutes. This end-diastolic reverse flow was not seen in any patients who did not have dizziness or syncope. After subjects were tilted from a supine to a 70 degrees upright position, decrease in the peripheral blood flow of the patients with orthostatic hypotension remained unchanged for at least 5 minutes, whereas that of control subjects was recovered within 2 minutes. However, no significant difference between the patients with and without clinical symptoms was observed. CONCLUSIONS: These results suggest that detection of this specific echographic pattern may be quantitatively useful in examination of clinical symptoms accompanying orthostatic hypotension and that duplex ultrasonography may be a helpful tool to evaluate the effect of drugs used for controlling these clinical signs.

PET studies on the early and differential diagnosis of Parkinson's disease.

A number of neurodegenerative diseases can manifest as parkinsonian disorders. Structural imaging, such as CT and MRI, is of limited value for differentiating these diseases. PET can demonstrate the selective patterns of disruption of regional cerebral metabolism and neurotransmitter systems associated with subcortical degenerations, such as Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, and corticobasal degeneration. It can also determine, where underlying Parkinson's disease may be suspected, whether nigral dysfunction is present in patients with isolated tremor or drug-associated rigidity. Finally, PET can detect the presence of subclinical disruption of the dopaminergic system in at-risk subjects, such as relatives of patients with Parkinson's disease, or subjects exposed to nigral toxins, such as MPTP. With the advent of putative neuroprotective agents for Parkinson's disease, PET can help identify patients with early disease who might benefit from therapy with these agents and monitor their disease progression.

[L-18F-dopa-PET in Parkinson-plus syndromes for the detection of a disordered presynaptic dopaminergic function]. / L-18F-DOPA-PET bei Parkinson-Plus-Syndromen zum Nachweis einer gestörten präsynaptischen dopaminergen Funktion.

PET examinations using L-18F-DOPA were performed on 14 patients with Parkinsonism-plus syndromes (PPLUS). A rate constant Ki was calculated by a graphical method using an arterial input function. Sequential PET images were obtained and no specific activity was measured both in cortical and cerebellar background regions. These results were compared with those in 20 normal controls and tested for intra- and interobserver variability. All patients with PPLUS showed reduced Ki values with a mean of 0.154 (ml/striatum/min), whereas controls exhibited Ki values with a mean of 0.690 (ml/striatum/min) using cortical background regions. The correlation coefficient was calculated to be r = 0.973 for the intraobserver variability and r = 0.879 for the interobserver variability in controls, and r = 0.989 or = 0.973 in PPLUS, resp. There was no significant difference in the Ki values for cortical and cerebellar background regions (p = 0.1). PET examinations using L-18F-DOPA can reliably assess the extent of nigrostriatal degeneration in vivo. Since this radiotracer binds irreversibly within the striatum PET examinations allow the quantification of a disturbed dopaminergic function which is observer-independent.

Positron emission tomography in Shy-Drager syndrome.

We studied the nigrostriatal dopaminergic pathway in 3 patients with Shy-Drager syndrome, by using positron emission tomography and [18F]6-fluoro-1-dopa to determine whether their parkinsonism correlated with impaired functional integrity of the presynaptic nigrostriatal pathway. One patient had short duration of disease, mild parkinsonism, and a normal positron emission tomographic scan, suggesting pathological changes functionally distal to the nigrostriatal pathway. Two patients with longer duration of disease had more severe parkinsonism and reduced [18F]6-fluoro-1-dopa uptake, suggesting impaired nigrostriatal dopaminergic function with progression of Shy-Drager syndrome.

Positron emission tomographic studies of the subcortical degenerations and dystonia.

Reported PET findings in subcortical and corticobasal degenerations, and in dystonia, are summarized in Table 3. It can be seen that, although PET is not a diagnostic technique, clinical examination combined with PET findings can help to distinguish between the various akinetic-rigid syndromes, with the proviso that pathologic validation of many PET studies is still awaited. More importantly, PET is now providing information about the functional effects of these various subcortical degenerations, and about dystonia. It is likely that more information will become available about the nature of the functional corrections between cortex, thalamus, and basal ganglia as increasingly sophisticated activation paradigms are designed for PET studies on movement disorders.

Multiple system atrophy (Shy-Drager syndrome): MR imaging.

The Shy-Drager syndrome (SDS) is a form of progressive autonomic nervous system failure (PAF) with orthostatic hypotension and associated extrapyramidal involvement that is often mistaken for Parkinson disease. SDS includes olivopontocerebellar atrophy and striatonigral degeneration which is attended by PAF. Eight patients with SDS were studied on a 0.5-T superconducting system utilizing T1-weighted inversion recovery (IR) and T2-weighted spin-echo pulse sequences and also on a 1.5-T system using spin-echo sequences. With IR sequences, atrophy of the putamina was demonstrated in patients with SDS that is consistent with findings of neuronal loss in these nuclei reported on postmortem examinations. An abnormal decrease in signal intensity of the putamina, particularly along their lateral and posterior portions, was also detected, predominantly on T2-weighted sequences, and in three cases on T1-weighted spin-echo sequences. Abnormalities were detected on both imagers but were shown with greater clarity on the 1.5-T device. SDS is the first disease in which convincing basal ganglia changes have been shown in vivo exclusively by MR imaging.

Rapid clearance of iodine-131 MIBG from the heart and liver of patients with adrenergic dysfunction and pheochromocytoma.

Iodine-131 MIBG, a radiolabeled adrenergic neuron-blocking agent, decreased rapidly from the heart and liver of patients with adrenergic dysfunction (n = 3) and pheochromocytoma (n = 2) when compared with eight controls. The 4-hr activity expressed as percentages (mean +/- s.d.) of the 20-min counts were as follows: 80 +/- 3.0% in the controls compared with 60 +/- 7.6% in the patients over the heart (p less than 0.01) and 79 +/- 3.2% in the controls compared with 51 +/- 17% in the patients over the liver (p less than 0.02). However, there was no significant difference in the rate of [131I]MIBG decrease in these organs between controls and patients in the intervals subsequent to 4 hr (p greater than 0.05). These findings suggest that adrenergic neuronal uptake of [131I]MIBG in these organs is smaller in the patients than in the controls. Measurements of time-activity relationships of radioiodinated MIBG may be useful for assessment of adrenergic function of these organs and thus of generalized disorders of adrenergic innervation.

Evaluation of the brainstem with high-resolution CT in cerebellar atrophic processes.

The authors studied the usefulness of computed tomography (CT) for evaluation of the brainstem in cerebellar atrophic processes. Twenty adult subjects without posterior fossa lesion were used for normal CT measurements of the brainstem. The measured values with CT corresponded to those with pneumotomography. Also reviewed were 49 patients with cerebellar atrophy which included spinocerebellar degeneration (25 patients), Shy-Drager syndrome (five), progressive supranuclear palsy (three), chronic phenytoin usage (10), and chronic alcoholism (six). All but the chronic alcoholism group showed atrophy of the brainstem at all locations of measurement when compared with normal controls (p less than 0.05). In addition, the patients with progressive supranuclear palsy had significantly more pronounced midbrain atrophy. In the chronic alcoholism group the measurements of the brachium pontis, the medulla, and the fourth ventricle differed significantly from those of normal controls (p less than 0.05).